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108 results on '"Mycologie moléculaire - Molecular Mycology"'

1. Multifocal cutaneous phaeohyphomycosis caused by Paraconiothyrium cyclothyrioides in an immunocompromised patient

Author

Malaure, Célie, Hoang, Stella, Bagny, Kelly, Tauziède-Espariat, Arnault, Garcia-Hermoso, Dea, Kamus, Laure, Traversier, Nicolas, Miltgen, Guillaume, Garrigos, Thomas, Laboratoire de microbiologie et virologie [CHU La Réunion], Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Service des maladies infectieuses [CHU La Réunion], Service de dermatologie [CHU La Réunion], GHU Paris Psychiatrie et Neurosciences, Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Processus Infectieux en Milieu Insulaire Tropical (PIMIT), Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IRD-Centre National de la Recherche Scientifique (CNRS), and Centre Régional en Antibiothérapie (CRATb)

Subjects
[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract

International audience

Published
2023
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2. The current state of clinical mycology in Africa: a European Confederation of Medical Mycology and International Society for Human and Animal Mycology survey

Author

Cândida Driemeyer, Diego R Falci, Rita O Oladele, Felix Bongomin, Bright K Ocansey, Nelesh P Govender, Martin Hoenigl, Jean Pierre Gangneux, Cornelia Lass-Flörl, Oliver A Cornely, Alexandre Alanio, Jesus Guinea, C Orla Morrissey, Riina Rautemaa-Richardson, Arunaloke Chakrabarti, Jacques F Meis, Caroline Bruns, Jannik Stemler, Alessandro C Pasqualotto, Federal University of Health Sciences of Porto Alegre = Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Hospital de Clínicas de Porto Alegre (HCPA), University of Lagos, Gulu University, Partenaires INRAE, University of Manchester [Manchester], University of the Witwatersrand [Johannesburg] (WITS), University of California [San Diego] (UC San Diego), University of California (UC), Medical University of Graz, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Leopold Franzens Universität Innsbruck - University of Innsbruck, German Center for Infection Research - Partner Site Bonn-Cologne (DZIF), Hôpitaux Universitaire Saint-Louis, Lariboisière, Fernand-Widal, Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Consejo Superior de Investigaciones Científicas [Spain] (CSIC), Monash university, CSIR-Institute of Microbial Technology [Chandigarh] (IMTech), Council of Scientific and Industrial Research [India] (CSIR), and Radboud University Medical Center [Nijmegen]

Subjects
MESH: Fungi, Microbiology (medical), Antifungal Agents, MESH: Humans, [SDV]Life Sciences [q-bio], Fungi, Nigeria, Mycology, MESH: Antifungal Agents, Microbiology, Infectious Diseases, Mycoses, Virology, Animals, Humans, MESH: Animals, MESH: Nigeria
Abstract

International audience; Africa, although not unique in this context, is a favourable environment for fungal infections, given the high burden of risk factors. An online survey was developed asking about laboratory infrastructure and antifungal drug availability. We received 40 responses (24.4% response rate) of 164 researchers contacted from 21 African countries. Only five institutions (12.5%) of 40 located in Cameroon, Kenya, Nigeria, Sudan, and Uganda potentially fulfilled the minimum laboratory requirements for European Confederation of Medical Mycology Excellence Centre blue status. Difficulties included low access to susceptibility testing for both yeasts and moulds (available in only 30% of institutions) and Aspergillus spp antigen detection (available in only 47.5% of institutions as an in-house or outsourced test), as well as access to mould-active antifungal drugs such as amphotericin B deoxycholate (available for 52.5% of institutions), itraconazole (52.5%), voriconazole (35.0%), and posaconazole (5.0%). United and targeted efforts are crucial to face the growing challenges in clinical mycology.

Published
2022
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3. An overview of using fungal DNA for the diagnosis of invasive mycoses

Author

P. Lewis White, Alexandre Alanio, Lottie Brown, Mario Cruciani, Ferry Hagen, Rebecca Gorton, Michaela Lackner, Laurence Millon, C. Oliver Morton, Riina Rautemaa-Richardson, Rosemary A. Barnes, J Peter Donnelly, Juergen Loffler, Public Health Wales [Cardiff, Royaume uni], Laboratoire de Parasitologie-Mycologie [CHU Saint Louis, Paris], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Manchester University NHS Foundation Trust (MFT), Fungal PCR Initiative (FPCRI), University Medical Center [Utrecht], National Health Laboratory Services, Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), Service de parasitologie et mycologie [CHRU de Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Laboratoire Chrono-environnement (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Western Sydney University, Cardiff University, and University Hospital Wuerzburg / Universitäts­klinikum Würzburg

Subjects
MESH: Fungi, mucorales PCR, MESH: Molecular Diagnostic Techniques, Polymerase Chain Reaction, Pathology and Forensic Medicine, Genetics, Humans, candida PCR, Fungi/genetics, DNA, Fungal, Molecular Biology, aspergillus PCR, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, MESH: Humans, Fungal/genetics, PCP PCR, Fungi, MESH: Polymerase Chain Reaction, DNA, fungal PCR, MESH: DNA, Fungal, Molecular Diagnostic Techniques, Molecular Medicine, Invasive fungal disease, Invasive Fungal Infections/diagnosis, Invasive Fungal Infections, MESH: Invasive Fungal Infections
Abstract

Introduction: Fungal PCR has undergone considerable standardization and together with the availability of commercial assays, external quality assessment schemes and extensive performance validation data, is ready for widespread use for the screening and diagnosis of invasive fungal disease (IFD).Areas Covered: Drawing on the experience and knowledge of the leads of the various working parties of the Fungal PCR initiative, this review will address general considerations concerning the use of molecular tests for the diagnosis of IFD, before focussing specifically on the technical and clinical aspects of molecular testing for the main causes of IFD and recent technological developments.Expert Opinion: For infections caused by Aspergillus, Candida and Pneumocystis jirovecii, PCR testing is recommended, combination with serological testing will likely enhance the diagnosis of these diseases. For other IFD (e.g. Mucormycosis) molecular diagnostics, represent the only non-classical mycological approach towards diagnoses and continued performance validation and standardization has improved confidence in such testing. The emergence of antifungal resistance can be diagnosed, in part, through molecular testing. Next-generation sequencing has the potential to significantly improve our understanding of fungal phylogeny, epidemiology, pathogenesis, mycobiome/microbiome and interactions with the host, while identifying novel and existing mechanisms of antifungal resistance and novel diagnostic/therapeutic targets.

Published
2022
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4. Multicenter Evaluation of the FilmArray Blood Culture Identification 2 Panel for Pathogen Detection in Bloodstream Infections

Author

François Caméléna, Gauthier Péan de Ponfilly, Hélène Pailhoriès, Lucas Bonzon, Alexandre Alanio, Thibaut Poncin, Matthieu Lafaurie, François Dépret, Emmanuel Cambau, Sylvain Godreuil, Rachel Chenouard, Alban Le Monnier, Hervé Jacquier, Béatrice Berçot, Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Hôpitaux Universitaire Saint-Louis, Lariboisière, Fernand-Widal, Groupe Hospitalier Paris Saint-Joseph (hpsj), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), SFR UA 4208 Interactions Cellulaires et Applications Thérapeutiques (ICAT), Université d'Angers (UA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institut de Biologie en Santé (PHB-IRIS) [CHU Angers] (IBS), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Mycologie Moléculaire, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Hôpital Lariboisière-Fernand-Widal [APHP], Université Paris-Saclay, Centre hospitalier Saint-Joseph [Paris], Laboratoire de Parasitologie-Mycologie [CHU Saint Louis, Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Service de maladies infectieuses et tropicales [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Hôpitaux Universitaires Saint-Louis, Lariboisière, Fernand-Widal, This study was supported by bioMérieux (Marcy L’Etoile, France), which providedconsumables. The funders had no role in study design, data collection and interpretation, ormanuscript preparation.F.C. received lecture fees from bioMérieux. F.D. received lecture fees from bioMérieuxand Sedana and grants from European Society of Intensive Care Medicine, Société Françaised’Anesthésie Reanimation, and the French Ministry of Research. A.A. received lecture feesand travel grants from Gilead Sciences and Pfizer and received grants from AgenceNationale de la Recherche. All other authors report no conflicts of interest., and bioMérieux (Marcy L’Etoile, France)European Society of Intensive Care MedicineSociété Française d’Anesthésie ReanimationFrench Ministry of Research. Gilead SciencesPfizerAgence Nationale de la Recherche

Subjects
Microbiology (medical), BCID2, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, FilmArray, Physiology, [SDV]Life Sciences [q-bio], bloodstream infection, MESH: Blood Culture, BSI, MESH: Gram-Positive Bacteria, sepsis, Biofire, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, resistance gene, MESH: Gram-Negative Bacteria, molecular diagnosis, Genetics, MESH: Bacteremia, MESH: Sepsis, rapid diagnosis, genotypic identification, MESH: Humans, General Immunology and Microbiology, Ecology, Cell Biology, MESH: Bacteria, Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology
Abstract

International audience; The FilmArray Blood Culture Identification 2 panel (BCID2; bioMérieux) is a fully automated PCR-based assay for identifying bacteria, fungi, and bacterial resistance markers in positive blood cultures (BC) in about 1 h. In this multicenter study, we evaluated the performance of the BCID2 panel for pathogen detection in positive BC. Conventional culture and BCID2 were performed in parallel at four tertiary-care hospitals. We included 152 positive BC-130 monomicrobial and 22 polymicrobial cultures-in this analysis. The BCID2 assay correctly identified 90% (88/98) of Gram-negative and 89% (70/79) of Gram-positive bacteria. Five bacterial isolates targeted by the BCID2 panel and recovered from five positive BC, including three polymicrobial cultures, were missed by the BCID2 assay. Fifteen isolates were off-panel organisms, accounting for 8% (15/182) of the isolates obtained from BC. The mean positive percent agreement between the BCID2 assay and standard culture was 97% (95% confidence interval, 95 to 99%), with agreement ranging from 67% for Candida albicans to 100% for 17 targets included in the BCID2 panel. BCID2 also identified the blaCTX-M gene in seven BC, including one for which no extended-spectrum β-lactamase (ESBL)-producing isolate was obtained in culture. However, it failed to detect ESBL-encoding genes in three BC. Two of the 18 mecA/C genes detected by the BCID2 were not confirmed. No carbapenemase, mecA/C, or MREJ targets were detected. The median turnaround time was significantly shorter for BCID2 than for culture. The BCID2 panel may facilitate faster pathogen identification in bloodstream infections. IMPORTANCE Rapid molecular diagnosis combining the identification of pathogens and the detection of antibiotic resistance genes from positive blood cultures (BC) can improve the outcome for patients with bloodstream infections. The FilmArray BCID2 panel, an updated version of the original BCID, can detect 11 Gram-positive bacteria, 15 Gram-negative bacteria, 7 fungal pathogens, and 10 antimicrobial resistance genes directly from a positive BC. Here, we evaluated the real-life microbiological performance of the BCID2 assay in comparison to the results of standard methods used in routine practice at four tertiary care hospitals.

Published
2023
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5. Solid-state NMR molecular snapshots of Aspergillus fumigatus cell wall architecture during a conidial morphotype transition

Author

Gaëlle Lamon, Alons Lends, Isabel Valsecchi, Sarah Sze Wah Wong, Vincent Duprès, Frank Lafont, James Tolchard, Christine Schmitt, Adeline Mallet, Axelle Grélard, Estelle Morvan, Erick J. Dufourc, Birgit Habenstein, J. Iñaki Guijarro, Vishukumar Aimanianda, Antoine Loquet, Chimie et Biologie des Membranes et des Nanoobjets (CBMN), Université de Bordeaux (UB)-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Européen de Chimie et Biologie (IECB), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plateforme Technologique de RMN Biologique et HDX-MS - Biological NMR and HDX-MS Technological Platform, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, Plate-forme de bioimagerie ultrastructurale - Ultrastructural BioImaging Core Facility, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), We are grateful for the support for equipment from the French Government Programme Investissements d’Avenir France BioImaging (FBI, Agence Nationale de la Recherche, N° ANR-10-INSB-04-01) and the French Government Investissement d’Avenir programme, Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (ANR-10-LABX-62-IBEID). We thank the ANR grants ANR-16-CE11-0020-02 to I.G., A.L., and V.A., ANR-21-CE17-0032-01 to V.A.), as well as the Swiss National Science Foundation (for early postdoc mobility project P2EZP2_184258 to A. Lends. This work has benefited from the Biophysical and Structural Chemistry Platform at Institut Européen de Chimie et Biologie IECB, Centre National de la Recherche Scientifique CNRS Unité d'Appui et de Recherche UAR 3033, INSERM US001, and the CNRS (IR‐RMN FR3050 and Infranalytics FR2054). We also acknowledge the access to the confocal microscope of the Ultrastructural BioImaging core facility of the Institut Pasteur, ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-16-CE11-0020,FUNHYDRO,Amyloïdes fonctionnels formés par les hydrophobines du pathogène fongique Aspergillus fumigatus(2016), and ANR-21-CE17-0032,FUNPOLYVAC,Explorer les polysaccharides fongiques de la paroi cellulaire pour les immunothérapies(2021)

Subjects
Multidisciplinary, germination, Aspergillus fumigatus, cell wall dynamics, [SDV]Life Sciences [q-bio], solid-state NMR, conidium
Abstract

While establishing an invasive infection, the dormant conidia of Aspergillus fumigatus transit through swollen and germinating stages, to form hyphae. During this morphotype transition, the conidial cell wall undergoes dynamic remodeling, which poses challenges to the host immune system and antifungal drugs. However, such cell wall reorganization during conidial germination has not been studied so far. Here, we explored the molecular rearrangement of Aspergillus fumigatus cell wall polysaccharides during different stages of germination. We took advantage of magic-angle spinning NMR to investigate the cell wall polysaccharides, without employing any destructive method for sample preparation. The breaking of dormancy was associated with a significant change in the molar ratio between the major polysaccharides β-1,3-glucan and α-1,3-glucan, while chitin remained equally abundant. The use of various polarization transfers allowed the detection of rigid and mobile polysaccharides; the appearance of mobile galactosaminogalactan was a molecular hallmark of germinating conidia. We also report for the first time highly abundant triglyceride lipids in the mobile matrix of conidial cell walls. Water to polysaccharides polarization transfers revealed an increased surface exposure of glucans during germination, while chitin remained embedded deeper in the cell wall, suggesting a molecular compensation mechanism to keep the cell wall rigidity. We complement the NMR analysis with confocal and atomic force microscopies to explore the role of melanin and RodA hydrophobin on the dormant conidial surface. Exemplified here using Aspergillus fumigatus as a model, our approach provides a powerful tool to decipher the molecular remodeling of fungal cell walls during their morphotype switching.

Published
2023
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6. Gradient concentration strip–specific epidemiological cut-off values of antifungal drugs in various yeast species and five prevalent Aspergillus species complexes

Author

Victor Mercier, Valérie Letscher-Bru, Marie-Elisabeth Bougnoux, Laurence Delhaes, Francoise Botterel, Danièle Maubon, Frédéric Dalle, Alexandre Alanio, Sandrine Houzé, Eric Dannaoui, Carole Cassagne, Sophie Cassaing, Marie-Fleur Durieux, Arnaud Fekkar, Jean-Philippe Bouchara, Jean-Pierre Gangneux, Julie Bonhomme, Damien Dupont, Damien Costa, Boualem Sendid, Taieb Chouaki, Nathalie Bourgeois, Antoine Huguenin, Sophie Brun, Caroline Mahinc, Lilia Hasseine, Solène Le Gal, Anne-Pauline Bellanger, Eric Bailly, Florent Morio, Céline Nourrisson, Nicole Desbois-Nogard, Estelle Perraud-Cateau, Anne Debourgogne, Hélène Yéra, Laurence Lachaud, Milène Sasso, Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Dynamique des interactions hôte pathogène (DIHP), Université de Strasbourg (UNISTRA), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Biologie et Pathogénicité fongiques - Fungal Biology and Pathogenicity (BPF), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU de Bordeaux Pellegrin [Bordeaux], Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Dynamic Microbiology - EA 7380 (DYNAMIC), École nationale vétérinaire - Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Université Paris-Est (UPE)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Laboratoire de parasitologie mycologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Procédés Alimentaires et Microbiologiques [Dijon] (PAM), Université de Bourgogne (UB)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Hopital Saint-Louis [AP-HP] (AP-HP), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Université Paris Cité (UPCité), Unité de Parasitologie-Mycologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Limoges, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Infections Respiratoires Fongiques (IRF), Université d'Angers (UA)-Université de Brest (UBO), SFR UA 4208 Interactions Cellulaires et Applications Thérapeutiques (ICAT), Université d'Angers (UA), Laboratoire de Parasitologie-Mycologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), CHU Pontchaillou [Rennes], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Hospices Civils de Lyon (HCL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Département de microbiologie [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Amiens-Picardie, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Epidémiosurveillance de protozooses à transmission alimentaire et vectorielle (ESCAPE), Université de Reims Champagne-Ardenne (URCA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Hôpital Avicenne [AP-HP], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre Hospitalier Universitaire de Nice (CHU Nice), Laboratoire de Parasitologie et Mycologiede [CHRU Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de parasitologie et mycologie [CHRU de Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Laboratoire Chrono-environnement (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Centre hospitalier universitaire de Nantes (CHU Nantes), Cibles et Médicaments des Infections et de l'Immunité (IICiMed), Nantes Université - UFR des Sciences Pharmaceutiques et Biologiques (Nantes Univ - UFR Pharmacie), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche en Nutrition Humaine d'Auvergne (CRNH d'Auvergne)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Clermont Auvergne (UCA), Infection Inflammation et Interaction Hôtes Pathogènes [CHU Clermont-Ferrand] (3IHP ), Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, CHU de la Martinique [Fort de France], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Ecologie et biologie des interactions (EBI), Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), Stress, Immunité, Pathogènes (SIMPA), Université de Lorraine (UL), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de parasitologie-mycologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Institut Pasteur [Paris] (IP)

Subjects
Microbiology (medical), Gradient concentration strip–specific, Infectious Diseases, Aspergillus, Epidemiological cut-off values, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV]Life Sciences [q-bio], [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, General Medicine, Antifungal susceptibility, Candida
Abstract

International audience; Objectives: To determine the epidemiological cut-off values (ECVs) of ten antifungal agents in a wide range of yeasts and Aspergillus spp. using gradient concentration strips.Methods: The minimum inhibitory concentrations for amphotericin B, anidulafungin, caspofungin, micafungin, flucytosine, fluconazole, itraconazole, isavuconazole, posaconazole, and voriconazole, determined with gradient concentration strips at 35 French microbiology laboratories between 2002 and 2020, were retrospectively collected. Then, the ECVs were calculated using the iterative method and a cut-off value of 97.5%.Results: Minimum inhibitory concentrations were available for 17 653 clinical isolates. In total, 48 ECVs (including 32 new ECVs) were determined: 29 ECVs for frequent yeast species (e.g. Candida albicans and itraconazole/flucytosine, and Candida glabrata species complex [SC] and flucytosine) and rare yeast species (e.g. Candida dubliniensis, Candida inconspicua, Saccharomyces cerevisiae, and Cryptococcus neoformans) and 19 ECVs for Aspergillusflavus SC, Aspergillusfumigatus SC, Aspergillusnidulans SC, Aspergillusniger SC, and Aspergillusterreus SC.Conclusions: These ECVs can be added to the already available gradient concentration strip-specific ECVs to facilitate minimum inhibitory concentration interpretation and streamline the identification of nonwild type isolates.

Published
2022
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7. Protective role of host complement system in Aspergillus fumigatus infection

Author

Rajashri Shende, Sarah Sze Wah Wong, Heikrujam Thoihen Meitei, Girdhari Lal, Taruna Madan, Vishukumar Aimanianda, Jayanta Kumar Pal, Arvind Sahu, Savitribai Phule Pune University [India], Dr. D. Y. Patil Vidyapeeth [Pune] (DPU), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Département de Mycologie - Department of Mycology, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), National Institute for Research in Reproductive and Child Health [Mumbai] (NIRRCH), AS is a J.C. Bose National Fellow. His lab is supported by the Department of Biotechnology, India, Project Grant BT/PR28506/MED/29/1307/2018. VA was supported by FUNHYDRO (ANR-16S-CE110020-01) and FUNPOLYVAC (ANR-21-CE17-0032) grants. SW was supported by Pasteur-Roux-Cantarini postdoctoral fellowship., ANR-16-CE11-0020,FUNHYDRO,Amyloïdes fonctionnels formés par les hydrophobines du pathogène fongique Aspergillus fumigatus(2016), and ANR-21-CE17-0032,FUNPOLYVAC,Explorer les polysaccharides fongiques de la paroi cellulaire pour les immunothérapies(2021)

Subjects
Aspergillus fumigatus, infectious disease, Immunology, MESH: Complement Factor B, MESH: Spores, Fungal, MESH: Complement C5, [SDV.IMM]Life Sciences [q-bio]/Immunology, Immunology and Allergy, MESH: Animals, MESH: Lung, MESH: Aspergillosis, MESH: Aspergillus fumigatus, innate immunity, MESH: Mice, complement system, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, systemic aspergillosis
Abstract

Invasive aspergillosis (IA) is a life-threatening fungal infection for immunocompromised hosts. It is, therefore, necessary to understand the immune pathways that control this infection. Although the primary infection site is the lungs, aspergillosis can disseminate to other organs through unknown mechanisms. Herein we have examined thein vivorole of various complement pathways as well as the complement receptors C3aR and C5aR1 during experimental systemic infection byAspergillus fumigatus, the main species responsible for IA. We show that C3 knockout (C3-/-) mice are highly susceptible to systemic infection ofA. fumigatus. Intriguingly, C4-/-and factor B (FB)-/-mice showed susceptibility similar to the wild-type mice, suggesting that either the complement pathways display functional redundancy during infection (i.e., one pathway compensates for the loss of the other), or complement is activated non-canonically byA. fumigatusprotease. Ourin vitrostudy substantiates the presence of C3 and C5 cleaving proteases inA. fumigatus. Examination of the importance of the terminal complement pathway employing C5-/-and C5aR1-/-mice reveals that it plays a vital role in the conidial clearance. This, in part, is due to the increased conidial uptake by phagocytes. Together, our data suggest that the complement deficiency enhances the susceptibility to systemic infection byA. fumigatus.

Published
2022
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8. Active Surveillance Program to Increase Awareness on Invasive Fungal Diseases: the French RESSIF Network (2012 to 2018)

Author

Bretagne, Stéphane, Sitbon, Karine, Desnos-Ollivier, Marie, Garcia-Hermoso, Dea, Letscher-Bru, Valérie, Cassaing, Sophie, Millon, Laurence, Morio, Florent, Gangneux, Jean-Pierre, Hasseine, Lilia, Favennec, Loïc, Cateau, Estelle, Bailly, Eric, Moniot, Maxime, Bonhomme, Julie, Desbois-Nogard, Nicole, Chouaki, Taieb, Paugam, André, Bouteille, Bernard, Pihet, Marc, Dalle, Frédéric, Eloy, Odile, Sasso, Milène, Demar, Magalie, Mariani-Kurkdjian, Patricia, Robert, Vincent, Lortholary, Olivier, Dromer, Françoise, French Mycoses Study Group, The, Damiani, Céline, Dupont, Hervé, Maizel, Julien, Totet, Anne, Bouchara, Jean-Philippe, Bellanger, Anne Pauline, Berceanu, Ana, Navellou, Jean Christophe, Scherer, Emeline, Abboud, Philippe, Aznar, Christine, Blanchet, Denis, Djossou, Félix, Cayot, Sophie, Garrouste, Cyril, Lesens, Olivier, Moluçon, Cécile, Nourrisson, Céline, Poirier, Philippe, Bailly, Éloïse, Basmaciyan, Louise, Belaid, Bouhemad, Blot, Mathieu, Caillot, Denis, Charles, Pierre-Emmanuel, Quenot, Jean Pierre, Amazan, Emmanuelle, Baubion, Emilie, Cabie, André, Chabartier, Cyrille, Deligny, Christophe, Emal, Violaine, Flechelle, Olivier, Hatchuel, Yves, Le Govic, Yohann, Merle, Harold, Miossec, Charline, Turmel, Jean-Marie, Valentino, Ruddy, Durieux, Marie-Fleur, Turlure, Pascal, Mercier, Victor, Gari-Toussaint, Martine, Risso, Karine, Simon, Loïc, Bretonnière, Cedric, Boutoille, David, Gastinne, Thomas, Lakhal, Karim, Launay, Elise, Lepoivre, Thierry, Peterlin, Pierre, Rialland, Fanny, Le Pape, Patrice, Canoui, Etienne, Dahane, Naima, Kerneis, Solène, Angebault, Cécile, Bougnoux, Marie-Elisabethh, Guennouni, Nadia, Lanternier, Fanny, Neven, Bennedicte, Oualha, Mehdi, Scemla, Anne, Sitterlé, Emilie, Suarez, Felipe, Toubiana, Julie, Bonacorci, Stéphane, Alanio, Alexandre, Bergeron, Anne, Denis, Blandine, Gits-Muselli, Maud, Hamane, Samia, Touratier, Sophie, Chaumeil, Christine, Merabet, Lilia, Claudéon, Joelle, Curlier, Elodie, Galantine, Valérie, Gallois, Jean Claude, Markowicz, Samuel, Nicolas, Muriel, Musson, Pascal, Schepers, Kinda, Minoza, Alida, Kauffmann-Lacroix, Catherine, Guégan, Hélène, Costa, Damien, Dehais, Marion, Gargala, Gilles, Bajolet, Odile, Banisadr, Firouze, Cousson, Joel, Himberlin, Chantal, Huguenin, Antoine, Toubas, Dominique, Flori, Pierre, Mahinc, Caroline, Raberin, Hélène, Denis, Julie, Herbrecht, Raoul, Mertes, Paul-Michel, Meziani, Fehrat, Sabou, Marcela, Schneider, Francis, Bertozzi, Anne-Isabelle, Chauvin, Pamela, Charpentier, Elena, Cointault, Olivier, Cottrel, Claire, Delavigne, Karen, Faguer, Stanislas, Fillaux, Judith, Guemas, Emilie, Iriart, Xavier, Lelièvre, Lucie, Ruiz, Jean, Bastides, Frédéric, Chesnay, Adélaïde, Desoubeaux, Guillaume, Therby, Audrey, Chachaty, Elisabeth, Gachot, Bertrand, Westerdijk Fungal Biodiversity Institute, Westerdijk Fungal Biodiversity Institute - Software and Databasing, Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Dynamique des interactions hôte pathogène (DIHP), Université de Strasbourg (UNISTRA), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Laboratoire Chrono-environnement (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Nantes Université (Nantes Univ), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre Hospitalier Universitaire de Nice (CHU Nice), CHU Rouen, Normandie Université (NU), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Ecologie et biologie des interactions (EBI), Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Clermont-Ferrand, CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU de la Martinique [Fort de France], CHU Amiens-Picardie, Hôpital Cochin [AP-HP], CHU Limoges, SFR UA 4208 Interactions Cellulaires et Applications Thérapeutiques (ICAT), Université d'Angers (UA), Laboratoire de Parasitologie-Mycologie (CHU d'Angers), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Infections Respiratoires Fongiques (IRF), Université d'Angers (UA)-Université de Brest (UBO), Procédés Alimentaires et Microbiologiques [Dijon] (PAM), Université de Bourgogne (UB)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Centre Hospitalier de Versailles André Mignot (CHV), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM), Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Hôpital Robert Debré Paris, Hôpital Robert Debré, Westerdijk Fungal Biodiversity Institute [Utrecht] (WI), Royal Netherlands Academy of Arts and Sciences (KNAW), Service des Maladies infectieuses et tropicales [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Simplification des soins chez les patients complexes - UR UPJV 7518 (SSPC), Université de Picardie Jules Verne (UPJV), Mécanismes physiopathologiques et conséquences des calcifications vasculaires - UR UPJV 7517 (MP3CV), Laboratoire de Parasitologie-Mycologie [CHU Angers], Hôpital Bretonneau, Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work was supported by recurrent financial support from Santé Publique France and Institut Pasteur. The funders had no role in study design, data collection, analysis, interpretation of data, or the decision to submit the work for publication., We thank Didier Che (Direction des Maladies Infectieuses, Santé Publique France) for his continuous support and interest in invasive fungal infections and Etienne Sevin (EpiConcept, Paris, France) for his contribution in the development of the RESSIF website using the VOOZANOO platform. We are thankful for the technical help of Catherine Blanc, Anne Boullié, Cécile Gautier, Virginie Geolier, and Damien Hoinard (Institut Pasteur) for the characterization of the isolates received at the NRCMA., The French Mycoses Study Group includes collaborators who contributed to these data by their involvement in the management of patients, expertise in diagnostic tools, and/or characterization of fungal isolates. They are listed in alphabetical order of a city in France and for each center, in alphabetical order of the last names: in Amiens, Céline Damiani, Hervé Dupont, Julien Maizel, and Anne Totet, in Angers, Jean-Philippe Bouchara, in Besançon, Anne Pauline Bellanger, Ana Berceanu, Jean Christophe Navellou, and Emeline Scherer, in Cayenne, Philippe Abboud, Christine Aznar, Denis Blanchet, and Félix Djossou, in Clermont-Ferrand, Sophie Cayot, Cyril Garrouste, Olivier Lesens, Cécile Moluçon, Céline Nourrisson, and Philippe Poirier, in Dijon, Éloïse Bailly, Louise Basmaciyan, Bouhemad Belaid, Mathieu Blot, Denis Caillot, Pierre-Emmanuel Charles, and Jean Pierre Quenot, in Fort de France, Emmanuelle Amazan, Emilie Baubion, André Cabie, Cyrille Chabartier, Christophe Deligny, Violaine Emal, Olivier Flechelle, Yves Hatchuel, Yohann Le Govic, Harold Merle, Charline Miossec, Jean-Marie Turmel, and Ruddy Valentino, in Limoges, Marie-Fleur Durieux and Pascal Turlure, in Nîmes, Victor Mercier, in Nice, Martine Gari-Toussaint, Karine Risso, and Loïc Simon, in Nantes, Cedric Bretonnière, David Boutoille, Thomas Gastinne, Karim Lakhal, Elise Launay, Thierry Lepoivre, Pierre Peterlin, Fanny Rialland, and Patrice Le Pape, in Paris, in Hôpital Cochin, Etienne Canoui, Naima Dahane, and Solène Kerneis, in Hôpital Necker-Enfants Malades, Cécile Angebault, Marie-Elisabethh Bougnoux, Nadia Guennouni, Fanny Lanternier, Bennedicte Neven, Mehdi Oualha, Anne Scemla, Emilie Sitterlé, Felipe Suarez, and Julie Toubiana, in Hôpital Robert-Debré, Stéphane Bonacorci, in Hôpital Saint-Louis, Alexandre Alanio, Anne Bergeron, Blandine Denis, Maud Gits-Muselli, Samia Hamane, and Sophie Touratier, in hôpital des XV-XX, Christine Chaumeil and Lilia Merabet, in Pointe-à-Pitre, Joelle Claudéon, Elodie Curlier, Valérie Galantine, Jean Claude Gallois, Samuel Markowicz, Muriel Nicolas, Pascal Musson, and Kinda Schepers, in Poitiers, Alida Minoza and Catherine Kauffmann-Lacroix, in Rennes, Hélène Guégan, in Rouen, Damien Costa, Marion Dehais, and Gilles Gargala, in Reims, Odile Bajolet, Firouze Banisadr, Joel Cousson, Chantal Himberlin, Antoine Huguenin, and Dominique Toubas, in Saint Etienne, Pierre Flori, Caroline Mahinc, and Hélène Raberin, in Strabourg, Julie Denis, Raoul Herbrecht, Paul-Michel Mertes, Fehrat Meziani, Marcela Sabou, and Francis Schneider, in Toulouse, Anne-Isabelle Bertozzi, Pamela Chauvin, Elena Charpentier, Olivier Cointault, Claire Cottrel, Karen Delavigne, Stanislas Faguer, Judith Fillaux, Emilie Guemas, Xavier Iriart, Lucie Lelièvre, and Jean Ruiz, in Tours, Frédéric Bastides, Adélaïde Chesnay, and Guillaume Desoubeaux, in Versailles, Audrey Therby, and in Villejuif, Elisabeth Chachaty and Bertrand Gachot., and CLEMENT, Nathalie

Subjects
Antifungal Agents, pneumocytosis, invasive fungal infections, Pneumonia, Pneumocystis, [SDV]Life Sciences [q-bio], candidemia, Microbiology, [SDV.MP.MYC] Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, mucormycosis, [SDV] Life Sciences [q-bio], [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Virology, Humans, aspergillosis, epidemiology, Watchful Waiting, Fungemia, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Aged
Abstract

International audience; The French National Reference Center for Invasive Mycoses and Antifungals leads an active and sustained nationwide surveillance program on probable and proven invasive fungal diseases (IFDs) to determine their epidemiology in France. Between 2012 and 2018, a total of 10,886 IFDs were recorded. The incidence increased slightly over time (2.16 to 2.36/10,000 hospitalization days, P = 0.0562) in relation with an increase of fungemia incidence (1.03 to 1.19/10,000, P = 0.0023), while that of other IFDs remained stable. The proportion of ≥65-year-old patients increased from 38.4% to 45.3% (P < 0.0001). Yeast fungemia (n = 5,444) was due mainly to Candida albicans (55.6%) with stable proportions of species over time. Echinocandins became the main drug prescribed (46.7% to 61.8%), but global mortality rate remained unchanged (36.3% at 1 month). Pneumocystis jirovecii pneumonia (n = 2,106) was diagnosed mostly in HIV-negative patients (80.7%) with a significantly higher mortality than in HIV-positive patients (21.9% versus 5.4% at 1 month, P < 0.0001). Invasive aspergillosis (n = 1,661) and mucormycosis (n = 314) were diagnosed mostly in hematology (>60% of the cases) with a global mortality rate of 42.5% and 59.3%, respectively, at 3 months and significant changes in diagnosis procedure over time. More concurrent infections were also diagnosed over time (from 5.4% to 9.4% for mold IFDs, P = 0.0115). In conclusion, we observed an aging of patients with IFD with a significant increase in incidence only for yeast fungemia, a trend toward more concurrent infections, which raises diagnostic and therapeutic issues. Overall, global survival associated with IFDs has not improved despite updated guidelines and new diagnostic tools.IMPORTANCE The epidemiology of invasive fungal diseases (IFDs) is hard to delineate given the difficulties in ascertaining the diagnosis that is often based on the confrontation of clinical and microbiological criteria. The present report underlines the interest of active surveillance involving mycologists and clinicians to describe the global incidence and that of the main IFDs. Globally, although the incidence of Pneumocystis pneumonia, invasive aspergillosis, and mucormycosis remained stable over the study period (2012 to 2018), that of yeast fungemia increased slightly. We also show here that IFDs seem to affect older people more frequently. The most worrisome observation is the lack of improvement in the global survival rate associated with IFDs despite the increasing use of more sensitive diagnostic tools, the availability of new antifungal drugs very active in clinical trials, and a still low/marginal rate of acquired in vitro resistance in France. Therefore, other tracks of improvement should be investigated actively.

Published
2022
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9. Cryptococcal Meningitis in Kidney Transplant Recipients: A Two-Decade Cohort Study in France

Author

Laurène Tardieu, Gillian Divard, Olivier Lortholary, Anne Scemla, Éric Rondeau, Isabelle Accoceberry, Rémi Agbonon, Alexandre Alanio, Adela Angoulvant, Laetitia Albano, Philippe Attias, Anne Pauline Bellanger, Dominique Bertrand, Julie Bonhomme, Françoise Botterel, Nicolas Bouvier, Matthias Buchler, Taieb Chouaki, Thomas Crépin, Marie-Fleur Durieux, Guillaume Desoubeaux, Gary Doppelt, Loïc Favennec, Arnaud Fekkar, Ophélie Fourdinier, Marie Frimat, Jean-Pierre Gangneux, Claire Garandeau, Lilia Hasseine, Christophe Hennequin, Xavier Iriart, Nassim Kamar, Hannah Kaminski, Raphael Kormann, Laurence Lachaud, Christophe Legendre, Moglie Le Quintrec Donnette, Jordan Leroy, Charlène Levi, Marie Machouart, David Marx, Jean Menotti, Valérie Moal, Florent Morio, Natacha Mrozek, Muriel Nicolas, Philippe Poirier, Marie-Noelle Peraldi, Benjamin Poussot, Stéphane Ranque, Jean-Philippe Rerolle, Boualem Sendid, Renaud Snanoudj, Jérôme Tourret, Marc Vasse, Cécile Vigneau, Odile Villard, Laurent Mesnard, Fanny Lanternier, Cédric Rafat, CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service Néphrologie et transplantation rénale Adultes [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Génomique évolutive, modélisation et santé (GEMS), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Laboratoire de Parasitologie-Mycologie [CHU Saint Louis, Paris], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de transplantation urologie-néphrologie (ITUN), Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Cibles et Médicaments des Infections et de l'Immunité (IICiMed), Nantes Université - UFR des Sciences Pharmaceutiques et Biologiques (Nantes Univ - UFR Pharmacie), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Infection Inflammation et Interaction Hôtes Pathogènes [CHU Clermont-Ferrand] (3IHP ), Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), CHU Pontchaillou [Rennes], and None

Subjects
Microbiology (medical), Infectious Diseases, General Immunology and Microbiology, cryptococcal meningitis, cryptococcosis, opportunistic infection, [SDV]Life Sciences [q-bio], Immunology and Allergy, transplant associated diseases, renal transplantation, graft outcome, Molecular Biology
Abstract

International audience; Cryptococcosis is the third most common cause of invasive fungal infection in solid organ transplant recipients and cryptococcal meningitis (CM) its main clinical presentation. CM outcomes, as well as its clinical features and radiological characteristics, have not yet been considered on a large scale in the context of kidney transplantation (KT). We performed a nationwide retrospective study of adult patients diagnosed with cryptococcosis after KT between 2002 and 2020 across 30 clinical centers in France. We sought to describe overall and graft survival based on whether KT patients with cryptococcosis developed CM or not. Clinical indicators of CNS involvement and brain radiological characteristics were assessed. Eighty-eight cases of cryptococcosis were diagnosed during the study period, with 61 (69.3%) cases of CM. Mortality was high (32.8%) at 12 months (M12) but not significantly different whether or not patients presented with CM. Baseline hyponatremia and at least one neurological symptom were independently associated with CM (p < 0.001). Positive serum cryptococcal antigen at diagnosis was also significantly associated with CM (p < 0.001). On magnetic resonance imaging (MRI), three patterns of brain injury were identified: parenchymal, meningeal, and vascular lesions. Although CM does not affect graft function directly, it entails a grim prognosis.

Published
2022
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10. Immune Checkpoint Blockade Plus Interferon-Γ Add-On Antifungal Therapy in the Treatment of Refractory Covid-Associated Pulmonary Aspergillosis and Cerebral Mucormycosis [Case Report]

Author

Serris, Alexandra, Ouedrani, Amani, Uhel, Fabrice, Gazzano, Marianne, Bedarida, Vincent, Rouzaud, Claire, Bougnoux, Marie-Elisabeth, Raphalen, Jean-Herlé, Poirée, Sylvain, Lambotte, Olivier, Martin-Blondel, Guillaume, Lanternier, Fanny, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Louis Mourier - AP-HP [Colombes], Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Lariboisière-Fernand-Widal [APHP], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Ecotoxicologie & Santé des écosystèmes - ECSECO (ECI), Laboratoire Ecologie Fonctionnelle et Environnement (LEFE), Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Observatoire Midi-Pyrénées (OMP), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Institut de Recherche pour le Développement (IRD)-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Météo-France -Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut Ecologie et Environnement (INEE), Université de Toulouse (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département Immunologie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), and Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité)

Subjects
cerebral mucormycosis, covid-associated pulmonary aspergillosis, anti-PD 1, immunotherapy, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, invasive fungal disease
Abstract

International audience; Invasive fungal diseases (IFD) still cause substantial morbidity and mortality, and new therapeutic approaches are urgently needed. Recent data suggest a benefit of checkpoint inhibitors (ICI). We report the case of a diabetic patient with refractory IFD following a SARSCoV-2 infection treated by ICI and interferon-gamma associated with antifungal treatment.

Published
2022
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11. Soluble mediators in anti-fungal immunity

Author

Sarah Sze Wah Wong, Vishukumar Aimanianda, Sarah Dellière, Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Parasitologie-Mycologie [CHU Saint Louis, Paris], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), SSWW is supported by Pasteur-Roux-Cantarini fellowship., and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Microbiology (medical), 0303 health sciences, Cellular immunity, Innate immune system, 030306 microbiology, Antimicrobial peptides, Fungi, Immunity, Collectin, Complement System Proteins, Biology, Microbiology, Complement system, 03 medical and health sciences, Infectious Diseases, Immune system, Mycoses, Immune System, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Humoral immunity, Animals, Humans, 030304 developmental biology
Abstract

International audience; Although soluble mediators of our innate immune system have a substantial impact on invading microbes, their role against fungal pathogens has been underexplored. Constituting the humoral immunity, soluble mediators comprise the complement system, collectins, acute-phase proteins, antibodies and antimicrobial peptides. These components can prevent fungal infection either by directly interacting with invading microbes, leading to their aggregation (microbistatic), destruction (microbicidal) or linking them to cellular immunity. The composition of soluble-mediator varies with human body-fluids, resulting in different antifungal mechanisms. Moreover, cellular immune system deploys both oxidative and non-oxidative mechanisms to destroy extracellular or internalized fungal pathogens; however, cellular immune activation is mainly influenced as well as regulated by soluble mediators. This review outlines the antifungal mechanism employed, directly or indirectly, by soluble mediators, and in response, the evading strategies of the fungal pathogens.

Published
2020
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12. Echinocandins Susceptibility Patterns of 2,787 Yeast Isolates: Importance of the Thresholds for the Detection of FKS Mutations

Author

Desnos-Ollivier, Marie, Bretagne, Stéphane, Lortholary, Olivier, Dromer, Françoise, French Mycoses Study Group, The, Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Laboratoire de Parasitologie-Mycologie [CHU Saint Louis, Paris], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), This work was supported by Santé Publique France and Institut Pasteur., Members of the French Mycoses Study Group who contributed to the data are, in alphabetical order of the cities, all the French microbiologists and mycologists who sent isolates for characterization of unusual antifungal susceptibility profiles or to contribute to the ongoing surveillance program on the epidemiology of invasive fungal infections in France (YEASTS and RESSIF programs): N. Brieu (CH Aix), T. Chouaki, C. Damiani, A. Totet (CHU Amiens), J. P. Bouchara, D. Chabasse, M. Pihet (CHU Angers), S. Bland (CH Annecy), V. Blanc (CH Antibes), S. Branger (CH Avignon), A. P. Bellanger, L. Millon (CHU Besançon), C. Plassart (CH Beauvais), I. Poilane (Hôpital Jean Verdier, Bondy), I. Accoceberry, L. Delhaes, B. Couprie, F. Gabriel (CH Bordeaux), J. Dunand, A. L. Roux, V. Sivadon-Tardy (Hôpital Ambroise Paré, Boulogne Billancourt), F. Laurent (CH, Bourg en Bresse), S. Legal, E. Moalic, G. Nevez, D. Quinio (CHU Brest), M. Cariou (CH Bretagne Sud), J. Bonhomme, C. Duhamel (CHU, Caen), B. Podac (CH, Chalon sur Saône), S. Lechatch (CH, Charleville-Mézières), C. Soler (Hopital d’Instruction des armées, Clamart), M. Cambon, C. Nourrisson, P. Poirier, D. Pons (CHU, Clermont Ferrand), O. Augereau, I. Grawey (CH, Colmar), N. Fauchet (CHIC, Créteil), A. Bonnin, F. Dalle (CHU, Dijon), P. Cahen, P. Honderlick (CMC, Foch), N. Desbois, C. Miossec (CHU, Fort de France), J. L. Hermann (Hôpital Raymond Poincaré, Garches), M. Cornet, R. Grillot, B. Lebeau, D. Maubon, H. Pelloux (CHU, Grenoble), M. Nicolas (CHU, Guadeloupe), C. Aznar, D. Blanchet, J. F. Carod, M. Demar, (CHU, Guyane), A. Angoulvant (Hôpital Bicêtre, le Kremlin Bicêtre), C. Ciupek (CH, Le Mans), A. Gigandon (Hôpital Marie Lannelongue, Le Plessis Robinson), B. Bouteille (CH Limoges), E. Frealle, D. Poulain, B. Sendid (CHU Lille), D. Dupont, J. Menotti, F. Persat, M.-A. Piens, M. Wallon (CHU, Lyon), C. Cassagne, S. Ranque (CHU, Marseille), T. Benoit-Cattin, L. Collet (CH Mayotte), A. Fiacre (CH Meaux), N. Bourgeois, L. Lachaud, P. Rispail, Y. Sterkers (CHU, Montpellier), M. Machouart (CHU, Nancy), F. Gay-Andrieu, P. Lepape, F. Morio (CHU, Nantes), O. Moquet (CH, Nevers), S. Lefrançois (Hôpital Américain, Neuilly), M. Sasso (CHU, Nimes), F. Reibel (GH, Nord-Essone), M. Gari-Toussaint, L. Hasseine (CHU Nice), L. Bret, D. Poisson (CHR Orléans), S. Brun (Hôpital Avicenne, Paris), C. Bonnal, C. Chochillon, S. Houzé (Hôpital Bichat, Paris), A. Paugam (Hôpital Cochin, Paris), N. Ait-Ammar, F. Botterel, R. Chouk (CHU Henri Mondor, Paris), M. E. Bougnoux, E. Sitterle (Hôpital Necker, Paris), A. Fekkar, R. Piarroux (Hôpital Pitié Salpêtrière, Paris), J. Guitard, C. Hennequin, J.-L. Poirot (Hôpital St Antoine, Paris), M. Gits-Muselli, S. Hamane, C. Lacroix (Hôpital Saint Louis, Paris), S. Bonacorsi, P. Mariani (Hôpital Robert Debré, Paris), D. Moissenet (Hôpital Trousseau, Paris), C. Kauffmann-Lacroix, A. Minoza, E. Perraud, M. H. Rodier (CHU Poitiers), G. Colonna (CH, Porto Vecchio), A. Huguenin, D. Toubas (CHU Reims), S. Chevrier, J. P. Gangneux, F. Robert-Gangneux, C. Guigen (CHU Rennes), O. Belmonte, G. Hoarau, M. C. Jaffar Bandjee, J. Jaubert, S. Picot, N. Traversier (CHU Réunion), L. Favennec, G. Gargala (CHU, Rouen), N. Godineau, C. Tournus (CH, St Denis), C. Mahinc, H. Raberin (CHU, St Etienne), V. Letscher Bru (CHU, Strasbourg), S. Cassaing (CHU, Toulouse), P. Patoz (CH Tourcoing), E. Bailly, J. Chandenier, G. Desoubeaux (CHU Tours), F. Moreau (CH Troyes), P. Munier (CH Valence), E. Mazars (CH Valenciennes), O. Eloy (CH Versailles), E. Chachaty (Institut Gustave Roussy, Villejuif), and and members of the NRCMA (Institut Pasteur, Paris): A. Bertho, C. Blanc, A. Boullié, C. Gautier, V. Geolier, D. Hoinard, and D. Raoux-Barbot for technical help, and K. Boukris-Sitbon, F. Lanternier, A. Alanio, and D. Garcia-Hermoso for their expertise and contribution to the surveillance programs.

Subjects
Pharmacology, Antifungal Agents, [SDV]Life Sciences [q-bio], yeasts, Microbial Sensitivity Tests, antifungal resistance, Anidulafungin, bacterial infections and mycoses, rare yeast, common yeast, Echinocandins, Lipopeptides, Infectious Diseases, Susceptibility, Caspofungin, Drug Resistance, Fungal, Mutation, Micafungin, polycyclic compounds, FKS mutation, Humans, Candidiasis, Invasive, Pharmacology (medical), MIC distribution
Abstract

International audience; Since echinocandins are recommended as first line therapy for invasive candidiasis, detection of resistance, mainly due to alteration in FKS protein, is of main interest. EUCAST AFST recommends testing both MIC of anidulafungin and micafungin, and breakpoints (BPs) have been proposed to detect echinocandin-resistant isolates. We analyzed MIC distribution for all three available echinocandins of 2,787 clinical yeast isolates corresponding to 5 common and 16 rare yeast species, using the standardized EUCAST method for anidulafungin and modified for caspofungin and micafungin (AM3-MIC). In our database, 64 isolates of common pathogenic species were resistant to anidulafungin, according to the EUCAST BP, and/or to caspofungin, using our previously published threshold (AM3-MIC ≥ 0.5 mg/L). Among these 64 isolates, 50 exhibited 21 different FKS mutations. We analyzed the capacity of caspofungin AM3-MIC and anidulafungin MIC determination in detecting isolates with FKS mutation. They were always identified using caspofungin AM3-MIC and the local threshold while some isolates were misclassified using anidulafungin MIC and EUCAST threshold. However, both methods misclassified four wild-type C. glabrata as resistant. Based on a large data set from a single center, the use of AM3-MIC testing for caspofungin looks promising in identifying non-wild-type C. albicans, C. tropicalis and P. kudiravzevii isolates, but additional multicenter comparison is mandatory to conclude on the possible superiority of AM3-MIC testing compared to the EUCAST method.

Published
2022
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13. A glutathione-responsive silica-based nanosystem capped with in-situ polymerized cell-penetrating poly(disulfide)s for precisely modulating immuno-inflammatory responses

Author

Xuan Li, Chuan Wang, Leilei Wang, Regina Huang, Wai-Chung Li, Xinna Wang, Sarah Sze Wah Wong, Zongwei Cai, Ken Cham-Fai Leung, Lijian Jin, The University of Hong Kong (HKU), Hong Kong Baptist University (HKBU), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and This work was supported by the Hong Kong Research Grants Council (GRF No. 17122918 & 17119819) and the Modern Dental Laboratory/HKU Endowment Fund to L.J. Jin as well as the Key Research Partnership Scheme of HKBU (RC-KRPS-20-21/02) to K.C.-F. Leung.

Subjects
Mesoporous silica nanoparticles, MESH: Drug Delivery Systems, MESH: Immunomodulation, MESH: Silicon Dioxide, Polymerization, Biomaterials, Immunomodulation, Colloid and Surface Chemistry, Drug Delivery Systems, MESH: Porosity, Intracellular drug delivery, Humans, [CHIM]Chemical Sciences, MESH: Disulfides, Disulfides, MESH: Periodontal Diseases, Periodontal Diseases, MESH: Glutathione, MESH: Humans, Silicon Dioxide, Glutathione, Surfaces, Coatings and Films, Electronic, Optical and Magnetic Materials, MESH: Flavanones, Cell-penetrating poly(disulfide)s, MESH: Polymerization, Flavanones, Nanoparticles, Periodontal disease, Porosity, MESH: Nanoparticles
Abstract

International audience; HypothesisPrecise modulation of immuno-inflammatory response is crucial to control periodontal diseases and related systemic comorbidities. The present nanosystem with the controlled-release and cell-penetrating manner enhances the inflammation modulation effects of baicalein in human gingival epithelial cells (hGECs) for better oral healthcare.ExperimentsWe constructed a red-emissive mesoporous silica nanoparticle-based nanosystem with cell-penetrating poly(disulfide) (CPD) capping, through a facile in-situ polymerization approach. It was featured with a glutathione-responsive manner and instant cellular internalization capacity for precisely delivering baicalein intracellularly. Laboratory experiments assessed whether and how the nanosystem per se with the delivered baicalein could modulate immuno-inflammatory responses in hGECs.FindingsThe in-situ polymerized CPD layer capped the nanoparticles and yet controlled the release of baicalein in a glutathione-responsive manner. The CPD coating could facilitate cellular internalization of the nanosystem via endocytosis and thiol-mediated approaches. Notably, the intracellularly released baicalein effectively downregulated the expression of pro-inflammatory cytokines through inhibiting the NF-κB signaling pathway. The nanosystem per se could modulate immuno-inflammatory responses by passivating the cellular response to interlukin-1β. This study highlights that the as-synthesized nanosystem may serve as a novel multi-functional vehicle to modulate innate host response via targeting the NF-κB pathway for precision healthcare.

Published
2022
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14. Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal Meningitis

Author

Jarvis, Joseph N, Lawrence, David S, Meya, David B, Kagimu, Enock, Kasibante, John, Mpoza, Edward, Rutakingirwa, Morris K, Ssebambulidde, Kenneth, Tugume, Lillian, Rhein, Joshua, Boulware, David R, Mwandumba, Henry C, Moyo, Melanie, Mzinganjira, Henry, Kanyama, Cecilia, Hosseinipour, Mina C, Chawinga, Chimwemwe, Meintjes, Graeme, Schutz, Charlotte, Comins, Kyla, Singh, Achita, Muzoora, Conrad, Jjunju, Samuel, Nuwagira, Edwin, Mosepele, Mosepele, Leeme, Tshepo, Siamisang, Keatlaretse, Ndhlovu, Chiratidzo E, Hlupeni, Admire, Mutata, Constantine, van Widenfelt, Erik, Chen, Tao, Wang, Duolao, Hope, William, Boyer-Chammard, Timothée, Loyse, Angela, Molloy, Síle F, Youssouf, Nabila, Lortholary, Olivier, Lalloo, David G, Jaffar, Shabbar, Harrison, Thomas S, Ambition Study Group, London School of Hygiene and Tropical Medicine (LSHTM), Bostwana Harvard AIDS Institute Partneship Gaborone, National Center for Atmospheric Research [Boulder] (NCAR), University of North Carolina Project-Malawi (UNC Project), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), University of Cape Town, Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris]-Université Paris Cité (UPC), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Supported by a grant (TRIA2015-1092) through the European and Developing Countries Clinical Trials Partnership, with assistance from the Swedish International Development Cooperation Agency, as well as by funding from the U.K. Department of Health and Social Care, the U.K. Foreign Commonwealth and Development Office, the U.K. Medical Research Council, and Wellcome Trust, through the Joint Global Health Trials scheme (MR/P006922/1). Funding was also provided by the National Institute for Health Research (NIHR) through a Global Health Research Professorship (RP-2017-08-ST2-012, to Dr. Jarvis) with aid from the U.K. government to support global health research. Dr. Meintjes was supported by grants (098316, 214321/Z/18/Z, and 203135/Z/16/Z) from the Wellcome Trust and a grant (64787) from the South African Research Chairs Initiative of the Department of Science and Technology and the National Research Foundation of South Africa. Diagnostic testing in Uganda was supported by a grant (R01NS086312) from the National Institute of Neurological Disorders and Stroke. Dr. Rhein was supported by a grant (K01 TW010268) from the Fogarty International Center. Liposomal amphotericin B (AmBisome) was donated by Gilead Sciences., We thank the trial participants and their families and caregivers, as well as all the clinical, laboratory, and administrative staff at all the sites who were not directly involved in the trial, Andrew Nunn, Sayoki Mfinanga, Robert Peck, and William Powderly for serving on the data and safety monitoring committee, and John Perfect, Andrew Kambugu, Saidi Kapigi, and Douglas Wilson for serving on the trial steering committee. We dedicate the trial to the memory of Siphokazi Hlungulu, who worked as a research nurse and study coordinator for the Cape Town Ambition site for the duration of the trial and died before seeing the results published., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité)

Subjects
wl_200, qv_350, General Medicine, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, wc_245
Abstract

BackgroundCryptococcal meningitis is a leading cause of human immunodeficiency virus (HIV)-related death in sub-Saharan Africa. Whether a treatment regimen that includes a single high dose of liposomal amphotericin B would be efficacious is not known.MethodsIn this phase 3 randomized, controlled, noninferiority trial conducted in five African countries, we assigned HIV-positive adults with cryptococcal meningitis in a 1:1 ratio to receive either a single high dose of liposomal amphotericin B (10 mg per kilogram of body weight) on day 1 plus 14 days of flucytosine (100 mg per kilogram per day) and fluconazole (1200 mg per day) or the current World Health Organization-recommended treatment, which includes amphotericin B deoxycholate (1 mg per kilogram per day) plus flucytosine (100 mg per kilogram per day) for 7 days, followed by fluconazole (1200 mg per day) for 7 days (control). The primary end point was death from any cause at 10 weeks; the trial was powered to show noninferiority at a 10-percentage-point margin.ResultsA total of 844 participants underwent randomization; 814 were included in the intention-to-treat population. At 10 weeks, deaths were reported in 101 participants (24.8%; 95% confidence interval [CI], 20.7 to 29.3) in the liposomal amphotericin B group and 117 (28.7%; 95% CI, 24.4 to 33.4) in the control group (difference, -3.9 percentage points); the upper boundary of the one-sided 95% confidence interval was 1.2 percentage points (within the noninferiority margin; P10 colony-forming units (CFU) per milliliter per day in the liposomal amphotericin B group and -0.42 log10 CFU per milliliter per day in the control group. Fewer participants had grade 3 or 4 adverse events in the liposomal amphotericin B group than in the control group (50.0% vs. 62.3%).ConclusionsSingle-dose liposomal amphotericin B combined with flucytosine and fluconazole was noninferior to the WHO-recommended treatment for HIV-associated cryptococcal meningitis and was associated with fewer adverse events. (Funded by the European and Developing Countries Clinical Trials Partnership and others; Ambition ISRCTN number, ISRCTN72509687.).

Published
2022
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15. Combination of Mycological Criteria: a Better Surrogate to Identify COVID-19-Associated Pulmonary Aspergillosis Patients and Evaluate Prognosis?

Author

Sarah Dellière, Emmanuel Dudoignon, Sébastian Voicu, Magalie Collet, Sofiane Fodil, Benoit Plaud, Benjamin Chousterman, Stéphane Bretagne, Elie Azoulay, Alexandre Mebazaa, François Dépret, Bruno Mégarbane, Alexandre Alanio, Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire de Parasitologie-Mycologie [CHU Saint Louis, Paris], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Anesthésie-Réanimation [AP-HP Hôpitaux Saint-Louis Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Réanimation Médicale et Toxicologique [Hôpital Lariboisière], Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, and Mégarbane, Bruno

Subjects
Invasive Pulmonary Aspergillosis, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Microbiology (medical), [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, diagnosis, COVID-19, Covid 19, Prognosis, Sensitivity and Specificity, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Mannans, [SDV.TOX] Life Sciences [q-bio]/Toxicology, critical care, Aspergillus, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.TOX]Life Sciences [q-bio]/Toxicology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Humans, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Pulmonary Aspergillosis, Bronchoalveolar Lavage Fluid
Abstract

International audience; Diagnosis of coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) remains unclear especially in nonimmunocompromised patients. The aim of this study was to evaluate seven mycological criteria and their combination in a large homogenous cohort of patients. All successive patients (n = 176) hospitalized for COVID-19 requiring mechanical ventilation and who clinically worsened despite appropriate standard of care were included over a 1-year period. Direct examination, culture, Aspergillus quantitative PCR (Af-qPCR), and galactomannan testing were performed on all respiratory samples (n = 350). Serum galactomannan, β-d-glucan, and plasma Af-qPCR were also assessed. The criteria were analyzed alone or in combination in relation to mortality rate. Mortality was significantly different in patients with 0, ≤2, and ≥3 positive criteria (log rank test, P = 0.04) with death rate of 43.1, 58.1, and 76.4%, respectively. Direct examination, plasma qPCR, and serum galactomannan were associated with a 100% mortality rate. Bronchoalveolar lavage (BAL) galactomannan and positive respiratory sample culture were often found as isolated markers (28.1 and 34.1%) and poorly repeatable when a second sample was obtained. Aspergillus DNA was detected in 13.1% of samples (46 of 350) with significantly lower quantitative cycle (Cq) when associated with at least one other criterion (30.2 versus 35.8) (P < 0.001). A combination of markers and/or blood biomarkers and/or direct respiratory sample examination seems more likely to identify patients with CAPA. Af-qPCR may help identifying false-positive results of BAL galactomannan testing and culture on respiratory samples while quantifying fungal burden accurately.

Published
2022
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16. Yarrowia lipolytica causes sporadic cases and local outbreaks of infections and colonisation

Author

Cécile Neuvéglise, Françoise Dromer, Marie Desnos-Ollivier, Valérie Letscher-Bru, Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Parasitologie et de Mycologie Médicale [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Institut de Parasitologie et de Pathologie Tropicale (IPPTS), Université de Strasbourg (UNISTRA), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Santé Publique FranceInstitut Pasteur, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Antifungal Agents, 030106 microbiology, Yarrowia, Human pathogen, Microbial Sensitivity Tests, Dermatology, Disease Outbreaks, Microbiology, 030207 dermatology & venereal diseases, 03 medical and health sciences, Minimum inhibitory concentration, 0302 clinical medicine, Intergenic region, Environmental Microbiology, medicine, Humans, candidaemia, Genotyping, [SDV.GEN]Life Sciences [q-bio]/Genetics, Genetic diversity, biology, molecular typing, Broth microdilution, Genetic Variation, Sequence Analysis, DNA, General Medicine, colonization, biology.organism_classification, 3. Good health, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Infectious Diseases, Mycoses, Genome, Fungal, yarrowia lipolytica, Fluconazole, medicine.drug
Abstract

Background Yarrowia lipolytica belongs to the normal human microbiota but is also found in substrates with high contents in lipids and used in biotechnological processes. It is sometimes reported as human pathogen and especially in catheter-related candidaemia. Objectives Two apparently grouped cases of infections and/or contamination were reported involving 3 and 9 patients, respectively, in two hospitals. The goal of this study was to design a molecular tool to study the genetic diversity of Y lipolytica and confirm or not the common source of contamination during these grouped cases. Methods Given that there is no genotyping method, we used genomic markers assessed on environmental isolates to determine intra-species relationship. We selected five highly polymorphic intergenic regions, totalling more than 3200 bp and sequenced them for clinical (n = 20) and environmental (n = 14) isolates. Antifungal susceptibility was determined by EUCAST broth microdilution method. Results Multiple alignment of the five sequences revealed divergence of 0%-5.8% between isolates as compared to approximately 0.2%-0.25% after alignment of whole genomes, suggesting their potential usefulness to establish genetic relatedness. The analysis showed the multiple origins of the isolates. It uncovered two grouped case of fungaemia involving 3 and 2 patients, respectively. It also revealed several unrelated sporadic cases despite their temporal relationship and one probable laboratory contamination by a common yet uncovered source, explaining several consecutive positive cultures without infection. All isolates had high minimal inhibitory concentration (MIC) for flucytosine, the majority (14/34) was susceptible to fluconazole, and all to the other antifungal agents tested. Conclusion This method could help elucidate cases related to the opportunistic pathogen Y lipolytica.

Published
2020
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17. Diagnostic implications of mycetoma derived from Madurella pseudomycetomatis isolates from Mexico

Author

Bertrand Nyuykonge, W. W. J. van de Sande, Marie Desnos-Ollivier, G.S. de Hoog, Sarah A. Ahmed, Willemien H A Zandijk, Alexandro Bonifaz, Annelies Verbon, Corné H. W. Klaassen, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Westerdijk Fungal Biodiversity Insitute [Utrecht] (WI), Royal Netherlands Academy of Arts and Sciences (KNAW), University of Khartoum, Mycologie moléculaire - Molecular Mycology, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris], Hospital General de México Dr. Eduardo Liceaga (HGM), W.W.J.vdS. was supported by an EUR fellowship of the Erasmus University and Aspasia grant 015.013.033 from the Dutch Scientific Organisation., Medical Microbiology & Infectious Diseases, Westerdijk Fungal Biodiversity Institute [Utrecht] (WI), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)

Subjects
0301 basic medicine, MESH: DNA Primers, Posaconazole, Madurella, 030106 microbiology, 030231 tropical medicine, Dermatology, Eumycetoma, Skin Infectiology, Venereology and Sexual Health, Microbiology, Flucytosine, 03 medical and health sciences, 0302 clinical medicine, Species Specificity, medicine, MESH: Madurella, Humans, MESH: Species Specificity, Internal transcribed spacer, Genotyping, Mexico, MESH: Mexico, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, DNA Primers, MESH: Humans, biology, business.industry, Madurella mycetomatis, Amplicon, biology.organism_classification, medicine.disease, 3. Good health, MESH: Mycetoma, Infectious Diseases, Mycetoma, Original Article, business, medicine.drug
Abstract

International audience; BackgroundAt the dermatology service of the General Hospital of Mexico City, Mexico, two patients, father and son, with black-grain mycetoma were seen. The grains were isolated, and the cultured fungi were identified as Madurella mycetomatis based on morphology. Using the M. mycetomatis specific PCR, amplicons of a different size than that of the M. mycetomatis type strain were obtained.ObjectiveTo determine the causative agent of the two black-grain mycetoma cases and develop non-culture-based diagnostic tools to identify them to the species level.MethodsThe M. mycetomatis specific, the internal transcribed spacer (ITS) region, β-tubulin (BT) and ribosomal binding protein 2 (RBP2) PCRs were used to confirm the identity of the isolates. Genetic variation was established by amplification fragment length polymorphisms. To determine the antifungal susceptibility profile, the Sensititre™ YeastOne™ assay was used. To develop a species-specific PCR primers were designed on the sequenced PCR amplicon from the M. mycetomatis specific PCR.ResultsBy analyzing the ITS, BT and RBP2 regions the isolates were identified as Madurella pseudomycetomatis. The isolates from father and son were similar but not identical to M. pseudomycetomatis from Venezuela and one from an unknown origin. Madurella pseudomycetomatis isolates were inhibited by itraconazole, posaconazole and voriconazole but showed increased MIC values for amphotericin B and fluconazole. They were not inhibited by the echinocandins and five flucytosine. The two patients were treated with itraconazole resulting in cure for the father while the son was lost to follow-up. The species-specific PCR developed for M. pseudomyceotmatis was discriminative and specific.ConclusionMadurella pseudomycetomatis is genetically diverse with same susceptibility profile as M. mycetomatis and causes eumycetoma in Latin America. The M. pseudomycetomatis specific PCR can be used to identify this causative agent to the species level; however, this needs to be validated in an endemic setting.

Published
2020
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18. Comparison of MultiLocus Sequence Typing (MLST) and Microsatellite Length Polymorphism (MLP) for Pneumocystis jirovecii genotyping

Author

Stéphane Bretagne, Pascal Campagne, Patrice Le Pape, Maud Gits-Muselli, Marie Desnos-Ollivier, Alexandre Alanio, Florent Morio, Laboratoire de Parasitologie-Mycologie [CHU Saint Louis, Paris], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Paris (UP), Mycologie moléculaire - Molecular Mycology, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris], Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Nantes (CHU Nantes), Cibles et médicaments de l'infection, de l'immunité et du cancer (IICiMed), Université de Nantes - UFR des Sciences Pharmaceutiques et Biologiques, Université de Nantes (UN)-Université de Nantes (UN), MGM’s salary was funded by Assistance Publique-Hôpitaux de Paris and Institut Pasteur (Poste d’ accueil APHP/CNRS/Institut Pasteur)., Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), and Cibles et Médicaments des Infections et de l'Immunité (IICiMed)

Subjects
Genotyping, lcsh:Biotechnology, Biophysics, Context (language use), MLP, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Structural Biology, lcsh:TP248.13-248.65, Genotype, Genetics, Pneumocystis jirovecii, Genotyping Techniques, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, 030304 developmental biology, 0303 health sciences, biology, Haplotype, biology.organism_classification, Computer Science Applications, Haplotypes, 030220 oncology & carcinogenesis, Microsatellite, Multilocus sequence typing, MultiLocus Sequence Typing, Biotechnology
Abstract

International audience; Pneumocystis jirovecii is an atypical fungus responsible for severe respiratory infections, often reported as local outbreaks in immunocompromised patients. Epidemiology of this infection, and transmission risk emphasises the need for developing genotyping techniques. Currently, two methods have emerged: Multilocus Sequence typing (MLST) and microsatellite length polymorphism (MLP). Here we compare an MLST strategy, including 2 nuclear loci and 2 mitochondrial loci, with an MLP strategy including 6 nuclear markers using 37 clinical PCR-positive respiratory samples from two French hospitals. Pneumocystis jirovecii MLST and MLP provided 30 and 35 different genotypes respectively. A higher number of mixed infections was detected using MLP (48.6% vs. 13.5% respectively; p = 0.002). Only one MLP marker (STR279) was statistically associated with the geographical origin of samples. Haplotype network inferred using the available genotypes yielded expanded network for MLP, characterized by more mutational steps as compared to MLST, suggesting that the MLP approach is more resolutive to separate genotypes. The correlation between genetic distances calculated based on MLST and MLP was modest with a R2 value = 0.32 (p

Published
2020
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19. Pearlsamp; Oy-sters: Spinal Cord Candidiasis Linked to CARD9 Deficiency Masquerading as a Longitudinally Extensive Transverse Myelitis

Author

Lina Jeantin, Isabelle Plu, Maria del Mar Amador, Elisabeth Maillart, Fanny Lanternier, Valérie Pourcher, Vincent Davy, Institut Mutualiste de Montsouris (IMM), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Sorbonne Université - Faculté de Médecine (SU FM), and Sorbonne Université (SU)

Subjects
Adult, Male, Antifungal Agents, [SDV]Life Sciences [q-bio], Candidiasis, Chronic Mucocutaneous, Candidiasis, Middle Aged, Myelitis, Transverse, CARD Signaling Adaptor Proteins, Spinal Cord, Adrenal Cortex Hormones, Humans, Neurology (clinical), Glucans
Abstract

Candida spp. myelopathies are very rare. We report a case of subacute longitudinally extensive transverse myelitis in an apparently immunocompetent 55-year-old man. After a negative infectious workup, corticosteroids and plasma exchange were initiated. Although there was a transient initial improvement, symptoms then worsened, and the lumbar puncture was repeated. Candida albicans was isolated in the CSF, and a diagnosis of spinal cord candidiasis was made. Gene panel sequencing for inborn immune deficiencies identified a homozygous disease-causing CARD9 variant. Despite antifungal treatment, necrotic myelitis, meningoencephalitis, and cerebral vasculitis developed. Fungal spinal cord infections can mimic inflammatory myelitis, and beta-D-glucan testing of both serum and CSF may help narrow down the diagnosis. In cases of severe or unexpected invasive Candida spp. infection, even adults and apparently immunocompetent patients should be screened for inborn immune deficiencies and CARD9 deficiency in particular.

Published
2022
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20. Bloodstream Infections Caused by Magnusiomyces capitatus and Magnusiomyces clavatus : Epidemiological, Clinical, and Microbiological Features of Two Emerging Yeast Species

Author

Janina Noster, Martin B. Koeppel, Marie Desnos-Olivier, Maria Aigner, Oliver Bader, Karl Dichtl, Stephan Göttig, Andrea Haas, Oliver Kurzai, Arthur B. Pranada, Yvonne Stelzer, Grit Walther, Axel Hamprecht, Carl Von Ossietzky Universität Oldenburg = Carl von Ossietzky University of Oldenburg (OFFIS), Ludwig-Maximilians-Universität München (LMU), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris] (IP), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), University Medical Center Göttingen (UMG), Goethe-Universität Frankfurt am Main, Julius-Maximilians-Universität Würzburg (JMU), Leibniz Institute for Natural Product Research and Infection Biology (Hans Knoell Institute), MVZ Dr. Eberhard & Partner Dortmund, German Centre for Infection Research (DZIF), Universität zu Köln = University of Cologne, and Work in the NRZMyk is supported by the Robert-Koch-Institute from funds provided by the German Ministry of Health (grant no. 1369-240). This study was supported by internal funding.

Subjects
Pharmacology, Saprochaete capitata, Infectious Diseases, Magnusiomyces clavatus, [SDV]Life Sciences [q-bio], Saprochaete clavata, Pharmacology (medical), bloodstream infection, MIC, Magnusiomyces capitatus, Geotrichum
Abstract

International audience; Magnusiomyces clavatus and Magnusiomyces capitatus are emerging yeasts with intrinsic resistance to many commonly used antifungal agents. Identification is difficult, and determination of susceptibility patterns with commercial and reference methods is equally challenging. For this reason, few data on invasive infections by Magnusiomyces spp. are available. Our objectives were to determine the epidemiology and susceptibility of Magnusiomyces isolates from bloodstream infections (BSI) isolated in Germany and Austria from 2001 to 2020. In seven institutions, a total of 34 Magnusiomyces BSI were identified. Identification was done by internal transcribed spacer (ITS) sequencing and matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS). Antifungal susceptibility was determined by EUCAST broth microdilution and gradient tests. Of the 34 isolates, M. clavatus was more common (n = 24) than M. capitatus (n = 10). BSI by Magnusiomyces spp. were more common in men (62%) and mostly occurred in patients with hemato-oncological malignancies (79%). The highest in vitro antifungal activity against M. clavatus/M. capitatus was observed for voriconazole (MIC50, 0.03/0.125 mg/L), followed by posaconazole (MIC50, 0.125/0.25 mg/L). M. clavatus isolates showed overall lower MICs than M. capitatus. With the exception of amphotericin B, low essential agreement between gradient test and microdilution was recorded for all antifungals (0 to 70%). Both species showed distinct morphologic traits on ChromAgar Orientation medium and Columbia blood agar, which can be used for differentiation if no MALDI-TOF MS or molecular identification is available. In conclusion, most BSI were caused by M. clavatus. The lowest MICs were recorded for voriconazole. Gradient tests demonstrated unacceptably low agreement and should preferably not be used for susceptibility testing of Magnusiomyces spp.

Published
2022
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21. Characterization of Blood Mucosal Associated Invariant T ( MAIT ) cells in Axial Spondyloarthritis and of resident MAITs from control axial enthesis

Author

Rosine, Nicolas, Rowe, Hannah, Koturan, Surya, Yahia‐cherbal, Hanane, Leloup, Claire, Watad, Abdulla, Berenbaum, Francis, Sellam, Jeremie, Dougados, Maxime, Aimanianda, Vishukumar, Cuthbert, Richard, Bridgewood, Charlie, Newton, Darren, Bianchi, Elisabetta, Rogge, Lars, Mcgonagle, Dennis, Miceli‐richard, Corinne, Immunorégulation - Immunoregulation, Institut Pasteur [Paris] (IP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), University of Leeds, Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Institut Pasteur [Paris] (IP), DMG is funded by the Leeds NIHR Biomedical Research Centre. Novartis UK Investigator Initiated non-clinical research funding support (HR, CB). AW was funded by the Celgene supported PARTNER fellowship program. Research funded by a Pfizer investigator initiated research grant (RJC) NR was funded by a Poste d’Accueil APHP and a grant fromSociété Française de Rhumatologie. This study was supported by grants from MSD Avenir (Project iCARE-SpA), a Sanofi Innovation award Europe, FOREUM Foundation for Research in Rheumatology, and from the Société Française de Rhumatologie., and Kop, Marie-Luce

Subjects
IL-17F, MAITs, [SDV.IMM] Life Sciences [q-bio]/Immunology, IL-17A, [SDV.IMM]Life Sciences [q-bio]/Immunology, axial spondyloarthritis, IL-17 producing cells
Abstract

International audience; ObjectivesThe importance of IL-17A in the pathogenesis of Axial Spondyloarthritis (AxSpA) has been demonstrated by the success of IL-17A blockade. However, the nature of the cell populations producing this important pro-inflammatory cytokine remains poorly defined. Accordingly, we characterized major IL-17A-producing blood cell populations in AxSpA, with reference to entheseal biology, with a focus on mucosal associated invariant T-cells, (MAITs) a population known to be capable of producing IL-17.MethodsIL-17A production from 5 sorted peripheral blood cell populations, namely MAITs, γδ T-cells, CD4+T-cells, CD8+T-cells and neutrophils was evaluated pre- and post-stimulation with PMA, the calcium ionophore A23187 and β1,3 glucan. IL-17A transcript and protein expression were determined using nCounter Technology and ultra-sensitive SimoA technology, respectively. MAITs from control human axial entheses (n=5) were further characterized by flow cytometric immunophenotyping, qPCR and IL-17 production assessed following stimulation.ResultsIn blood, on a per cell basis, MAIT cells produced the highest amount of IL-17A compared to CD4+ (p

Published
2022
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22. Genetics and immunity of Anopheles response to the entomopathogenic fungus Metarhizium anisopliae overlap with immunity to Plasmodium

Author

Tullu Bukhari, Vishukumar Aimanianda, Emmanuel Bischoff, Emma Brito-Fravallo, Karin Eiglmeier, Michelle M. Riehle, Kenneth D. Vernick, Christian Mitri, International Centre of Insect Physiology and Ecology (ICIPE), ICIPE, Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Génétique et Génomique des Insectes Vecteurs - Genetics and Genomics of Insect Vectors, Medical College of Wisconsin [Milwaukee] (MCW), This study received financial support to KV from the European Commission Horizon 2020 Infrastructures #731060 Infravec2, European Research Council Support for Frontier Research, Advanced Grant #323173 AnoPath, Agence Nationale de la Recherche #ANR-19-CE35-0004 ArboVec, to MMR from National Institutes of Health, NIAID #AI145999, and French Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' #ANR-10-LABX-62-IBEID., We thank Dr. N.K. Maniania for the provision of spores of M. anisopliae (ICIPE30)., ANR-19-CE35-0004,ArboVEC,Barrières d'hôtes dans la spécificité des interactions entre moustiques vecteurs et arbovirus(2019), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 731060,INFRAVEC2(2017), and European Project: 323173,EC:FP7:ERC,ERC-2012-ADG_20120314,ANOPATH(2013)

Subjects
Metarhizium, Plasmodium, Multidisciplinary, [SDV]Life Sciences [q-bio], fungi, parasitic diseases, Anopheles, Animals, Humans, Female, Mosquito Vectors, Malaria
Abstract

Entomopathogenic fungi have been explored as a potential biopesticide to counteract the insecticide resistance issue in mosquitoes. However, little is known about the possibility that genetic resistance to fungal biopesticides could evolve in mosquito populations. Here, we detected an important genetic component underlying Anopheles coluzzii survival after exposure to the entomopathogenic fungus Metarhizium anisopliae. A familiality study detected variation for survival among wild mosquito isofemale pedigrees, and genetic mapping identified two loci that significantly influence mosquito survival after fungus exposure. One locus overlaps with a previously reported locus for Anopheles susceptibility to the human malaria parasite Plasmodium falciparum. Candidate gene studies revealed that two LRR proteins encoded by APL1C and LRIM1 genes in this newly mapped locus are required for protection of female A. coluzzii from M. anisopliae, as is the complement-like factor Tep1. These results indicate that natural Anopheles populations already segregate frequent genetic variation for differential mosquito survival after fungal challenge and suggest a similarity in Anopheles protective responses against fungus and Plasmodium. However, this immune similarity raises the possibility that fungus-resistant mosquitoes could also display enhanced resistance to Plasmodium, suggesting an advantage of selecting for fungus resistance in vector populations to promote naturally diminished malaria vector competence.

Published
2022
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23. Coronavirus Disease 2019-Associated Mucormycosis in France: A Rare but Deadly Complication

Author

Danion, François, Letscher-Bru, Valérie, Guitard, Juliette, Sitbon, Karine, Dellière, Sarah, Angoulvant, Adela, Desoubeaux, Guillaume, Botterel, Francoise, Bellanger, Anne-Pauline, Gargala, Gilles, Uhel, Fabrice, Bougnoux, Marie-Elisabeth, Gerber, Victor, Michel, Justin, Cornu, Marjorie, Bretagne, Stéphane, Lanternier, Fanny, Merdji, Hamid, Delabranche, Xavier, Parrot, Antoine, Voiriot, Guillaume, Urbina, Tomas, Mebazaa, Alexandre, Chousterman, Benjamin, el Kalioubie, Ahmed, Six, Sophie, Coulon, Pauline, Sendid, Boualem, Anguel, Nadia, Damoisel, Charles, Mussini, Charlotte, Villate, Alban, Navellou, Jean-Christophe, Girault, Christophe, Cassagne, Carole, Augereau, Olivier, Dromer, Francoise, Garcia-Hermoso, Dea, Lortholary, Olivier, Alanio, Alexandre, Center of Experimental and Molecular Medicine, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération Hospitalo-Universitaire (OMICARE), Centre de Recherche d’Immunologie et d’Hématologie [Strasbourg], CHU Strasbourg, Dynamique des interactions hôte pathogène (DIHP), Mucoviscidose: physiopathologie et phénogénomique [CRSA], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), COVID-Mucor study group, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de parasitologie, mycologie, médecine tropicale [CHRU Tours], Dynamic Microbiology - EA 7380 (DYNAMIC), École nationale vétérinaire - Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Université Paris-Est (UPE)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Henri Mondor [Créteil], Service de parasitologie et mycologie [CHRU de Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Laboratoire de Biologie Médicale de Référence Pneumopathie d'hypersensibilité, Laboratoire Chrono-environnement (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), CHU Necker - Enfants Malades [AP-HP], Aix Marseille Université (AMU), CHU Lille, Service de Médecine Intensive et Réanimation [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), CHU Tenon [AP-HP], Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), COVID-Mucor St Group Hamid Merdji (Médecine Intensive et Réanimation, Hôpitaux Universitaires de Strasbourg, Strasbourg, France), Xavier Delabranche (Réanimation Chirugicale, Hôpitaux Universitaires de Strasbourg, Strasbourg, France), Antoine Parrot (Service de Pneumologie, Hôpital Tenon, AP-HP, Paris, France), Guillaume Voiriot (Service de Médecine Intensive et Réanimation, Hôpital Tenon, AP-HP, Paris, France), Tomas Urbina (Service de Réanimation Médicale, Hôpital Saint Antoine, AP-HP, Paris, France), Alexandre Mebazaa (Réanimation Chirurgicale, Hôpital Saint-Louis, AP-HP, Paris, France), Benjamin Chousterman (Réanimation, Hôpital Lariboisière, AP-HP, Paris, France), Ahmed El Kalioubie (Réanimation, CHU de Lille), Sophie Six (Réanimation, CHU de Lille, Lille, France), Pauline Coulon and Boualem Sendid (Service de Mycologie, CHU de Lille, France), Nadia Anguel (Réanimation Médicale, Le Kremlin-Bicêtre, AP-HP, Paris, France), Charles Damoisel (Réanimation Polyvalente, Clamart, AP-HP, France), Charlotte Mussini (Service d’Anatomopathologie, Le Kremlin-Bicêtre, AP-HP, Paris, France), Alban Villate (Hématologie, Tours, France), Jean-Christophe Navellou (Réanimation, CHU Besançon, France), Christophe Girault (Médecine Intensive et Réanimation, CHU Rouen, France), Carole Cassagne (Laboratoire de Mycologie, CHU Timone, Marseille, France), Olivier Augereau (Laboratoire de Microbiologie, Colmar, France), Francoise Dromer, Dea Garcia-Hermoso, Olivier Lortholary, Alexandre Alanio (CNRMA, Institut Pasteur, Paris, France)., Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées (IRBA), and Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille)

Subjects
medicine.medical_specialty, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, CAM, Coronavirus disease 2019 (COVID-19), business.industry, Brief Report, General surgery, Mucormycosis, COVID-19, CAPA, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, mucormycosis, AcademicSubjects/MED00290, Infectious Diseases, Oncology, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, medicine, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, business, Complication
Abstract

We studied COVID-19 associated mucormycosis based on 17 cases reported nationwide and assessed the differences with India. They differed by frequencies of diabetes mellitus (47% in France versus up to 95% in India), hematological malignancies (35% versus 1%), anatomical sites (12% versus >80% rhino-orbito-cerebral) and prognosis (88% mortality versus, We reported 17 cases of COVID-19 associated mucormycosis in France. Compared to India, they differed by frequencies of diabetes mellitus (47% versus up to 95% in India), hematological malignancies (35% versus 1%), anatomical sites and mortality (88% versus

Published
2022
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24. Aspergillus and Aspergillosis

Author

Sarah Dellière, Emmanuel Lafont, Sarah Sze Wah Wong, Vishukumar Aimanianda, Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité)

Subjects
Aspergillus, biology, business.industry, Diseases, Antifungal resistance, Aspergillosis, medicine.disease, biology.organism_classification, Diagnosis and treatment, Microbiology, Pathogenic Aspergillus, medicine, Host-immunity, business, Biology and pathogenesis, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology
Abstract

International audience; The name “Aspergillus” was first coined by an Italian priest Pier Antonio Micheli in 1729, as the asexual spore-bearing structure of this fungal genus resembled aspergillus, a holy water sprinkler. The genus Aspergillus belongs to the fungal division “Ascomycota” and is consisted of a few hundred filamentous (mold) species that are found in various climatic conditions. In this article, we describe the current knowledge on the Aspergillus species that are pathogenic to humans, regarding to their biology and pathogenesis, interaction with the host immunity, and clinical aspects (diseases caused, diagnosis and currently available therapeutic strategies, and emergence of antifungal resistance).

Published
2022
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25. The role of glycosylphosphatidylinositol (gpi) anchored proteins in Cryptococcusneoformans

Author

Eveline Snelders, Frédérique Moyrand, Aude Sturny-Leclère, Frédérique Vernel-Pauillac, Stevenn Volant, Guilhem Janbon, Alexandre Alanio, Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Biologie des ARN des Pathogènes fongiques - RNA Biology of Fungal Pathogens, Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Laboratoire de Parasitologie-Mycologie [CHU Saint Louis, Paris], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This research received no external funding., Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), and Institut Pasteur [Paris]-Université Paris Cité (UPC)

Subjects
Glycosylphosphatidylinositols, Immunology, Cell Membrane, Cryptococcosis, glycophosphatidylinositol (GPI)-anchored proteins, Microbiology, Fungal Proteins, Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Cell Wall, Cryptococcus neoformans, Humans, Life Science
Abstract

International audience; It is becoming increasingly obvious that glycophosphatidylinositol (GPI)-anchored proteins (GAPs) play a prominent role in fungi, a full understanding of GAPs is however lacking especially for the human opportunistic fungus Cryptococcus neoformans. Using online GPI prediction tools, GAPs were identified and subsequently a mutant library for these GAP-encoding genes was developed and a publicly available knock out (KO) mutant library was used. In total, 41 overexpression and 34 KO mutants, representing 47 unique genes, were analyzed. From the analysis of the two libraries, two main gene candidates, a mannoprotein 88 (MP88) (CNAG_00776) and an uncharacterized protein (CNAG_00137) were further investigated by constructing additional independent mutant strains. The CNAG_00776 mutant showed an impaired growth upon plasma membrane stress and significant decreased phagocytosis. The CNAG_00137 mutant showed impaired growth during cell wall stress or increased temperature as well as decreased phagocytosis compared. By performing a large genetic screen of GAPs in the genome of the human fungal pathogen C. neoformans, we identified two candidate GAP genes involved in C. neoformans/host interaction and stress response. Further research into these two genes could potentially result in new targets for antifungals, treatment strategies or vaccines to manage C. neoformans disease.

Published
2022
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26. Conidium Specific Polysaccharides in Aspergillus fumigatus

Author

Zhonghua Liu, Isabel Valsecchi, Rémy A. Le Meur, Catherine Simenel, J. Iñaki Guijarro, Catherine Comte, Laetitia Muszkieta, Isabelle Mouyna, Bernard Henrissat, Vishukumar Aimanianda, Jean-Paul Latgé, Thierry Fontaine, Aspergillus, Institut Pasteur [Paris] (IP), Université Paris-Est Créteil Val-de-Marne - Faculté de médecine (UPEC Médecine), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Plateforme Technologique de RMN Biologique et HDX-MS - Biological NMR and HDX-MS Technological Platform, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Biologie des ARN des Pathogènes fongiques - RNA Biology of Fungal Pathogens, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Architecture et fonction des macromolécules biologiques (AFMB), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Mycologie moléculaire - Molecular Mycology, Biologie et Pathogénicité fongiques - Fungal Biology and Pathogenicity (BPF), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), This research was funded by the Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases (Grant No ANR-10-LABX-62-IBEID) and l’Agence Nationale pour la Recherche (AfuInf ANR-16-CE92-0039). The 800-MHz NMR spectrometer of the Institut Pasteur was partially funded by the Région Ile de France (SESAME 2014 NMRCHR grant no 4014526)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), and ANR-16-CE92-0039,AfuInf,Protéome and polysaccharidome d'Aspergillus fumigatus lors des étapes précoces de l'infection(2016)

Subjects
Microbiology (medical), Aspergillus fumigatus, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], polysaccharidome, cell wall, conidium, Plant Science, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Ecology, Evolution, Behavior and Systematics
Abstract

International audience; Earlier studies have shown that the outer layers of the conidial and mycelial cell walls of Aspergillus fumigatus are different. In this work, we analyzed the polysaccharidome of the resting conidial cell wall and observed major differences within the mycelium cell wall. Mainly, the conidia cell wall was characterized by (i) a smaller amount of α-(1,3)-glucan and chitin; (ii) a larger amount of β-(1,3)-glucan, which was divided into alkali-insoluble and water-soluble fractions, and (iii) the existence of a specific mannan with side chains containing galactopyranose, glucose, and N-acetylglucosamine residues. An analysis of A. fumigatus cell wall gene mutants suggested that members of the fungal GH-72 transglycosylase family play a crucial role in the conidia cell wall β-(1,3)-glucan organization and that α-(1,6)-mannosyltransferases of GT-32 and GT-62 families are essential to the polymerization of the conidium-associated cell wall mannan. This specific mannan and the well-known galactomannan follow two independent biosynthetic pathways.

Published
2023
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27. Surfactant protein D inhibits growth, alters cell surface polysaccharide exposure and immune activation potential of Aspergillus fumigatus

Author

Sarah Sze Wah Wong, Sarah Dellière, Natalia Schiefermeier-Mach, Lukas Lechner, Susanne Perkhofer, Perrine Bomme, Thierry Fontaine, Anders G. Schlosser, Grith L. Sorensen, Taruna Madan, Uday Kishore, Vishukumar Aimanianda, Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Health University of Applied Sciences Tyrol (FH Gesundheit), Plateforme BioImagerie Ultrastructurale – Ultrastructural BioImaging Platform (UTechS UBI), Institut Pasteur [Paris] (IP), Biologie et Pathogénicité fongiques - Fungal Biology and Pathogenicity (BPF), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Southern Denmark (SDU), National Institute for Research in Reproductive and Child Health [Mumbai] (NIRRCH), Brunel University London [Uxbridge], SSWW is supported by the Pasteur Roux-Cantarini Fellowship. We gratefully acknowledge the UtechS Photonic BioImaging (Imagopole), C2RT, Institut Pasteur, supported by the French National Research Agency (France BioImaging, ANR-10–INBS–04, Investments for the Future)., and ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010)

Subjects
Innate immunity, QH573-671, surfactant protein D, Cell wall, Aspergillus fumigatus, Surfactant protein D, fungi, polysaccharides, Cell Biology, Applied Microbiology and Biotechnology, Microbiology, Polysaccharides, pattern-recognition receptor, Pattern-recognition receptor, cell wall, Cytology, innate immunity, Molecular Biology, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology
Abstract

© 2022 The Authors. Humoral immunity plays a defensive role against invading microbes. However, it has been largely overlooked with respect to Aspergillus fumigatus, an airborne fungal pathogen. Previously, we have demonstrated that surfactant protein D (SP-D), a major humoral component in human lung-alveoli, recognizes A. fumigatus conidial surface exposed melanin pigment. Through binding to melanin, SP-D opsonizes conidia, facilitates conidial phagocytosis, and induces the expression of protective pro-inflammatory cytokines in the phagocytic cells. In addition to melanin, SP-D also interacts with galactomannan (GM) and galactosaminogalactan (GAG), the cell wall polysaccharides exposed on germinating conidial surfaces. Therefore, we aimed at unravelling the biological significance of SP-D during the germination process. Here, we demonstrate that SP-D exerts direct fungistatic activity by restricting A. fumigatus hyphal growth. Conidial germination in the presence of SP-D significantly increased the exposure of cell wall polysaccharides chitin, α-1,3-glucan and GAG, and decreased β-1,3-glucan exposure on hyphae, but that of GM was unaltered. Hyphae grown in presence of SP-D showed positive immunolabelling for SP-D. Additionally, SP-D treated hyphae induced lower levels of pro-inflammatory cytokine, but increased IL-10 (anti-inflammatory cytokine) and IL-8 (a chemokine) secretion by human peripheral blood mononuclear cells (PBMCs), compared to control hyphae. Moreover, germ tube surface modifications due to SP-D treatment resulted in an increased hyphal susceptibility to voriconazole, an antifungal drug. It appears that SP-D exerts its anti-A. fumigatus functions via a range of mechanisms including hyphal growth-restriction, hyphal surface modification, masking of hyphal surface polysaccharides and thus altering hyphal immunostimulatory properties. Pasteur Roux-Cantarini Fellowship; UtechS Photonic BioImaging (Imagopole), C2RT, Institut Pasteur, supported by the French National Research Agency (France BioImaging; ANR-10–INBS–04; Investments for the Future).

Published
2022
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28. Elimination of fluconazole during continuous renal replacement therapy. An in vitro assessment

Author

Tarik Abarou, Pierre Carli, Pascal Houzé, Frédéric J. Baud, Benoit Pilmis, Jean-Herlé Raphalen, Lionel Lamhaut, Vincent Jullien, Laboratoire de Microbiologie Clinique [AP-HP Hôpital Necker-Enfants Malades], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Pharmacologie et évaluations thérapeutiques chez l'enfant et la femme enceinte (URP_7323), Université de Paris (UP), Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie Analytique de Paris-Sud, EA 3343, Faculté de Pharmacie de Châtenay-Malabry, Université Paris Sud Orsay, Centre hospitalier Saint-Joseph [Paris], MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service des Maladies infectieuses et tropicales [CHU Necker], Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Institut de Chimie du CNRS (INC)-Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Tâche, Roselyne, and Université Paris-Sud - Paris 11 (UP11)

Subjects
Continuous Renal Replacement Therapy, medicine.medical_treatment, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Biomedical Engineering, Medicine (miscellaneous), Bioengineering, Pharmacology, law.invention, Biomaterials, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, law, medicine, Humans, Renal replacement therapy, Fluconazole, Filtration, filtration, alternative to animal testing, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, 030208 emergency & critical care medicine, General Medicine, In vitro, [SDV] Life Sciences [q-bio], adsorption, business, renal replacement therapy, pharmacokinetics, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract

Introduction: Continuous renal replacement therapy (CRRT) efficiently eliminates fluconazole. However, the routes of elimination were not clarified. Adsorption of fluconazole by filters is a pending question. We studied the elimination of fluconazole in a model mimicking a session of CRRT in humans using the NeckEpur® model. Two filters were studied. Methods: The AV1000®-polysulfone filter with the Multifiltrate Pro. Fresenius and the ST150®-polyacrylonitrile filter with the Prismaflex. Baxter-Gambro were studied. Continuous filtration used a flowrate of 2.5 L/h in post-dilution only. Session were made in duplicate. Routes of elimination were assessed using the NeckEpur® model. Results: The mean measured initial fluconazole concentration (mean ± SD) for the four sessions in the central compartment (CC) was 14.9 ± 0.2 mg/L. The amount eliminated from the CC at the end of 6 h-session at a 2.5 L/h filtration flowrate for the AV1000®-polysulfone and the ST150®-polyacrylonitrile filters were 90%–93% and 96%–94%, respectively; the clearances from the central compartment (CC) were 2.5–2.6 and 2.4–2.3 L/h, respectively. The means of the instantaneous sieving coefficient were 0.94%–0.91% and 0.99%–0.91%, respectively. The percentages of the amount eliminated from the CC by filtration/adsorption were 100/0%–95/5% and 100/0%–100/0%, respectively. Conclusion: Neither the ST150®-polyacrylonitrile nor the AV1000®-polysulfone filters result in any significant adsorption of fluconazole.

Published
2021
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29. Wnt-β-Catenin Signaling in Human Dendritic Cells Mediates Regulatory T-Cell Responses to Fungi via the PD-L1 Pathway

Author

Karnam, Anupama, Bonam, Srinivasa Reddy, Rambabu, Naresh, Wong, Sarah Sze Wah, Aimanianda, Vishukumar, Bayry, Jagadeesh, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Indian Institut of Technology [Palakkad] (ITT Palakkad), We acknowledge financial support from Agence Nationale de la Recherche, France (ANR-19-CE17-0021 [BASIN]) and a research fellowship to A.K. from La Fondation pour la Recherche Médicale (no. FDT201805005552)., ANR-19-CE17-0021,BASIN,Cibler la voie IL-3 pour inhiber la fonction basophile en conditions inflammatoires(2019), HAL-SU, Gestionnaire, Cibler la voie IL-3 pour inhiber la fonction basophile en conditions inflammatoires - - BASIN2019 - ANR-19-CE17-0021 - AAPG2019 - VALID, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and École Pratique des Hautes Études (EPHE)

Subjects
CD4-Positive T-Lymphocytes, PD-L1, [SDV]Life Sciences [q-bio], chemical and pharmacologic phenomena, CD8-Positive T-Lymphocytes, Wnt-β-catenin, T-Lymphocytes, Regulatory, Microbiology, DC-SIGN, B7-H1 Antigen, regulatory T cells, Aspergillosis, Humans, dendritic cells, human, Wnt Signaling Pathway, beta Catenin, Tumor Necrosis Factor-alpha, Aspergillus fumigatus, hemic and immune systems, Wnt-b-catenin, Wnt signaling, QR1-502, Interleukin-10, [SDV] Life Sciences [q-bio], dectin-2, dectin-1, Research Article
Abstract

The signaling pathways activated following interaction between dendritic cells (DCs) and a pathogen determine the polarization of effector T-cell and regulatory T-cell (Treg) responses to the infection. Several recent studies, mostly in the context of bacterial infections, have shown that the Wnt/β-catenin pathway plays a major role in imparting tolerogenic features in DCs and in promotion of Treg responses. However, the significance of the Wnt/β-catenin pathway’s involvement in regulating the immune response to the fungal species is not known. Using Aspergillus fumigatus, a ubiquitous airborne opportunistic fungal species, we show here that fungi activate the Wnt/β-catenin pathway in human DCs and are critical for mediating the immunosuppressive Treg responses. Pharmacological inhibition of this pathway in DCs led to inhibition of maturation-associated molecules and interleukin 10 (IL-10) secretion without affecting the majority of the inflammatory cytokines. Furthermore, blockade of Wnt signaling in DCs suppressed DC-mediated Treg responses in CD4+ T cells and downregulated both tumor necrosis factor alpha (TNF-α) and IL-10 responses in CD8+ T cells. Mechanistically, induction of β-catenin pathway by A. fumigatus required C-type lectin receptors and promoted Treg polarization via the induction of programmed death-ligand 1 on DCs. Further investigation on the identity of fungal molecular patterns has revealed that the cell wall polysaccharides β-(1, 3)-glucan and α-(1, 3)-glucan, but not chitin, possess the capacity to activate the β-catenin pathway. Our data suggest that the Wnt/β-catenin pathway is a potential therapeutic target to selectively suppress the Treg response and to sustain the protective Th1 response in the context of invasive aspergillosis caused by A. fumigatus. IMPORTANCE The balance between effector CD4+ T-cell and immunosuppressive regulatory T-cell (Treg) responses determines the outcome of an infectious disease. The signaling pathways that regulate human CD4+ T-effector versus Treg responses to the fungi are not completely understood. By using Aspergillus fumigatus, a ubiquitous opportunistic fungal species, we show that fungi activate the Wnt/β-catenin pathway in human dendritic cells (DCs) that promotes Treg responses via induction of immune checkpoint molecule programmed death ligand 1 on DCs. Blockade of the Wnt/β-catenin pathway in DCs led to the selective inhibition of Treg without affecting the Th1 response. Dissection of the identity of A. fumigatus pathogen-associated molecular patterns (PAMPs) revealed that cell wall polysaccharides exhibit selectivity in their capacity to activate the β-catenin pathway in DCs. Our data thus provide a pointer that Wnt/β-catenin pathway represents potential therapeutic target to selectively suppress Treg responses and to sustain protective a Th1 response against invasive fungal diseases.

Published
2021
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30. Complement-Mediated Differential Immune Response of Human Macrophages to Sporothrix Species Through Interaction With Their Cell Wall Peptidorhamnomannans

Author

Catherine Simenel, Vishukumar Aimanianda, Leila M. Lopes-Bezerra, J. Iñaki Guijarro, Sarah Sze Wah Wong, Neil A. R. Gow, Gabriela W. P. Neves, Janet A. Willment, Carol A. Munro, Gordon D. Brown, Catriona A Walls, State University of Rio de Janeiro, Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Plateforme Technologique de RMN Biologique et HDX-MS - Biological NMR and HDX-MS Technological Platform, University of Aberdeen, University of Exeter, Universidade de São Paulo = University of São Paulo (USP), This work was supported by Fundação de Apoio à Pesquisa do Distrito Federal (FAP-DF)/CNPq, PRONEX grant ID: FAP-DF, 0193.001.200/2016. VA is supported by the Centre Franco-Indien pour la Promotion de la Recherche Avancée (CEFIPRA) grant no. 5403-1 and ANR-DFG AfuINF grant. JG, VA, and CS were supported by the ANR-FUNHYDRO (ANR-16S-CE110020-01) grant. NG, GB, and JW are supported by the Welcome Trust (102705, 097377, 101873, 215599, and 200208) and the Medical Research Council Centre for Medical Mycology (MR/N006364/2)., and ANR-16-CE11-0020,FUNHYDRO,Amyloïdes fonctionnels formés par les hydrophobines du pathogène fongique Aspergillus fumigatus(2016)

Subjects
peptidorhamnomannan (PRM), Antigens, Fungal, Immunology, Macrophage-1 Antigen, Microbiology, Immune system, Phagocytosis, Cell Wall, medicine, Sporothrix brasiliensis, Immunology and Allergy, Sporothrix schenckii, Humans, skin and connective tissue diseases, Complement Activation, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Original Research, Glycoproteins, human macrophages, Innate immune system, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], biology, Sporotrichosis, L-Lactate Dehydrogenase, Macrophages, Sporothrix, Pathogen-Associated Molecular Pattern Molecules, Complement System Proteins, RC581-607, biology.organism_classification, medicine.disease, bacterial infections and mycoses, Complement system, Antibody opsonization, complement receptor-3 (CR3), Integrin alpha M, biology.protein, innate immune response, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, Immunologic diseases. Allergy
Abstract

In this study, the human immune response mechanisms againstSporothrix brasiliensisandSporothrix schenckii, two causative agents of human and animal sporotrichosis, were investigated. The interaction ofS. brasiliensisandS. schenckiiwith human monocyte-derived macrophages (hMDMs) was shown to be dependent on the thermolabile serum complement protein C3, which facilitated the phagocytosis ofSporothrixyeast cells through opsonization. The peptidorhamnomannan (PRM) component of the cell walls of these twoSporothrixyeasts was found to be one of their surfaces exposed pathogen-associated molecular pattern (PAMP), leading to activation of the complement system and deposition of C3b on theSporothrixyeast surfaces. PRM also showed direct interaction with CD11b, the specific component of the complement receptor-3 (CR3). Furthermore, the blockade of CR3 specifically impacted the interleukin (IL)-1β secretion by hMDM in response to bothS. brasiliensisandS. schenckii, suggesting that the host complement system plays an essential role in the inflammatory immune response against theseSporothrixspecies. Nevertheless, the structural differences in the PRMs of the twoSporothrixspecies, as revealed by NMR, were related to the differences observed in the host complement activation pathways. Together, this work reports a new PAMP of the cell surface of pathogenic fungi playing a role through the activation of complement system andviaCR3 receptor mediating an inflammatory response toSporothrixspecies.

Published
2021
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31. COVID-19-Associated Pulmonary Aspergillosis, Fungemia, and Pneumocystosis in the Intensive Care Unit: a Retrospective Multicenter Observational Cohort during the First French Pandemic Wave

Author

Bretagne, Stéphane, Sitbon, Karine, Botterel, Françoise, Dellière, Sarah, Letscher-Bru, Valérie, Chouaki, Taieb, Bellanger, Anne-Pauline, Bonnal, Christine, Fekkar, Arnault, Persat, Florence, Costa, Damien, Bourgeois, Nathalie, Dalle, Frédéric, Lussac-Sorton, Florian, Paugam, André, Cassaing, Sophie, Hasseine, Lilia, Huguenin, Antoine, Guennouni, Nadia, Mazars, Edith, Le Gal, Solène, Sasso, Milène, Brun, Sophie, Cadot, Lucile, Cassagne, Carole, Cateau, Estelle, Gangneux, Jean-Pierre, Moniot, Maxime, Roux, Anne-Laure, Tournus, Céline, Desbois-Nogard, Nicole, Le Coustumier, Alain, Moquet, Olivier, Alanio, Alexandre, Dromer, Françoise, Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Génomique évolutive, modélisation et santé (GEMS), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire de Parasitologie-Mycologie [CHU Saint Louis, Paris], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Mycologie moléculaire - Molecular Mycology, CHU Henri Mondor [Créteil], Laboratoire de Parasitologie et de Mycologie Médicale [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Laboratoire de parasitologie et de mycologie médicales [CHU Amiens], CHU Amiens-Picardie, Service de parasitologie et mycologie [CHRU de Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de parasitologie et mycologie médicale [Hôpital de la Croix Rousse, Lyon], Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), CHU Rouen, Normandie Université (NU), Laboratoire de Parasitologie-Mycologie (CHU de Montpellier), Pôle Biologie-Pathologie [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Laboratoire de parasitologie mycologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Bordeaux [Bordeaux], Hôpital Cochin [AP-HP], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Laboratoire de Parasitologie-Mycologie, Nice, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Reims (CHU Reims), Epidémiosurveillance de protozooses à transmission alimentaire et vectorielle (ESCAPE), Université de Reims Champagne-Ardenne (URCA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Centre hospitalier [Valenciennes, Nord], Laboratoire de Parasitologie et Mycologiede [CHRU Brest], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Hôpital Universitaire Carémeau [Nîmes] (CHU Nîmes), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service de Parasitologie [Avicenne], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Sorbonne Paris Nord, CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Clermont-Ferrand, Hôpital Raymond Poincaré [AP-HP], Hôpital Ambroise Paré [AP-HP], Centre Hospitalier de Saint-Denis [Ile-de-France], Centre Hospitalier Universitaire de Martinique [Fort-de-France, Martinique], Centre Hospitalier de Beauvais, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), The NRCMA is supported by Santé Publique France and Institut Pasteur, Institut Pasteur [Paris], Génomique évolutive, modélisation et santé (CNRS-UMR2000), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), CHU Henri Mondor, Service de parasitologie - mycologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre d'Immunologie et de Maladies Infectieuses (CIMI), CHU Toulouse [Toulouse], Université Nice Sophia Antipolis (... - 2019) (UNS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Service de Parasitologie - Mycologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées (IRBA), Gestionnaire, Hal Sorbonne Université, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Hôpital Henri Mondor, Laboratoire de parasitologie et mycologie médicale [CHU Strasbourg], CHU Strasbourg, Service de Parasitologie Mycologie[Bichat], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]

Subjects
Male, Antifungal Agents, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Mannans, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: COVID-19, aspergillosis, MESH: Treatment Outcome, MESH: Aged, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, MESH: Middle Aged, fungemia, Coinfection, Pneumonia, Pneumocystis, Middle Aged, QR1-502, Intensive Care Units, Treatment Outcome, Aspergillus, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, MESH: Pulmonary Aspergillosis, France, Research Article, MESH: Galactose, Microbiology, pneumocystosis, MESH: Mannans, MESH: Critical Care, MESH: Fungemia, Humans, MESH: SARS-CoV-2, Aged, Retrospective Studies, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, MESH: Humans, SARS-CoV-2, Galactose, COVID-19, MESH: Retrospective Studies, MESH: Antifungal Agents, MESH: Male, MESH: Coinfection, MESH: France, critical care, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, MESH: Intensive Care Units, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Pulmonary Aspergillosis, MESH: Female, MESH: Pneumonia, Pneumocystis
Abstract

International audience; The aim of this study was to evaluate diagnostic means, host factors, delay of occurrence, and outcome of patients with COVID-19 pneumonia and fungal coinfections in the intensive care unit (ICU). From 1 February to 31 May 2020, we anonymously recorded COVID-19-associated pulmonary aspergillosis (CAPA), fungemia (CA-fungemia), and pneumocystosis (CA-PCP) from 36 centers, including results on fungal biomarkers in respiratory specimens and serum. We collected data from 154 episodes of CAPA, 81 of CA-fungemia, 17 of CA-PCP, and 5 of other mold infections from 244 patients (male/female [M/F] ratio = 3.5; mean age, 64.7 ± 10.8 years). CA-PCP occurred first after ICU admission (median, 1 day; interquartile range [IQR], 0 to 3 days), followed by CAPA (9 days; IQR, 5 to 13 days), and then CA-fungemia (16 days; IQR, 12 to 23 days) (P < 10-4). For CAPA, the presence of several mycological criteria was associated with death (P < 10-4). Serum galactomannan was rarely positive (

Published
2021
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32. Pleiotropic Effects of the P5-Type ATPase SpfA on Stress Response Networks Contribute to Virulence in the Pathogenic Mold Aspergillus fumigatus

Author

Ginés Luengo-Gil, Shivani Reddy, David S. Askew, Laura A. Woollett, Vishukumar Aimanianda, Sarah Sze Wah Wong, José P. Guirao-Abad, Nikita Malev, Christina Grisham, Martin Weichert, University of Cincinnati College of Medicine, Instituto Murciano de Investigación Biosanitaria Pascual Parrilla (IMIB), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and This work was supported by National Institutes of Health (NIH) grant R01 AI123158-01A1 to D.S.A. and a University of Cincinnati Department of Pathology and Laboratory Medicine pilot research grant to J.P.G.-A.

Subjects
Male, MESH: Signal Transduction, Protein Folding, ATPase, UPR, sterols, Moths, MESH: Virulence, Endoplasmic Reticulum, medicine.disease_cause, Aspergillus fumigatus, Gene Knockout Techniques, Mice, HacA, MESH: Endoplasmic Reticulum Stress, Protein targeting, lipid metabolism, MESH: Sequence Analysis, RNA, Homeostasis, MESH: Animals, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, MESH: Gene Knockout Techniques, Adenosine Triphosphatases, Virulence, biology, MESH: Moths, Spf1, Endoplasmic Reticulum Stress, QR1-502, Cell biology, MESH: Homeostasis, Larva, Female, MESH: Fungal Proteins, MESH: Aspergillus fumigatus, ER stress, Research Article, Signal Transduction, P5-type ATPases, MESH: Protein Folding, Microbiology, Fungal Proteins, redox balance, MESH: Endoplasmic Reticulum, Virology, SERCA, medicine, MESH: Adenosine Triphosphatases, Animals, SpfA, Secretion, MESH: Mice, Secretory pathway, redox homeostasis, Sequence Analysis, RNA, Endoplasmic reticulum, fungi, biology.organism_classification, MESH: Male, lipid homeostasis, biology.protein, Unfolded protein response, cell wall, MESH: Female, MESH: Larva
Abstract

International audience; Aspergillus fumigatus is a human-pathogenic mold that extracts nutrients from the environment or from host tissues by secreting hydrolytic enzymes. The ability of A. fumigatus to adjust secretion levels in proportion to demand relies on the assistance of the unfolded protein response (UPR), an adaptive stress response pathway that regulates the unique protein-folding environment of the endoplasmic reticulum (ER). The P5-type ATPase Spf1 has recently been implicated in a novel mechanism of ER homeostasis that involves correcting errors in ER-membrane protein targeting. However, the contribution of this protein to the biology of A. fumigatus is unknown. Here, we employed a gene knockout and RNA sequencing strategy to determine the functional role of the A. fumigatus gene coding for the orthologous P5 ATPase SpfA. The data reveal that the spfA gene is induced by ER stress in a UPR-dependent manner. In the absence of spfA, the A. fumigatus transcriptome shifts toward a profile of altered redox and lipid balance, in addition to a signature of ER stress that includes srcA, encoding a second P-type ATPase in the ER. A ΔspfA deletion mutant showed increased sensitivity to ER stress, oxidative stress, and antifungal drugs that target the cell wall or plasma membrane. The combined loss of spfA and srcA exacerbated these phenotypes and attenuated virulence in two animal infection models. These findings demonstrate that the ER-resident ATPases SpfA and SrcA act jointly to support diverse adaptive functions of the ER that are necessary for fitness in the host environment.IMPORTANCE The fungal UPR is an adaptive signaling pathway in the ER that buffers fluctuations in ER stress but also serves as a virulence regulatory hub in species of pathogenic fungi that rely on secretory pathway homeostasis for pathogenicity. This study demonstrates that the gene encoding the ER-localized P5-type ATPase SpfA is a downstream target of the UPR in the pathogenic mold A. fumigatus and that it works together with a second ER-localized P-type ATPase, SrcA, to support ER homeostasis, oxidative stress resistance, susceptibility to antifungal drugs, and virulence of A. fumigatus.

Published
2021
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33. Development of a dosing-adjustment tool for fluoroquinolones in osteoarticular infections: The Fluo-pop study

Author

Florian, Lemaitre, Fabien, Fily, Jean-Baptiste, Foulquier, Matthieu, Revest, Vincent, Jullien, Antoine, Petitcollin, Pierre, Tattevin, Camille, Tron, Jean-Louis, Polard, Marie-Clémence, Verdier, Emmanuelle, Comets, Denis, Huten, Cédric, Arvieux, Eric, Bellissant, Bruno, Laviolle, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Epicentre [Paris] [Médecins Sans Frontières], Hôpital Broussais, ARN régulateurs bactériens et médecine (BRM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université Paris 13 (UP13), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de référence des Infections Ostéo-articulaires du Grand Ouest [Nantes] (CRIOGO - Nantes), Centre hospitalier universitaire de Nantes (CHU Nantes), This work was supported by a local research grant (COmité de la REcherche Clinique et Translationnelle, CORECT, Rennes University Hospital, Rennes, France)., The authors want to thank the COmité de la REcherche Clinique et Translationnelle, CORECT from the Rennes University Hospital for their support., Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Jonchère, Laurent

Subjects
Adult, Male, Ofloxacin, Staphylococcus, Levofloxacin, RM1-950, Models, Biological, Joint infection, Young Adult, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Humans, Pharmacokinetics, Prospective Studies, Aged, Aged, 80 and over, [SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Modeling, Middle Aged, Bone Diseases, Infectious, Anti-Bacterial Agents, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Female, Therapeutics. Pharmacology, Joint Diseases, Monte Carlo Method, Bone infection, Fluoroquinolones
Abstract

International audience; Fluoroquinolones efficacy depend on both the drug exposure and the level of drug resistance of the bacteria responsible for the infection. Specifically for the Staphylococcus species, which is the microorganism mainly involved in osteoarticular infections (OAI), in-vitro data reported that an AUC/MIC ratio above 115 h maximizes drug efficacy. However, data on OAI patients are lacking and a simple approach to access AUCs is still a clinical issue. We conducted a prospective, single-center study in 30 OAI patients hospitalized in the Rennes University Hospital to model ofloxacin pharmacokinetics and to define a limited sampling strategy (LSS) suitable for ofloxacin and levofloxacin treatments. Modeling was conducted with the Monolix software. The final model was externally validated using levofloxacin data. Monte-Carlo simulations were used to evaluate the probability of target attainment (PTA) of different dosing regimens. Two hundred and ninety-seven (297) ofloxacin concentrations were available for the pharmacokinetic modeling. Ofloxacin pharmacokinetics was best described using a bicompartmental model with a first order elimination, and a transit compartment model absorption. CKD-EPI and sex explained half of ofloxacin pharmacokinetic variability. For LSS, the 0, 1 h and 3 h sampling scheme resulted in the best approach both for BID and TID dosages (R(2) adjusted = 91.1% and 95.0%, outliers = 4.8% and 5.0%, respectively). PTA allows choosing the best drug and dosage according to various hypotheses. A simple 3-sample protocol (pre-dose, 1 h after intake and 3 h after intake) to estimate ofloxacin and levofloxacin AUC allows optimal drug dosage for the treatment of osteoarticular infections.

Published
2021
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34. Childhood encephalitis in the Greater Mekong region (the SouthEast Asia Encephalitis Project): a multicentre prospective study

Author

Jean David Pommier, Chris Gorman, Yoann Crabol, Kevin Bleakley, Heng Sothy, Ky Santy, Huong Thi Thu Tran, Lam Van Nguyen, Em Bunnakea, Chaw Su Hlaing, Aye Mya Min Aye, Julien Cappelle, Magali Herrant, Patrice Piola, Bruno Rosset, Veronique Chevalier, Arnaud Tarantola, Mey Channa, Jerome Honnorat, Anne Laure Pinto, Sayaphet Rattanavong, Manivanh Vongsouvath, Mayfong Mayxay, Sommanikhone Phangmanixay, Khounthavy Phongsavath, Ommar Swe Tin, Latt Latt Kyaw, Htay Htay Tin, Kyaw Linn, Thi Mai Hung Tran, Philippe Pérot, Nguyen Thi Thu Thuy, Nguyen Hien, Phuc Huu Phan, Philippe Buchy, Philippe Dussart, Denis Laurent, Marc Eloit, Audrey Dubot-Pérès, Olivier Lortholary, Xavier de Lamballerie, Paul N Newton, Marc Lecuit, Jérôme Honnorat, Tran Thi Mai Hung, Tran Thi Thu Huong, Nguyen Van Lam, Paul Newton, Philippe Perot, Phan Huu Phuc, Anne-Laurie Pinto, Jean-David Pommier, Pham Nhat An, Dang Duc Anh, Pascal Bonnet, Kimrong Bun, Danoy Chommanam, Viengmon Davong, Patrice Debré, Jean-François Delfraissy, Christian Devaux, Anousone Douangnouvong, Veasna Duong, Benoit Durand, Chanreaksmey Eng, Catherine Ferrant, Didier Fontenille, Lukas Hafner, Le Thanh Hai, Do Thu Huong, Marc Jouan, May July, Magali Lago, Jean-Paul Moatti, Bernadette Murgue, Khin Yi Oo, MengHeng Oum, Khansoudaphone Phakhounthong, Anh Tuan Pham, Do Quyen, Malee Seephonelee, Maud Seguy, Bountoy Sibounheunang, Kanarith Sim, Luong Minh Tan, Cho Thair, Win Thein, Phung Bich Thuy, Hervé Tissot-Dupont, Malavanh Vongsouvath, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), Biologie des Infections - Biology of Infection, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Statistique mathématique et apprentissage (CELESTE), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire de Mathématiques d'Orsay (LMO), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Direction Internationale de l'Institut Pasteur, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), SCO/IAC-CIRAD, Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut Agronomique Néo-Calédonien (IAC), Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Découverte de pathogènes – Pathogen discovery, University of Oxford, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Pasteur, Institut Pasteur International Network, Fondation Merieux, Aviesan Sud, INSERM,Wellcome Trust, Institut de Recherche pour le Développement (IRD), and Fondation Total., Authors List Philippe Buchy Em Bunnakea Julien Cappelle Mey Channa Veronique Chevalier Yoann Crabol Xavier de Lamballerie Audrey Dubot-Pérès Philippe Dussart Marc Eloit Chris Gorman Magali Herrant Nguyen Hien Chaw Su Hlaing Jérôme Honnorat Tran Thi Mai Hung Tran Thi Thu Huong Latt Latt Kyaw Nguyen Van Lam Denis Laurent Marc Lecuit Kyaw Linn Olivier Lortholary Mayfong Mayxay Aye Mya Min Aye Paul Newton Philippe Perot Sommanikhone Phangmanixay Khounthavy Phongsavath Phan Huu Phuc Anne-Laurie Pinto Patrice Piola Jean-David Pommier Sayaphet Rattanavong Bruno Rosset Ky Santy Heng Sothy Arnaud Tarantola Nguyen Thi Thu Thuy Htay Htay Tin Ommar Swe Tin Manivanh Vongsouvath Pham Nhat An Dang Duc Anh Pascal Bonnet Kimrong Bun Danoy Chommanam Viengmon Davong Patrice Debré Jean-François Delfraissy Christian Devaux Anousone Douangnouvong Veasna Duong Benoit Durand Chanreaksmey Eng Catherine Ferrant Didier Fontenille Lukas Hafner Le Thanh Hai Do Thu Huong Marc Jouan May July Magali Lago Jean-Paul Moatti Bernadette Murgue Khin Yi Oo MengHeng Oum Khansoudaphone Phakhounthong Anh Tuan Pham Do Quyen Malee Seephonelee Maud Seguy Bountoy Sibounheunang Kanarith Sim Luong Minh Tan Cho Thair Win Thein Phung Bich Thuy Hervé Tissot-Dupont Malavanh Vongsouvath, and Consortium, SEAe

Subjects
Enfant, Male, Fever, agent infectieux, Évolution, Hashimoto Disease, Agent pathogène, Encéphalite, [STAT.ML]Statistics [stat]/Machine Learning [stat.ML], [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Humans, Diagnostic, Prospective Studies, Child, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Enquête, Analyse multivariée, General Medicine, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Survie, Laos, S50 - Santé humaine, Child, Preschool, Collecte de données, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Encephalitis, Female, Hôpital, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Background Encephalitis is a worldwide public health issue, with a substantially high burden among children in southeast Asia. We aimed to determine the causes of encephalitis in children admitted to hospitals across the Greater Mekong region by implementing a comprehensive state-of-the-art diagnostic procedure harmonised across all centres, and identifying clinical characteristics related to patients’ conditions. Methods In this multicentre, observational, prospective study of childhood encephalitis, four referral hospitals in Cambodia, Vietnam, Laos, and Myanmar recruited children (aged 28 days to 16 years) who presented with altered mental status lasting more than 24 h and two of the following minor criteria: fever (within the 72 h before or after presentation), one or more generalised or partial seizures (excluding febrile seizures), a new-onset focal neurological deficit, cerebrospinal fluid (CSF) white blood cell count of 5 per mL or higher, or brain imaging (CT or MRI) suggestive of lesions of encephalitis. Comprehensive diagnostic procedures were harmonised across all centres, with first-line testing was done on samples taken at inclusion and results delivered within 24 h of inclusion for main treatable causes of disease and second-line testing was done thereafter for mostly non-treatable causes. An independent expert medical panel reviewed the charts and attribution of causes of all the included children. Using multivariate analyses, we assessed risk factors associated with unfavourable outcomes (ie, severe neurological sequelae and death) at discharge using data from baseline and day 2 after inclusion. This study is registered with ClinicalTrials.gov, NCT04089436, and is now complete. Findings Between July 28, 2014, and Dec 31, 2017, 664 children with encephalitis were enrolled. Median age was 4·3 years (1·8–8·8), 295 (44%) children were female, and 369 (56%) were male. A confirmed or probable cause of encephalitis was identified in 425 (64%) patients: 216 (33%) of 664 cases were due to Japanese encephalitis virus, 27 (4%) were due to dengue virus, 26 (4%) were due to influenza virus, 24 (4%) were due to herpes simplex virus 1, 18 (3%) were due to Mycobacterium tuberculosis, 17 (3%) were due to Streptococcus pneumoniae, 17 (3%) were due to enterovirus A71, 74 (9%) were due to other pathogens, and six (1%) were due to autoimmune encephalitis. Diagnosis was made within 24 h of admission to hospital for 83 (13%) of 664 children. 119 (18%) children had treatable conditions and 276 (42%) had conditions that could have been preventable by vaccination. At time of discharge, 153 (23%) of 664 children had severe neurological sequelae and 83 (13%) had died. In multivariate analyses, risk factors for unfavourable outcome were diagnosis of M tuberculosis infection upon admission (odds ratio 3·23 [95% CI 1·04–10·03]), coma on day 2 (2·90 [1·78–4·72]), supplementary oxygen requirement (1·89 [1·25–2·86]), and more than 1 week duration between symptom onset and admission to hospital (3·03 [1·68–5·48]). At 1 year after inclusion, of 432 children who were discharged alive from hospital with follow-up data, 24 (5%) had died, 129 (30%) had neurological sequelae, and 279 (65%) had completely recovered. Interpretation In southeast Asia, most causes of childhood encephalitis are either preventable or treatable, with Japanese encephalitis virus being the most common cause. We provide crucial information that could guide public health policy to improve diagnostic, vaccination, and early therapeutic guidelines on childhood encephalitis in the Greater Mekong region. Funding Institut Pasteur, Institut Pasteur International Network, Fondation Merieux, Aviesan Sud, INSERM, Wellcome Trust, Institut de Recherche pour le Développement (IRD), and Fondation Total. Translations For the Khmer, Lao, Vietnamese and Burmese translation of the abstract see Supplementary Materials section.

Published
2021
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35. Aspergillus fumigatus Acetate Utilization Impacts Virulence Traits and Pathogenicity

Author

Vishukumar Aimanianda, Jacob L. Steenwyk, Agostinho Carvalho, Cláudio Duarte-Oliveira, Laure Nicolas Annick Ries, Fernando Rodrigues, Fausto Almeida, Taicia Pacheco Fill, Antonis Rokas, Lilian Pereira Silva, Patrícia Alves de Castro, Iola F. Duarte, Sarah Sze Wah Wong, Jonas Henrique Costa, Gustavo H. Goldman, Clara Valero, Relber Aguiar Gonçales, Raquel Saborano, Gabriela F. Persinoti, Thaila Fernanda dos Reis, Universidade de São Paulo = University of São Paulo (USP), University of Birmingham [Birmingham], Universidade de Aveiro, Centro Nacional de Pesquisa em Energia e Materiais = Brazilian Center for Research in Energy and Materials (CNPEM), Vanderbilt University [Nashville], Universidade Estadual de Campinas = University of Campinas (UNICAMP), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Universidade do Minho = University of Minho [Braga], Life and Health Sciences Research Institute [Braga] (ICVS), University of Minho [Braga], We thank Universidade do Minho, Portugal and Universidade do São Paulo, Brazil for providing support for the scientific collaboration (G.H.G. and A.C., Edital USP-UMinho 2019). We thank the São Paulo Research Foundation (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [FAPESP], Brazil) grants 2017/14159-2 (L.N.A.R.), 2016/12948-7 (P.A.D.C.), 2017/08750-0 (T.F.D.R.), 2016/07870-9 (G.H.G.), 2018/00715-3 (C.V.), and the Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil (CNPq) grants 301058/2019-9 and 404735/2018-5 (G.H.G.) for financial support. I.F.D. acknowledges CICECO-Aveiro Institute of Materials (UIDB/50011/2020 and UIDP/50011/2020) financed by national funds through the Foundation for Science and Technology/MCTES, and the National NMR Network (PTNMR) partially supported by Infrastructure Project 022161 (cofinanced by FEDER through COMPETE 2020, POCI and PORL and FCT through PIDDAC). A.C., R.A.G., and C.D.-O. were supported by the Fundação para a Ciência e a Tecnologia (FCT) (PTDC/MED-GEN/28778/2017, UIDB/50026/2020, and UIDP/50026/2020). Additional support was provided by the Northern Portugal Regional Operational Program (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) (NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023), the European Union’s Horizon 2020 research and innovation program under grant agreement 847507, and the 'la Caixa' Foundation (ID 100010434) and FCT under the agreement LCF/PR/HP17/52190003. Individual support was provided by FCT (SFRH/BD/141127/2018 to C.D.-O., and CEECIND/03628/2017 to A.C.). This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil (CAPES) - Finance Code 001 (J.H.C. scholarship). S.S.W.W. was supported by Pasteur-Roux-Cantarini fellowship. J.L.S. and A.R. are supported by the Howard Hughes Medical Institute through the James H. Gilliam Fellowships for Advanced Study program, A.R. is additionally supported by the National Institutes of Health/National Institute of Allergy and Infectious Diseases (1R56AI146096-01A1)., and European Project: 847507,H2020-SC1-2019-Two-Stage-RTD,HDM-FUN(2020)

Subjects
Male, Neutrophils, Secondary Metabolism, Acetates, Moths, MESH: Neutrophils, MESH: Virulence, Aspergillus fumigatus, Mice, Gene Expression Regulation, Fungal, MESH: Animals, skin and connective tissue diseases, transcription factor, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, 0303 health sciences, Virulence, biology, secondary metabolites, MESH: Moths, QR1-502, MESH: Secondary Metabolism, Phenotype, Larva, acetate assimilation, MESH: Fungal Proteins, MESH: Acetates, MESH: Aspergillus fumigatus, Acetate utilization, MESH: Gene Expression Regulation, Fungal, Research Article, MESH: Phenotype, Microbiology, Fungal Proteins, 03 medical and health sciences, MESH: Mice, Inbred C57BL, Virology, Animals, Aspergillosis, Humans, MESH: Aspergillosis, Transcription factor, MESH: Mice, 030304 developmental biology, Final version, MESH: Humans, 030306 microbiology, biology.organism_classification, Pathogenicity, MESH: Male, Mice, Inbred C57BL, cell wall, MESH: Larva
Abstract

International audience; Aspergillus fumigatus is a major opportunistic fungal pathogen of immunocompromised and immunocompetent hosts. To successfully establish an infection, A. fumigatus needs to use host carbon sources, such as acetate, present in the body fluids and peripheral tissues. However, utilization of acetate as a carbon source by fungi in the context of infection has not been investigated. This work shows that acetate is metabolized via different pathways in A. fumigatus and that acetate utilization is under the regulatory control of a transcription factor (TF), FacB. A. fumigatus acetate utilization is subject to carbon catabolite repression (CCR), although this is only partially dependent on the TF and main regulator of CCR CreA. The available extracellular carbon source, in this case glucose and acetate, significantly affected A. fumigatus virulence traits such as secondary metabolite secretion and cell wall composition, with the latter having consequences for resistance to oxidative stress, antifungal drugs, and human neutrophil-mediated killing. Furthermore, deletion of facB significantly impaired the in vivo virulence of A. fumigatus in both insect and mammalian models of invasive aspergillosis. This is the first report on acetate utilization in A. fumigatus, and this work further highlights the importance of available host-specific carbon sources in shaping fungal virulence traits and subsequent disease outcome, and a potential target for the development of antifungal strategies.IMPORTANCE Aspergillus fumigatus is an opportunistic fungal pathogen in humans. During infection, A. fumigatus is predicted to use host carbon sources, such as acetate, present in body fluids and peripheral tissues, to sustain growth and promote colonization and invasion. This work shows that A. fumigatus metabolizes acetate via different pathways, a process that is dependent on the transcription factor FacB. Furthermore, the type and concentration of the extracellular available carbon source were determined to shape A. fumigatus virulence determinants such as secondary metabolite secretion and cell wall composition. Subsequently, interactions with immune cells are altered in a carbon source-specific manner. FacB is required for A. fumigatus in vivo virulence in both insect and mammalian models of invasive aspergillosis. This is the first report that characterizes acetate utilization in A. fumigatus and highlights the importance of available host-specific carbon sources in shaping virulence traits and potentially subsequent disease outcome.

Published
2021
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36. Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths

Author

Bastard, Paul, Gervais, Adrian, Le Voyer, Tom, Rosain, Jérémie, Philippot, Quentin, Manry, Jérémy, Michailidis, Eleftherios, Hoffmann, Hans-Heinrich, Eto, Shohei, Garcia-Prat, Marina, Bizien, Lucy, Parra-Martínez, Alba, Yang, Rui, Haljasmägi, Liis, Migaud, Mélanie, Särekannu, Karita, Maslovskaja, Julia, de Prost, Nicolas, Tandjaoui-Lambiotte, Yacine, Luyt, Charles-Edouard, Amador-Borrero, Blanca, Gaudet, Alexandre, Poissy, Julien, Morel, Pascal, Richard, Pascale, Cognasse, Fabrice, Troya, Jesus, Trouillet-Assant, Sophie, Belot, Alexandre, Saker, Kahina, Garçon, Pierre, Rivière, Jacques G., Lagier, Jean-Christophe, Gentile, Stéphanie, Rosen, Lindsey B., Shaw, Elana, Morio, Tomohiro, Tanaka, Junko, Dalmau, David, Tharaux, Pierre-Louis, Sene, Damien, Stepanian, Alain, Megarbane, Bruno, Triantafyllia, Vasiliki, Fekkar, Arnaud, Heath, James R., Franco, José Luis, Anaya, Juan-Manuel, Solé-Violán, Jordi, Imberti, Luisa, Biondi, Andrea, Bonfanti, Paolo, Castagnoli, Riccardo, Delmonte, Ottavia M., Zhang, Yu, Snow, Andrew L., Holland, Steven M., Biggs, Catherine M., Moncada-Vélez, Marcela, Arias, Andrés Augusto, Lorenzo, Lazaro, Boucherit, Soraya, Coulibaly, Boubacar, Anglicheau, Dany, Planas, Anna M., Haerynck, Filomeen, Duvlis, Sotirija, Nussbaum, Robert L., Ozcelik, Tayfun, Keles, Sevgi, Bousfiha, Ahmed A., El Bakkouri, Jalila, Ramirez-Santana, Carolina, Paul, Stéphane, Pan-Hammarström, Qiang, Hammarström, Lennart, Dupont, Annabelle, Kurolap, Alina, Metz, Christine N., Aiuti, Alessandro, Casari, Giorgio, Lampasona, Vito, Ciceri, Fabio, Barreiros, Lucila A., Dominguez-Garrido, Elena, Vidigal, Mateus, Zatz, Mayana, van de Beek, Diederik, Sahanic, Sabina, Tancevski, Ivan, Stepanovskyy, Yurii, Boyarchuk, Oksana, Nukui, Yoko, Tsumura, Miyuki, Vidaur, Loreto, Tangye, Stuart G., Burrel, Sonia, Duffy, Darragh, Quintana-Murci, Lluis, Klocperk, Adam, Kann, Nelli Y., Shcherbina, Anna, Lau, Yu-Lung, Leung, Daniel, Coulongeat, Matthieu, Marlet, Julien, Koning, Rutger, Reyes, Luis Felipe, Chauvineau-Grenier, Angélique, Venet, Fabienne, Monneret, Guillaume, Nussenzweig, Michel C., Arrestier, Romain, Boudhabhay, Idris, Baris-Feldman, Hagit, Hagin, David, Wauters, Joost, Meyts, Isabelle, Dyer, Adam H., Kennelly, Sean P., Bourke, Nollaig M., Halwani, Rabih, Sharif-Askari, Narjes Saheb, Dorgham, Karim, Sallette, Jérome, Mehlal Sedkaoui, Souad, AlKhater, Suzan, Rigo-Bonnin, Raúl, Morandeira, Francisco, Roussel, Lucie, Vinh, Donald C., Ostrowski, Sisse Rye, Condino-Neto, Antonio, Prando, Carolina, Bondarenko, Anastasiia, Spaan, András N., Gilardin, Laurent, Fellay, Jacques, Lyonnet, Stanislas, Bilguvar, Kaya, Lifton, Richard P., Mane, Shrikant, Anderson, Mark S., Boisson, Bertrand, Béziat, Vivien, Zhang, Shen-Ying, Andreakos, Evangelos, Hermine, Olivier, Pujol, Aurora, Peterson, Pärt, Mogensen, Trine H., Rowen, Lee, Mond, James, Debette, Stéphanie, de Lamballerie, Xavier, Duval, Xavier, Mentré, France, Zins, Marie, Soler-Palacin, Pere, Colobran, Roger, Gorochov, Guy, Solanich, Xavier, Susen, Sophie, Martinez-Picado, Javier, Raoult, Didier, Vasse, Marc, Gregersen, Peter K., Piemonti, Lorenzo, Rodríguez-Gallego, Carlos, Notarangelo, Luigi D., Su, Helen C., Kisand, Kai, Okada, Satoshi, Puel, Anne, Jouanguy, Emmanuelle, Rice, Charles M., Tiberghien, Pierre, Zhang, Qian, Cobat, Aurélie, Abel, Laurent, Casanova, Jean-Laurent, Bigio, Benedetta, de la Chapelle, Aliénor, Chen, Jie, Chrabieh, Maya, Liu, Dana, Nemirowskaya, Yelena, Cruz, Inés Marín, Materna, Marie, Pelet, Sophie, Seeleuthner, Yoann, Thibault, Chloé, Liu, Zhiyong, Abad, Jorge, Accordino, Giulia, Achille, Cristian, Aguilera-Albesa, Sergio, Aguiló-Cucurull, Aina, Özkan, Esra Akyüz, Darazam, Ilad Alavi, Roblero Albisures, Jonathan Antonio, Aldave, Juan C, Ramos, Miquel Alfonso, Khan, Taj Ali, Aliberti, Anna, Nadji, Seyed Alireza, Alkan, Gulsum, Alkhater, Suzan A., Allardet-Servent, Jerome, Allende, Luis M, Alonso-Arias, Rebeca, Alshahrani, Mohammed S, Alsina, Laia, Alyanakian, Marie-Alexandra, Borrero, Blanca Amador, Amoura, Zahir, Antolí, Arnau, Aubart, Mélodie, Auguet, Teresa, Avramenko, Iryna, Aytekin, Gökhan, Azot, Axelle, Bahram, Seiamak, Bajolle, Fanny, Baldanti, Fausto, Baldolli, Aurélie, Ballester, Maite, Feldman, Hagit Baris, Barrou, Benoit, Barzagh, Federica, Basso, Sabrina, Bayhan, Gulsum Iclal, Bezrodnik, Liliana, Bilbao, Agurtzane, Blanchard-Rohner, Geraldine, Blanco, Ignacio, Blandinières, Adeline, Blázquez-Gamero, Daniel, Bleibtreu, Alexandre, Bloomfield, Marketa, Bolivar-Prados, Mireia, Borghesi, Alessandro, Borie, Raphael, Botdhlo-Nevers, Elisabeth, Bousfiha, Ahmed A, Bousquet, Aurore, Boutolleau, David, Bouvattier, Claire, Bravais, Juliette, Briones, M. Luisa, Brunner, Marie-Eve, Bruno, Raffaele, Bueno, Maria Rita P, Bukhari, Huda, Bustamante, Jacinta, Cáceres Agra, Juan José, Capra, Ruggero, Carapito, Raphael, Carrabba, Maria, Casasnovas, Carlos, Caseris, Marion, Cassaniti, Irene, Castelle, Martin, Castelli, Francesco, de Vera, Martín Castillo, Castro, Mateus V, Catherinot, Emilie, Celik, Jale Bengi, Ceschi, Alessandro, Chalumeau, Martin, Charbit, Bruno, Cheng, Matthew P., Clavé, Père, Clotet, Bonaventura, Codina, Anna, Cohen, Yves, Comarmond, Cloé, Combes, Alain, Comoli, Patrizia, Corsico, Angelo G, Coşkuner, Taner, Cvetkovski, Aleksandar, Cyrus, Cyril, Danion, François, Darley, David Ross, Das, Vincent, Dauby, Nicolas, Dauger, Stéphane, De Munter, Paul, de Pontual, Loic, Dehban, Amin, Delplancq, Geoffroy, Demoule, Alexandre, Desguerre, Isabelle, Di Sabatino, Antonio, Diehl, Jean-Luc, Dobbelaere, Stephanie, Domínguez-Garrido, Elena, Dubost, Clément, Ekwall, Olov, Bozdemir, Şefika Elmas, Elnagdy, Marwa H, Emiroglu, Melike, Endo, Akifumi, Erdeniz, Emine Hafize, Aytekin, Selma Erol, Lasa, Maria Pilar Etxart, Euvrard, Romain, Fabio, Giovanna, Faivre, Laurence, Falck, Antonin, Fartoukh, Muriel, Faure, Morgane, Arquero, Miguel Fernandez, Ferrer, Ricard, Ferreres, Jose, Flores, Carlos, Francois, Bruno, Fumadó, Victoria, Fung, Kitty S C, Fusco, Francesca, Gagro, Alenka, Solis, Blanca Garcia, Gaussem, Pascale, Gayretli, Zeynep, Gil-Herrera, Juana, Gatineau, Audrey Giraud, Girona-Alarcón, Mònica, Cifuentes Godínez, Karen Alejandra, Goffard, Jean-Christophe, Gonzales, Nacho, Gonzalez-Granado, Luis I, González-Montelongo, Rafaela, Guerder, Antoine, Gülhan, Belgin, Gumucio, Victor Daniel, Hanitsch, Leif Gunnar, Gunst, Jan, Gut, Marta, Hadjadj, Jérôme, Hancerli, Selda, Hariyan, Tetyana, Hatipoglu, Nevin, Heppekcan, Deniz, Hernandez-Brito, Elisa, Ho, Po-ki, Holanda-Peña, María Soledad, Horcajada, Juan P, Hraiech, Sami, Humbert, Linda, Hung, Ivan F N, Iglesias, Alejandro D., Íñigo-Campos, Antonio, Jamme, Matthieu, Arranz, María Jesús, Jimeno, Marie-Thérèse, Jordan, Iolanda, Yüksek, Saliha Kanık, Kara, Yalcin Burak, Karahan, Aydın, Karbuz, Adem, Yasar, Kadriye Kart, Kasapcopur, Ozgur, Kashimada, Kenichi, Demirkol, Yasemin Kendir, Kido, Yasutoshi, Kizil, Can, Kılıç, Ahmet Osman, Koutsoukou, Antonia, Król, Zbigniew J., Ksouri, Hatem, Kuentz, Paul, Kwan, Arthur M C, Kwan, Yat Wah M, Kwok, Janette S Y, Lam, David S Y, Lampropoulou, Vicky, Lanternier, Fanny, Le Bourgeois, Fleur, Leo, Yee-Sin, Lopez, Rafael Leon, Levin, Michael, Levy, Michael, Lévy, Romain, Li, Zhi, Lilleri, Daniele, Lima, Edson Jose Adrian Bolanos, Linglart, Agnes, López-Collazo, Eduardo, Lorenzo-Salazar, José M., Louapre, Céline, Lubetzki, Catherine, Lung, Kwok-Cheung, Lye, David C, Magnone, Cinthia, Mansouri, Davood, Marchioni, Enrico, Marioli, Carola, Marjani, Majid, Marques, Laura, Pereira, Jesus Marquez, Martín-Nalda, Andrea, Pueyo, David Martínez, Marzana, Iciar, Mata-Martínez, Carmen, Mathian, Alexis, Matos, Larissa RB, Matthews, Gail V, Mayaux, Julien, McLaughlin-Garcia, Raquel, Meersseman, Philippe, Mège, Jean-Louis, Mekontso-Dessap, Armand, Melki, Isabelle, Meloni, Federica, Meritet, Jean-François, Merlani, Paolo, Akcan, Özge Metin, Mezidi, Mehdi, Migeotte, Isabelle, Millereux, Maude, Million, Matthieu, Mirault, Tristan, Mircher, Clotilde, Mirsaeidi, Mehdi, Mizoguchi, Yoko, Modi, Bhavi P, Mojoli, Francesco, Moncomble, Elsa, Melián, Abián Montesdeoca, Martinez, Antonio Morales, Morange, Pierre-Emmanuel, Mordacq, Clémence, Morelle, Guillaume, Mouly, Stéphane J, Muñoz-Barrera, Adrián, Nafati, Cyril, Nagashima, Shintaro, Nakagama, Yu, Neven, Bénédicte, Neves, João Farela, Ng, Lisa FP, Ng, Yuk-Yung, Nielly, Hubert, Medina, Yeray Novoa, Cuadros, Esmeralda Nuñez, Ocejo-Vinyals, J. 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Alessandra, Tüter Öz, Şadiye Kübra, Ursini, Matilde Valeria, Utsumi, Takanori, Uzunhan, Yurdagul, Vabres, Pierre, Valencia-Ramos, Juan, Van Den Rym, Ana Maria, Vandernoot, Isabelle, Velez-Santamaria, Valentina, Zuniga Veliz, Silvia Patricia, Vidigal, Mateus C, Viel, Sébastien, Vilain, Cédric, Vilaire-Meunier, Marie E, Villar-García, Judit, Vincent, Audrey, Vogt, Guillaume, Voiriot, Guillaume, Volokha, Alla, Vuotto, Fanny, Wauters, Els, Wu, Alan K L, Wu, Tak-Chiu, Yahşi, Aysun, Yesilbas, Osman, Yildiz, Mehmet, Young, Barnaby E, Yükselmiş, Ufuk, Zecca, Marco, Zuccaro, Valentina, Jens, Van Praet, Lambrecht, Bart N., Eva, Van Braeckel, Cédric, Bosteels, Levi, Hoste, Eric, Hoste, Bauters, Fré, De Clercq, Jozefien, Cathérine, Heijmans, Hans, Slabbynck, Leslie, Naesens, Florkin, Benoit, Boulanger, Cécile, Vanderlinden, Dimitri, Foti, Giuseppe, Bellani, Giacomo, Citerio, Giuseppe, Contro, Ernesto, Pesci, Alberto, Valsecchi, Maria Grazia, Cazzaniga, Marina, Danielson, Jeffrey J., Dobbs, Kerry, 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Michèle, Wouters, Dorien, Zwinderman, A. H (Koos, Brouwer, Matthijs C., Wiersinga, W. Joost, Vlaar, Alexander P.J., Al-Muhsen, Saleh, Al-Mulla, Fahd, Arias, Andrés A., Bogunovic, Dusan, Bolze, Alexandre, Bryceson, Yenan, Bustamante, Carlos D., Butte, Manish J., Chakravorty, Samya, Christodoulou, John, Constantinescu, Stefan N., Cooper, Megan A., Desai, Murkesh, Drolet, Beth A., El Baghdadi, Jamila, Espinosa-Padilla, Sara, Froidure, Antoine, Henrickson, Sarah E., Hsieh, Elena W.Y., Husebye, Eystein S., Imai, Kohsuke, Itan, Yuval, Jarvis, Erich D., Karamitros, Timokratis, Ku, Cheng-Lung, Ling, Yun, Lucas, Carrie L., Maniatis, Tom, Maródi, László, Milner, Joshua D., Mironska, Kristina, Ng, Lisa F.P., Novelli, Antonio, Novelli, Giuseppe, de Diego, Rebeca Perez, Renia, Laurent, Resnick, Igor, Sancho-Shimizu, Vanessa, Seppänen, Mikko R.J., Shahrooei, Mohammed, Slaby, Ondrej, Abou Tayoun, Ahmad, Ramaswamy, Sathishkumar, Turvey, Stuart E, Uddin, K M Furkan, Uddin, Mohammed J., von Bernuth, Horst, Zawadzki, Pawel, Nadif, Rachel, Goldberg, Marcel, Ozguler, Anna, Henny, Joseph, Lemonnier, Sylvie, Coeuret-Pellicer, Mireille, Le Got, Stéphane, Tzourio, Christophe, Dufouil, Carole, Soumaré, Aïcha, Lachaize, Morgane, Fievet, Nathalie, Flaig, Amandine, Martin, Fernando, Bonneaudeau, Brigitte, Cannet, Dorothée, Gallian, Pierre, Jeanne, Michel, Perroquin, Magali, Hamzeh-Cognasse, Hind, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Groupe de recherche clinique CARMAS (Cardiovascular and Respiratory Manifestations of Acute lung injury and Sepsis) (CARMAS), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-CHU Henri Mondor [Créteil], Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Hôpital Lariboisière-Fernand-Widal [APHP], Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Hôpital Roger Salengro [Lille], Etablissement Français du Sang [La Plaine Saint-Denis] (EFS), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Santé Ingénierie Biologie Saint-Etienne (SAINBIOSE), Centre Ingénierie et Santé (CIS-ENSMSE), École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Hospices Civils de Lyon (HCL), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Grand Hôpital de l'Est Francilien (GHEF), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut Hospitalier Universitaire Méditerranée Infection (IHU Marseille), Assistance Publique - Hôpitaux de Marseille (APHM), Centre d'études et de recherche sur les services de santé et la qualité de vie (CEReSS), Aix Marseille Université (AMU), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Recherche clinique appliquée à l'hématologie ((EA_3518)), Université Paris Diderot - Paris 7 (UPD7), Service de Réanimation Médicale et Toxicologique [Hôpital Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre d'Investigation Clinique - Epidémiologie Clinique Saint-Etienne (CIC-EC), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires - U1011 (RNMCD), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Collège de France - Chaire Génomique humaine et évolution, Collège de France (CdF (institution)), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Robert Ballanger [Aulnay-sous-Bois], Hôpital Edouard Herriot [CHU - HCL], Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques / Pathophysiology of Injury-induced Immunosuppression (PI3), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hôpital Jean Verdier [AP-HP], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'investigation Clinique [CHU Bichat] - Épidémiologie clinique (CIC 1425), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Cohortes épidémiologiques en population (CONSTANCES), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Modeling & analysis for medical imaging and Diagnosis (MYRIAD), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, CHU Amiens-Picardie, French COVID cohort study group, Howard Hughes Medical Institute, Rockefeller University, European Commission, Jeffrey Modell Foundation, Université de Bordeaux, Meath Foundation, National Human Genome Research Institute, Agence Nationale de la Recherche, Fondation pour la Recherche Médicale, Fondation du Souffle, Instituto de Salud Carlos III, Institut National de la Santé et de la Recherche Médicale, St. Giles Foundation, Ministère des Solidarités et de la Santé, Sorbonne Université, Mutuelle Générale de l'Education Nationale, Conseil Régional Aquitaine, Conseil régional de Bourgogne-Franche-Comté, Meyer Foundation, Fondation de France, National Cancer Institute, European Regional Development Fund, Fundación DISA, Ministero della Salute, ANR-20-COVI-0003,GENCOVID,Identification des défauts monogéniques de l'immunité responsables des formes sévères de COVID-19 chez les patients précédemment en bonne santé(2020), ANR-20-CE93-0003,GENVIR,Analyse multi-omique de l'immunité anti-virale: de l'identification des circuits biologiques pertinents à la découverte de défauts monogéniques héréditaires de l'immunité chez les patients avec infections virales sévères(2020), ANR-20-CO11-0001,AABIFNCOV,Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19.(2020), European Project: IdEx Bordeaux (ANR-10-IDEX- 003-02), Bastard, Paul, Gervais, Adrian, Le Voyer, Tom, Rosain, Jérémie, Philippot, Quentin, Manry, Jérémy, Michailidis, Eleftherio, Hoffmann, Hans-Heinrich, Eto, Shohei, Garcia-Prat, Marina, Bizien, Lucy, Parra-Martínez, Alba, Yang, Rui, Haljasmägi, Lii, Migaud, Mélanie, Särekannu, Karita, Maslovskaja, Julia, de Prost, Nicola, Tandjaoui-Lambiotte, Yacine, Luyt, Charles-Edouard, Amador-Borrero, Blanca, Gaudet, Alexandre, Poissy, Julien, Morel, Pascal, Richard, Pascale, Cognasse, Fabrice, Troya, Jesu, Trouillet-Assant, Sophie, Belot, Alexandre, Saker, Kahina, Garçon, Pierre, Rivière, Jacques G, Lagier, Jean-Christophe, Gentile, Stéphanie, Rosen, Lindsey B, Shaw, Elana, Morio, Tomohiro, Tanaka, Junko, Dalmau, David, Tharaux, Pierre-Loui, Sene, Damien, Stepanian, Alain, Megarbane, Bruno, Triantafyllia, Vasiliki, Fekkar, Arnaud, Heath, James R, Franco, José Lui, Anaya, Juan-Manuel, Solé-Violán, Jordi, Imberti, Luisa, Biondi, Andrea, Bonfanti, Paolo, Castagnoli, Riccardo, Delmonte, Ottavia M, Zhang, Yu, Snow, Andrew L, Holland, Steven M, Biggs, Catherine, Moncada-Vélez, Marcela, Arias, Andrés Augusto, Lorenzo, Lazaro, Boucherit, Soraya, Coulibaly, Boubacar, Anglicheau, Dany, Planas, Anna M, Haerynck, Filomeen, Duvlis, Sotirija, Nussbaum, Robert L, Ozcelik, Tayfun, Keles, Sevgi, Bousfiha, Ahmed A, El Bakkouri, Jalila, Ramirez-Santana, Carolina, Paul, Stéphane, Pan-Hammarström, Qiang, Hammarström, Lennart, Dupont, Annabelle, Kurolap, Alina, Metz, Christine N, Aiuti, Alessandro, Casari, Giorgio, Lampasona, Vito, Ciceri, Fabio, Barreiros, Lucila A, Dominguez-Garrido, Elena, Vidigal, Mateu, Zatz, Mayana, van de Beek, Diederik, Sahanic, Sabina, Tancevski, Ivan, Stepanovskyy, Yurii, Boyarchuk, Oksana, Nukui, Yoko, Tsumura, Miyuki, Vidaur, Loreto, Tangye, Stuart G, Burrel, Sonia, Duffy, Darragh, Quintana-Murci, Llui, Klocperk, Adam, Kann, Nelli Y, Shcherbina, Anna, Lau, Yu-Lung, Leung, Daniel, Coulongeat, Matthieu, Marlet, Julien, Koning, Rutger, Reyes, Luis Felipe, Chauvineau-Grenier, Angélique, Venet, Fabienne, Monneret, Guillaume, Nussenzweig, Michel C, Arrestier, Romain, Boudhabhay, Idri, Baris-Feldman, Hagit, Hagin, David, Wauters, Joost, Meyts, Isabelle, Dyer, Adam H, Kennelly, Sean P, Bourke, Nollaig M, Halwani, Rabih, Sharif-Askari, Narjes Saheb, Dorgham, Karim, Sallette, Jérome, Sedkaoui, Souad Mehlal, Alkhater, Suzan, Rigo-Bonnin, Raúl, Morandeira, Francisco, Roussel, Lucie, Vinh, Donald C, Ostrowski, Sisse Rye, Condino-Neto, Antonio, Prando, Carolina, Bonradenko, Anastasiia, Spaan, András N, Gilardin, Laurent, Fellay, Jacque, Lyonnet, Stanisla, Bilguvar, Kaya, Lifton, Richard P, Mane, Shrikant, Anderson, Mark S, Boisson, Bertrand, Béziat, Vivien, Zhang, Shen-Ying, Vandreakos, Evangelo, Hermine, Olivier, Pujol, Aurora, Peterson, Pärt, Mogensen, Trine H, Rowen, Lee, Mond, Jame, Debette, Stéphanie, de Lamballerie, Xavier, Duval, Xavier, Mentré, France, Zins, Marie, Soler-Palacin, Pere, Colobran, Roger, Gorochov, Guy, Solanich, Xavier, Susen, Sophie, Martinez-Picado, Javier, Raoult, Didier, Vasse, Marc, Gregersen, Peter K, Piemonti, Lorenzo, Rodríguez-Gallego, Carlo, Notarangelo, Luigi D, Su, Helen C, Kisand, Kai, Okada, Satoshi, Puel, Anne, Jouanguy, Emmanuelle, Rice, Charles M, Tiberghien, Pierre, Zhang, Qian, Cobat, Aurélie, Abel, Laurent, Casanova, Jean-Laurent, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], CHU Necker - Enfants Malades [AP-HP], Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hiroshima University, Vall d’Hebron Research Institute (VHIR), University of Tartu, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Henri Mondor [Créteil], Service de Réanimation Médicale [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Mycologie moléculaire - Molecular Mycology, Members of the The Milieu Intérieur Consortium: Laurent Abel1 , Andres Alcover2 , Hugues Aschard2 , Philippe Bousso2 , Nollaig Bourke3 , Petter Brodin4 , Pierre Bruhns2 , Nadine Cerf-Bensussan5 , Ana Cumano2 , Christophe D’Enfert2 , Ludovic Deriano2 , Marie-Agnès Dillies2 , James Di Santo2 , Françoise Dromer2 , Gérard Eberl2 , Jost Enninga2 , Jacques Fellay6 , Ivo Gomperts-Boneca2 , Milena Hasan2 , Gunilla Karlsson Hedestam4 , Serge Hercberg7 , Molly A. Ingersoll2 , Olivier Lantz8 , Rose Anne Kenny3 , Mickaël Ménager5 , Frédérique Michel2 , Hugo Mouquet2 , Cliona O’Farrelly3 , Etienne Patin2 , Sandra Pellegrini2 , Antonio Rausell5 , Frédéric Rieux-Laucat5 , Lars Rogge2 , Magnus Fontes9 , Anavaj Sakuntabhai2 , Olivier Schwartz2 , Benno Schwikowski2 , Spencer Shorte2 , Frédéric Tangy2 , Antoine Toubert10 , Mathilde Touvier12 , Marie-Noëlle Ungeheuer2 , Christophe Zimmer2 , Matthew L. Albert11 , Darragh Duffy2 , Lluis Quintana-Murc, ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 824110,H2020-INFRAIA-2018-1,EASI-Genomics(2019), European Project: 948959,ERC-2020-STG,MORE2ADA2(2021), National Institutes of Health (US), National Center for Advancing Translational Sciences (US), George Mason University, National Human Genome Research Institute (US), Agence Nationale de la Recherche (France), Institut National de la Santé et de la Recherche Médicale (France), Université de Paris, Ministère des Solidarités et de la Santé (France), National Health and Medical Research Council (Australia), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Cabildo de Tenerife, Fondation Bettencourt Schueller, Estonian Research Council, Michailidis, Eleftherios, García-Prat, Marina, Paul, Stephanie, Metz, Christine N., Barreiros, Lucila, Domínguez-Garrido, Elena, Vidigal, Mateus, Beek, Diederik van der, Stepanovskyy, Yuriy, Tangye, Stuart G., Quintana-Murci, Lluis, Kan, Nelli, Nussenzweig, Michel C., Baris, Hagit N., Dyer, Adam, Bourke, Nollaig, Vinh, Donald C., Spaan, András N., Fellay, Jacques, Mane, Shrikant M., Anderson, MarK S., Andreakos, Evangelos, Haljasmägi, Liis, Mogensen, Trine, Lamballerie, Xavier de, Soler-Palacín, Pere, Martínez-Picado, Javier, Gregersen, Peter K., Rodríguez-Gallego, Carlos, Notarangelo, Luigi D., Su, Helen C., Prost, Nicolas de, Amador-Borrero, Blanco, Troya, Jesús, Rivière, Jacques G., Gentile, Stephanie, Rosen, Lindsey B., Tharaux, Pierre-Louis, Stépanian, Alain, Mégarbane, Bruno, Heath, James R., Franco, José Luis, Anaya, Juan Manuel, Snow, Andrew L., Holland, Steven M., Biggs, Catherine M., Moncada-Velez, Marcela, Planas, Anna M., Nussbaum, Robert, Bousfiha, Ahmed Aziz, Ramírez-Santana, Carolina, Intensive care medicine, Internal medicine, AII - Infectious diseases, Pulmonary medicine, ACS - Pulmonary hypertension & thrombosis, Pathology, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Amsterdam Neuroscience - Complex Trait Genetics, ACS - Diabetes & metabolism, Amsterdam Cardiovascular Sciences, Radiology and nuclear medicine, AMS - Rehabilitation & Development, VU University medical center, Laboratory Medicine, Amsterdam Neuroscience - Neurodegeneration, Amsterdam Neuroscience - Neuroinfection & -inflammation, Anesthesiology, APH - Quality of Care, ACS - Heart failure & arrhythmias, Özçelik, Tayfun, Children's Hospital, HUS Children and Adolescents, Clinicum, Department of Medicine, Infektiosairauksien yksikkö, HUS Inflammation Center, Admin, Oskar, Identification des défauts monogéniques de l'immunité responsables des formes sévères de COVID-19 chez les patients précédemment en bonne santé - - GENCOVID2020 - ANR-20-COVI-0003 - COVID-19 - VALID, Analyse multi-omique de l'immunité anti-virale: de l'identification des circuits biologiques pertinents à la découverte de défauts monogéniques héréditaires de l'immunité chez les patients avec infections virales sévères - - GENVIR2020 - ANR-20-CE93-0003 - AAPG2020 - VALID, Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19. - - AABIFNCOV2020 - ANR-20-CO11-0001 - COVID-19 - VALID, Program Initiative d’Excellence - IdEx Bordeaux (ANR-10-IDEX- 003-02) - INCOMING, CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Henri Mondor, Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), INSERM U1059, SAINBIOSE - Santé, Ingénierie, Biologie, Saint-Etienne (SAINBIOSE-ENSMSE), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Parasitologie - Mycologie [CHU Pitié-Salpétrière], CIC Saint Etienne, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Nord (Saint Etienne), Récepteurs Nucléaires, Maladies Métaboliques et Cardiovasculaires (RNMCD - U1011), Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques - EA 7426 (PI3), École pratique des hautes études (EPHE), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Neurology, ANS - Neuroinfection & -inflammation, Graduate School, Infectious diseases, Center of Experimental and Molecular Medicine, APH - Aging & Later Life, APH - Global Health, AII - Amsterdam institute for Infection and Immunity, APH - Health Behaviors & Chronic Diseases, Global Health, APH - Methodology, APH - Digital Health, APH - Personalized Medicine, ACS - Microcirculation, Bastard, P, Gervais, A, Le Voyer, T, Rosain, J, Philippot, Q, Manry, J, Michailidis, E, Hoffmann, H, Eto, S, Garcia-Prat, M, Bizien, L, Parra-Martínez, A, Yang, R, Haljasmägi, L, Migaud, M, Särekannu, K, Maslovskaja, J, de Prost, N, Tandjaoui-Lambiotte, Y, Luyt, C, Amador-Borrero, B, Gaudet, A, Poissy, J, Morel, P, Richard, P, Cognasse, F, Troya, J, Trouillet-Assant, S, Belot, A, Saker, K, Garçon, P, Rivière, J, Lagier, J, Gentile, S, Rosen, L, Shaw, E, Morio, T, Tanaka, J, Dalmau, D, Tharaux, P, Sene, D, Stepanian, A, Megarbane, B, Triantafyllia, V, Fekkar, A, Heath, J, Franco, J, Anaya, J, Solé-Violán, J, Imberti, L, Biondi, A, Bonfanti, P, Castagnoli, R, Delmonte, O, Zhang, Y, Snow, A, Holland, S, Biggs, C, Moncada-Vélez, M, Arias, A, Lorenzo, L, Boucherit, S, Coulibaly, B, Anglicheau, D, Planas, A, Haerynck, F, Duvlis, S, Nussbaum, R, Ozcelik, T, Keles, S, Bousfiha, A, El Bakkouri, J, Ramirez-Santana, C, Paul, S, Pan-Hammarström, Q, Hammarström, L, Dupont, A, Kurolap, A, Metz, C, Aiuti, A, Casari, G, Lampasona, V, Ciceri, F, Barreiros, L, Dominguez-Garrido, E, Vidigal, M, Zatz, M, van de Beek, D, Sahanic, S, Tancevski, I, Stepanovskyy, Y, Boyarchuk, O, Nukui, Y, Tsumura, M, Vidaur, L, Tangye, S, Burrel, S, Duffy, D, Quintana-Murci, L, Klocperk, A, Kann, N, Shcherbina, A, Lau, Y, Leung, D, Coulongeat, M, Marlet, J, Koning, R, Reyes, L, Chauvineau-Grenier, A, Venet, F, Monneret, G, Nussenzweig, M, Arrestier, R, Boudhabhay, I, Baris-Feldman, H, Hagin, D, Wauters, J, Meyts, I, Dyer, A, Kennelly, S, Bourke, N, Halwani, R, Sharif-Askari, N, Dorgham, K, Sallette, J, Sedkaoui, S, Alkhater, S, Rigo-Bonnin, R, Morandeira, F, Roussel, L, Vinh, D, Ostrowski, S, Condino-Neto, A, Prando, C, Bonradenko, A, Spaan, A, Gilardin, L, Fellay, J, Lyonnet, S, Bilguvar, K, Lifton, R, Mane, S, Anderson, M, Boisson, B, Béziat, V, Zhang, S, Vandreakos, E, Hermine, O, Pujol, A, Peterson, P, Mogensen, T, Rowen, L, Mond, J, Debette, S, de Lamballerie, X, Duval, X, Mentré, F, Zins, M, Soler-Palacin, P, Colobran, R, Gorochov, G, Solanich, X, Susen, S, Martinez-Picado, J, Raoult, D, Vasse, M, Gregersen, P, Piemonti, L, Rodríguez-Gallego, C, Notarangelo, L, Su, H, Kisand, K, Okada, S, Puel, A, Jouanguy, E, Rice, C, Tiberghien, P, Zhang, Q, Cobat, A, Abel, L, Casanova, J, Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Laboratory of Human Genetics of Infectious Diseases (Necker Branch - INSERM U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), HGID Lab, COVID Clinicians, COVID-STORM Clinicians, NIAID Immune Response to COVID Group, NH-COVAIR Study Group, Danish CHGE, Danish Blood Donor Study, St. James's Hospital, SARS CoV2 Interest group, French COVID Cohort Study Group, Imagine COVID-Group, Milieu Intérieur Consortium, CoV-Contact Cohort, Amsterdam UMC Covid-19, Biobank Investigators, COVID Human Genetic Effort, CONSTANCES cohort, 3C-Dijon Study, Cerba Health-Care, Etablissement du Sang study group, Bigio, B., Boucherit, S., de la Chapelle, A., Chen, J., Chrabieh, M., Coulibaly, B., Liu, D., Nemirowskaya, Y., Cruz, I.M., Materna, M., Pelet, S., Seeleuthner, Y., Thibault, C., Liu, Z., Abad, J., Accordino, G., Achille, C., Aguilera-Albesa, S., Aguiló-Cucurull, A., Aiuti, A., Özkan, E.A., Darazam, I.A., Roblero Albisures, J.A., Aldave, J.C., Ramos, M.A., Khan, T.A., Aliberti, A., Nadji, S.A., Alkan, G., Alkhater, S.A., Allardet-Servent, J., Allende, L.M., Alonso-Arias, R., Alshahrani, M.S., Alsina, L., Alyanakian, M.A., Borrero, B.A., Amoura, Z., Antolí, A., Arrestier, R., Aubart, M., Auguet, T., Avramenko, I., Aytekin, G., Azot, A., Bahram, S., Bajolle, F., Baldanti, F., Baldolli, A., Ballester, M., Feldman, H.B., Barrou, B., Barzagh, F., Basso, S., Bayhan, G.I., Belot, A., Bezrodnik, L., Bilbao, A., Blanchard-Rohner, G., Blanco, I., Blandinières, A., Blázquez-Gamero, D., Bleibtreu, A., Bloomfield, M., Bolivar-Prados, M., Bondarenko, A., Borghesi, A., Borie, R., Botdhlo-Nevers, E., Bousfiha, A.A., Bousquet, A., Boutolleau, D., Bouvattier, C., Boyarchuk, O., Bravais, J., Briones, M.L., Brunner, M.E., Bruno, R., Bueno, MRP, Bukhari, H., Bustamante, J., Cáceres Agra, J.J., Capra, R., Carapito, R., Carrabba, M., Casari, G., Casasnovas, C., Caseris, M., Cassaniti, I., Castelle, M., Castelli, F., de Vera, M.C., Castro, M.V., Catherinot, E., Celik, J.B., Ceschi, A., Chalumeau, M., Charbit, B., Cheng, M.P., Clavé, P., Clotet, B., Codina, A., Cohen, Y., Colobran, R., Comarmond, C., Combes, A., Comoli, P., Corsico, A.G., Coşkuner, T., Cvetkovski, A., Cyrus, C., Dalmau, D., Danion, F., Darley, D.R., Das, V., Dauby, N., Dauger, S., De Munter, P., de Pontual, L., Dehban, A., Delplancq, G., Demoule, A., Desguerre, I., Di Sabatino, A., Diehl, J.L., Dobbelaere, S., Domínguez-Garrido, E., Dubost, C., Ekwall, O., Bozdemir, Ş.E., Elnagdy, M.H., Emiroglu, M., Endo, A., Erdeniz, E.H., Aytekin, S.E., Lasa, MPE, Euvrard, R., Fabio, G., Faivre, L., Falck, A., Fartoukh, M., Faure, M., Arquero, M.F., Ferrer, R., Ferreres, J., Flores, C., Francois, B., Fumadó, V., Fung, KSC, Fusco, F., Gagro, A., Solis, B.G., Gaussem, P., Gayretli, Z., Gil-Herrera, J., Gilardin, L., Gatineau, A.G., Girona-Alarcón, M., Cifuentes Godínez, K.A., Goffard, J.C., Gonzales, N., Gonzalez-Granado, L.I., González-Montelongo, R., Guerder, A., Gülhan, B., Gumucio, V.D., Hanitsch, L.G., Gunst, J., Gut, M., Hadjadj, J., Haerynck, F., Halwani, R., Hammarström, L., Hancerli, S., Hariyan, T., Hatipoglu, N., Heppekcan, D., Hernandez-Brito, E., Ho, P.K., Holanda-Peña, M.S., Horcajada, J.P., Hraiech, S., Humbert, L., Hung, IFN, Iglesias, A.D., Íñigo-Campos, A., Jamme, M., Arranz, M.J., Jimeno, M.T., Jordan, I., Yüksek, S.K., Kara, Y.B., Karahan, A., Karbuz, A., Yasar, K.K., Kasapcopur, O., Kashimada, K., Keles, S., Demirkol, Y.K., Kido, Y., Kizil, C., Kılıç, A.O., Klocperk, A., Koutsoukou, A., Król, Z.J., Ksouri, H., Kuentz, P., Kwan, AMC, Kwan, YWM, Kwok, JSY, Lagier, J.C., Lam, DSY, Lampropoulou, V., Lanternier, F., Lau, Y.L., Le Bourgeois, F., Leo, Y.S., Lopez, R.L., Leung, D., Levin, M., Levy, M., Lévy, R., Li, Z., Lilleri, D., Lima, EJAB, Linglart, A., López-Collazo, E., Lorenzo-Salazar, J.M., Louapre, C., Lubetzki, C., Lung, K.C., Luyt, C.E., Lye, D.C., Magnone, C., Mansouri, D., Marchioni, E., Marioli, C., Marjani, M., Marques, L., Pereira, J.M., Martín-Nalda, A., Pueyo, D.M., Martinez-Picado, J., Marzana, I., Mata-Martínez, C., Mathian, A., Matos, L.R., Matthews, G.V., Mayaux, J., McLaughlin-Garcia, R., Meersseman, P., Mège, J.L., Mekontso-Dessap, A., Melki, I., Meloni, F., Meritet, J.F., Merlani, P., Akcan, Ö.M., Meyts, I., Mezidi, M., Migeotte, I., Millereux, M., Million, M., Mirault, T., Mircher, C., Mirsaeidi, M., Mizoguchi, Y., Modi, B.P., Mojoli, F., Moncomble, E., Melián, A.M., Martinez, A.M., Morandeira, F., Morange, P.E., Mordacq, C., Morelle, G., Mouly, S.J., Muñoz-Barrera, A., Nafati, C., Nagashima, S., Nakagama, Y., Neven, B., Neves, J.F., Ng, L.F., Ng, Y.Y., Nielly, H., Medina, Y.N., Cuadros, E.N., Ocejo-Vinyals, J.G., Okamoto, K., Oualha, M., Ouedrani, A., Özçelik, T., Ozkaya-Parlakay, A., Pagani, M., Pan-Hammarström, Q., Papadaki, M., Parizot, C., Parola, P., Pascreau, T., Paul, S., Paz-Artal, E., Pedraza, S., González Pellecer, N.C., Pellegrini, S., de Diego, R.P., Pérez-Fernández, X.L., Philippe, A., Philippot, Q., Picod, A., de Chambrun, M.P., Piralla, A., Planas-Serra, L., Ploin, D., Poissy, J., Poncelet, G., Poulakou, G., Pouletty, M.S., Pourshahnazari, P., Qiu-Chen, J.L., Quentric, P., Rambaud, T., Raoult, D., Raoult, V., Rebillat, A.S., Redin, C., Resmini, L., Ricart, P., Richard, J.C., Rigo-Bonnin, R., Rivet, N., Rivière, J.G., Rocamora-Blanch, G., Rodero, M.P., Rodrigo, C., Rodriguez, L.A., Rodriguez-Gallego, C., Rodriguez-Palmero, A., Romero, C.S., Rothenbuhler, A., Roux, D., Rovina, N., Rozenberg, F., Ruch, Y., Ruiz, M., Ruiz Del Prado, M.Y., Ruiz-Rodriguez, J.C., Sabater-Riera, J., Saks, K., Salagianni, M., Sanchez, O., Sánchez-Montalvá, A., Sánchez-Ramón, S., Schidlowski, L., Schluter, A., Schmidt, J., Schmidt, M., Schuetz, C., Schweitzer, C.E., Scolari, F., Sediva, A., Seijo, L., Seminario, A.G., Sene, D., Seng, P., Senoglu, S., Seppänen, M., Llovich, A.S., Shahrooei, M., Shcherbina, A., Siguret, V., Siouti, E., Smadja, D.M., Smith, N., Sobh, A., Solanich, X., Solé-Violán, J., Soler, C., Soler-Palacín, P., Sözeri, B., Stella, G.M., Stepanovskiy, Y., Stoclin, A., Taccone, F., Tandjaoui-Lambiotte, Y., Taupin, J.L., Tavernier, S.J., Tello, L.V., Terrier, B., Thiery, G., Thorball, C., Thorn, K., Thumerelle, C., Tipu, I., Tolstrup, M., Tomasoni, G., Toubiana, J., Alvarez, J.T., Triantafyllia, V., Trouillet-Assant, S., Troya, J., Tsang, OTY, Tserel, L., Tso, EYK, Tucci, A., Tüter Öz, Ş.K., Ursini, M.V., Utsumi, T., Uzunhan, Y., Vabres, P., Valencia-Ramos, J., Van Den Rym, A.M., Vandernoot, I., Velez-Santamaria, V., Zuniga Veliz, S.P., Vidigal, M.C., Viel, S., Vilain, C., Vilaire-Meunier, M.E., Villar-García, J., Vincent, A., Vogt, G., Voiriot, G., Volokha, A., Vuotto, F., Wauters, E., Wauters, J., Wu, AKL, Wu, T.C., Yahşi, A., Yesilbas, O., Yildiz, M., Young, B.E., Yükselmiş, U., Zatz, M., Zecca, M., Zuccaro, V., Jens, V.P., Lambrecht, B.N., Eva, V.B., Cédric, B., Levi, H., Eric, H., Bauters, F., De Clercq, J., Cathérine, H., Hans, S., Leslie, N., Florkin, B., Boulanger, C., Vanderlinden, D., Foti, G., Bellani, G., Citerio, G., Contro, E., Pesci, A., Valsecchi, M.G., Cazzaniga, M., Danielson, J.J., Dobbs, K., Kashyap, A., Ding, L., Dalgard, C.L., Sottini, A., Quaresima, V., Quiros-Roldan, E., Rossi, C., Bettini, L.R., D'Angio', M., Beretta, I., Montagna, D., Licari, A., Marseglia, G.L., Batten, I., Reddy, C., McElheron, M., Noonan, C., Connolly, E., Fallon, A., Storgaard, M., Jørgensen, S., Erikstrup, C., Pedersen, O.B., Sørensen, E., Mikkelsen, S., Dinh, K.M., Larsen, MAH, Paulsen, I.W., Von Stemann, J.H., Hansen, M.B., Ostrowski, S.R., Townsend, L., Cheallaigh, C.N., Bergin, C., Martin-Loeches, I., Dunne, J., Conlon, N., Bourke, N., O'Farrelly, C., Abel, L., Allavena, C., Andrejak, C., Angoulvant, F., Azoulay, C., Bachelet, D., Bartoli, M., Basmaci, R., Behilill, S., Beluze, M., Benech, N., Benkerrou, D., Bhavsar, K., Bitker, L., Bouadma, L., Bouscambert-Duchamp, M., Paz, P.C., Cervantes-Gonzalez, M., Chair, A., Chirouze, C., Coelho, A., Cordel, H., Couffignal, C., Couffin-Cadiergues, S., d'Ortenzio, E., De Montmollin, E., Debard, A., Debray, M.P., Deplanque, D., Descamps, D., Desvallée, M., Diallo, A., Diouf, A., Dorival, C., Dubos, F., Duval, X., Eloy, P., Enouf, V., Epaulard, O., Esperou, H., Esposito-Farese, M., Etienne, M., Garot, D., Gault, N., Gaymard, A., Ghosn, J., Gigante, T., Gilg, M., Goehringer, F., Guedj, J., Hoctin, A., Hoffmann, I., Houas, I., Hulot, J.S., Jaafoura, S., Kafif, O., Kaguelidou, F., Kali, S., Kerroumi, Y., Khalil, A., Khan, C., Kimmoun, A., Laine, F., Laouénan, C., Laribi, S., Le, M., Le Bris, C., Le Gac, S., Le Hingrat, Q., Le Mestre, S., Le Nagard, H., Lemaignen, A., Lemee, V., Lescure, F.X., Letrou, S., Levy, Y., Lina, B., Lingas, G., Lucet, J.C., Machado, M., Malvy, D., Mambert, M., Manuel, A., Mentré, F., Meziane, A., Mouquet, H., Mullaert, J., Neant, N., Nguyen, D., Noret, M., Papadopoulos, A., Paul, C., Peiffer-Smadja, N., Peigne, V., Petrov-Sanchez, V., Peytavin, G., Pham, H., Picone, O., Piquard, V., Puéchal, O., Rosa-Calatrava, M., Rossignol, B., Rossignol, P., Roy, C., Schneider, M., Su, R., Tardivon, C., Tellier, M.C., Téoulé, F., Terrier, O., Timsit, J.F., Tual, C., Tubiana, S., Van Der Werf, S., Vanel, N., Veislinger, A., Visseaux, B., Wiedemann, A., Yazdanpanah, Y., Annereau, J.P., Briseño-Roa, L., Gribouval, O., Pelet, A., Alcover, A., Aschard, H., Bousso, P., Brodin, P., Bruhns, P., Cerf-Bensussan, N., Cumano, A., D'Enfert, C., Deriano, L., Dillies, M.A., Di Santo, J., Dromer, F., Eberl, G., Enninga, J., Fellay, J., Gomperts-Boneca, I., Hasan, M., Hedestam, G.K., Hercberg, S., Ingersoll, M.A., Lantz, O., Kenny, R.A., Ménager, M., Michel, F., Patin, E., Rausell, A., Rieux-Laucat, F., Rogge, L., Fontes, M., Sakuntabhai, A., Schwartz, O., Schwikowski, B., Shorte, S., Tangy, F., Toubert, A., Touvier, M., Ungeheuer, M.N., Zimmer, C., Albert, M.L., Duffy, D., Quintana-Murci, L., Alavoine, L., Behillil, S., Burdet, C., Charpentier, C., Dechanet, A., Ecobichon, J.L., Frezouls, W., Houhou, N., Lehacaut, J., Manchon, P., Nouroudine, M., Quintin, C., Thy, M., van der Werf, S., Vignali, V., Chahine, A., Waucquier, N., Migaud, M.C., Djossou, F., Mergeay-Fabre, M., Lucarelli, A., Demar, M., Bruneau, L., Gérardin, P., Maillot, A., Payet, C., Laviolle, B., Paris, C., Desille-Dugast, M., Fouchard, J., Pistone, T., Perreau, P., Gissot, V., Le Goas, C., Montagne, S., Richard, L., Bouiller, K., Desmarets, M., Meunier, A., Lefévre, B., Jeulin, H., Legrand, K., Lomazzi, S., Tardy, B., Gagneux-Brunon, A., Bertholon, F., Botelho-Nevers, E., Kouakam, C., Leturque, N., Roufai, L., Amat, K., Espérou, H., Hendou, S., van Agtmael, M., Algera, A.G., Appelman, B., van Baarle, F., Bax, D., Beudel, M., Bogaard, H.J., Bomers, M., Bonta, P., Bos, L., Botta, M., de Brabander, J., de Bree, G., de Bruin, S., Buis, DTP, Bugiani, M., Bulle, E., Chouchane, O., Cloherty, A., Dijkstra, M., Dongelmans, D.A., Dujardin, RWG, Elbers, P., Fleuren, L., Geijtenbeek, SGT, Girbes, A., Goorhuis, B., Grobusch, M.P., Hafkamp, F., Hagens, L., Hamann, J., Harris, V., Hemke, R., Hermans, S.M., Heunks, L., Hollmann, M., Horn, J., Hovius, J.W., de Jong, M.D., Koning, R., Lim, EHT, van Mourik, N., Nellen, J., Nossent, E.J., Paulus, F., Peters, E., Pina-Fuentes, DAI, van der Poll, T., Preckel, 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Hans-Heinrich [0000-0003-0554-0244], Eto, Shohei [0000-0002-2885-7490], García-Prat, Marina [0000-0001-5387-1908], Bizien, Lucy [0000-0001-9163-9122], Parra-Martínez, Alba [0000-0002-9564-8912], Dorgham, Karim [0000-0001-9539-3203], Alkhater, Suzan [0000-0001-7315-6581], Rigo-Bonnin, Raúl [0000-0001-5511-074X], Roussel, Lucie [0000-0001-5355-702X], Vinh, Donald C. [0000-0003-1347-7767], Ostrowski, Sisse Rye [0000-0001-5288-3851], Condino-Neto, Antonio [0000-0002-1069-3117], Prando, Carolina [0000-0002-9570-9770], Spaan, András N. [0000-0001-5981-7259], Gilardin, Laurent [0000-0001-9212-0859], Yang, Rui [0000-0003-4427-2158], Fellay, Jacques [0000-0002-8240-939X], Bilguvar, Kaya [0000-0002-7313-7652], Mane, Shrikant M. [0000-0002-3267-5139], Anderson, MarK S. [0000-0002-3093-4758], Boisson, Bertrand [0000-0001-5240-3555], Béziat, Vivien [0000-0002-4020-824X], Andreakos, Evangelos [0000-0001-5536-1661], Hermine, Olivier [0000-0003-2574-3874], Pujol, Aurora [0000-0002-9606-0600], Peterson, Pärt [0000-0001-6755-791X], Haljasmägi, Liis [0000-0001-7162-9808], Mogensen, Trine [0000-0002-1853-9704], Lamballerie, Xavier de [0000-0001-7895-2720], Zins, Marie [0000-0002-4540-4282], Soler-Palacín, Pere [0000-0002-0346-5570], Colobran, Roger [0000-0002-5964-536X], Gorochov, Guy [0000-0003-2097-9677], Solanich, Xavier [0000-0002-2572-2187], Susen, Sophie [0000-0001-5953-163X], Martínez-Picado, Javier [0000-0002-4916-2129], Gregersen, Peter K. [0000-0003-1613-1518], Migaud, Mélanie [0000-0003-3062-1214], Piemonti, Lorenzo [0000-0002-2172-2198], Rodríguez-Gallego, Carlos [0000-0002-4344-8644], Notarangelo, Luigi D. [0000-0002-8335-0262], Su, Helen C. [0000-0002-5582-9110], Kisand, Kai [0000-0002-5426-4648], Okada, Satoshi [0000-0002-4622-5657], Puel, Anne [0000-0003-2603-0323], Jouanguy, Emmanuelle [0000-0002-7358-9157], Tiberghien, Pierre [0000-0002-9310-8322], Zhang, Qian [0000-0002-9040-3289], Särekannu, Karita [0000-0002-5984-668X], Cobat, Aurélie [0000-0001-7209-6257], Abel, Laurent [0000-0001-7016-6493], Casanova, Jean-Laurent [0000-0002-7782-4169], Prost, Nicolas de [0000-0002-4833-4320], Tandjaoui-Lambiotte, Yacine [0000-0003-1123-4788], Luyt, Charles-Edouard [0000-0001-7424-2705], Amador-Borrero, Blanco [0000-0001-6170-8721], Poissy, Julien [0000-0001-6017-5353], Richard, Pascale [0000-0003-1864-3824], Cognasse, Fabrice [0000-0001-8041-928X], Troya, Jesús [0000-0001-7323-114X], Trouillet-Assant, Sophie [0000-0001-6439-4705], Belot, Alexandre [0000-0003-4902-5332], Saker, Kahina [0000-0001-8825-5400], Rivière, Jacques G. [0000-0003-1055-2063], Gentile, Stephanie [0000-0003-3858-9503], Rosen, Lindsey B. [0000-0001-5894-3878], Shaw, Elana [0000-0001-9265-8026], Dalmau, David [0000-0003-1936-478X], Tharaux, Pierre-Louis [0000-0002-6062-5905], Stépanian, Alain [0000-0002-2942-0901], Mégarbane, Bruno [0000-0002-2522-2764], Triantafyllia, Vasiliki [0000-0001-5832-4014], Fekkar, Arnaud [0000-0001-9954-075X], Heath, James R. [0000-0001-5356-4385], Franco, José Luis [0000-0001-5664-6415], Anaya, Juan Manuel [0000-0002-6444-1249], Imberti, Luisa[0000-0002-2075-8391], Bonfanti, Paolo [0000-0001-7289-8823], Castagnoli, Riccardo [0000-0003-0029-9383], Snow, Andrew L. [0000-0002-8728-6691], Holland, Steven M. [0000-0003-3207-5464], Biggs, Catherine M. [0000-0002-4363-2660], Moncada-Velez, Marcela [0000-0002-3073-5345], Arias, Andrés Augusto [0000-0002-9478-8403], Lorenzo, Lazaro [0000-0001-6648-8684], Boucherit, Soraya [0000-0002-8819-7594], Anglicheau, Dany [0000-0001-5793-6174], Planas, Anna M. [0000-0002-6147-1880], Haerynck, Filomeen [0000-0001-9161-7361], Duvlis, Sotirija [0000-0001-8587-7386], Nussbaum, Robert [0000-0003-3445-8880], Bousfiha, Ahmed Aziz [0000-0002-5011-9873], El Bakkouri, Jalila [0000-0003-2303-3369], Ramírez-Santana, Carolina [0000-0003-2137-4899], Paul, Stephanie [0000-0002-8830-4273], Pan-Hammarström, Qiang [0000-0003-1990-8804], Hammarström, Lennart [0000-0002-8635-9609], Dupont, Annabelle [0000-0002-1554-9931], Kurolap, Alina [0000-0002-7005-3621], Metz, Christine N. [0000-0002-1013-1691], Aiuti, Alessandro [0000-0002-5398-1717], Casari, Giorgio [0000-0002-0115-8980], Lampasona, Vito [0000-0001-5162-8445], Ciceri, Fabio [0000-0003-0873-0123], Barreiros, Lucila [0000-0002-9818-2345], Domínguez-Garrido, Elena [0000-0002-2066-0511], Vidigal, Mateus [0000-0002-8895-652X], Zatz, Mayana [0000-0003-3970-8025], Beek, Diederik van der [0000-0002-4571-044X], Stepanovskyy, Yuriy [0000-0001-6339-5490], Boyarchuk, Oksana [0000-0002-1234-0040], Nukui, Yoko [0000-0002-6123-5212], Vidaur, Loreto [0000-0002-6720-4900], Tangye, Stuart G. [0000-0002-5360-5180], Burrel, Sonia [0000-0002-7783-2601], Duffy, Darragh [0000-0002-8875-2308], Quintana-Murci, Lluis [0000-0003-2429-6320], Klocperk, Adam [0000-0002-1526-4557], Kan, Nelli [0000-0003-3564-6496], Shcherbina, Anna [0000-0002-3113-4939], Lau, Yu-Lung [0000-0002-4780-0289], Leung, Daniel [0000-0002-9360-6233], Coulongeat, Matthieu [0000-0003-1986-3546], Marlet, Julien [0000-0002-8645-8703], Koning, Rutger [0000-0003-3128-5072], Reyes, Luis Felipe [0000-0003-1172-6539], Venet, Fabienne [0000-0003-0462-4235], Monneret, Guillaume [0000-0002-9961-5739], Nussenzweig, Michel C. [0000-0003-0592-8564], Baris, Hagit N. [0000-0003-4065-7560], Hagin, David [0000-0003-2702-1031], Wauters, Joost [0000-0002-5983-3897], Meyts, Isabelle [0000-0003-1214-0302], Dyer, Adam [0000-0003-1356-510X], Bourke, Nollaig [0000-0003-4313-6859], Halwani, Rabih [0000-0002-6516-7771], and Sharif-Askari, Narjes Saheb [0000-0003-0482-6777]

Subjects
Interferon Type I/immunology, AUTOIMMUNITY, [SDV]Life Sciences [q-bio], Interferó, Gastroenterology, COVID-19 (Malaltia), Immunoglobulin G, Basic medicine, 0302 clinical medicine, Medicine and Health Sciences, 80 and over, Immunologia, Young adult, Child, Neutralizing, MYASTHENIA-GRAVIS PATIENTS, ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, 0303 health sciences, education.field_of_study, biology, General Medicine, Middle Aged, 3. Good health, COVID-19/immunology, Settore MED/03, 030220 oncology & carcinogenesis, Child, Preschool, Interferon Type I, Antibody, medicine.symptom, INTERFERON, Adult, medicine.medical_specialty, Adolescent, Critical Illness, Immunology, Population, Aged, Antibodies, Neutralizing, Autoantibodies, COVID-19, Case-Control Studies, Humans, Infant, Infant, Newborn, Interferon-alpha, Young Adult, Alpha interferon, Immunoglobulins, IMMUNITY, Asymptomatic, PATIENT, 03 medical and health sciences, Internal medicine, medicine, Preschool, education, Antibodies, Neutralizing/blood, HOMENS, 030304 developmental biology, ANTINUCLEAR, business.industry, Autoantibody, Case-control study, Antibodies, Neutralizing/immunology, Autoantibodies/blood, Autoantibodies/immunology, COVID-19/mortality, Immunoglobulin G/blood, Immunoglobulin G/immunology, Interferon-alpha/immunology, Newborn, DISTINCT FUNCTIONS, ALPHA, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, 3121 General medicine, internal medicine and other clinical medicine, ANTIBODIES, biology.protein, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, Immunoglobulines
Abstract

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/ml; in plasma diluted 1:10) of IFN-α and/or IFN-ω are found in about 10% of patients with critical COVID-19 (coronavirus disease 2019) pneumonia but not in individuals with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or IFN-ω (100 pg/ml; in 1:10 dilutions of plasma) in 13.6% of 3595 patients with critical COVID-19, including 21% of 374 patients >80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1124 deceased patients (aged 20 days to 99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-β. We also show, in a sample of 34,159 uninfected individuals from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or IFN-ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of individuals carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals 80 years. By contrast, auto-Abs neutralizing IFN-β do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over 80s and total fatal COVID-19 cases., The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI088364), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Awards (CTSA) program (UL1 TR001866), a Fast Grant from Emergent Ventures, Mercatus Center at George Mason University, the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956), the Yale High Performance Computing Center (S10OD018521), the Fisher Center for Alzheimer’s Research Foundation, the Meyer Foundation, the JPB Foundation, the French National Research Agency (ANR) under the “Investments for the Future” program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the FRM and ANR GENCOVID project (ANR-20-COVI-0003), ANRS Nord-Sud (ANRS-COV05), ANR GENVIR (ANR-20-CE93-003) and ANR AABIFNCOV (ANR-20-CO11-0001) projects, the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 824110 (EASI-Genomics), the Square Foundation, Grandir–Fonds de solidarité pour l’Enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, Institut National de la Santé et de la Recherche Médicale (INSERM), REACTing-INSERM; and the University of Paris. P.B. was supported by the FRM (EA20170638020). P.B., J.R., and T.L.V. were supported by the MD-PhD program of the Imagine Institute (with the support of the Fondation Bettencourt Schueller). Work in the Laboratory of Virology and Infectious Disease was supported by the NIH (P01AI138398-S1, 2U19AI111825, and R01AI091707-10S1), a George Mason University Fast Grant, and the G. Harold and Leila Y. Mathers Charitable Foundation. The French COVID Cohort study group was sponsored by INSERM and supported by the REACTing consortium and by a grant from the French Ministry of Health (PHRC 20-0424). The Cov-Contact Cohort was supported by the REACTing consortium, the French Ministry of Health, and the European Commission (RECOVER WP 6). This work was also partly supported by the Intramural Research Program of the NIAID and NIDCR, NIH (grants ZIA AI001270 to L.D.N. and 1ZIAAI001265 to H.C.S.). This program is supported by the Agence Nationale de la Recherche (reference ANR-10-LABX-69-01). K.K.’s group was supported by the Estonian Research Council grants PRG117 and PRG377. R.H. was supported by an Al Jalila Foundation Seed Grant (AJF202019), Dubai, UAE, and a COVID-19 research grant (CoV19-0307) from the University of Sharjah, UAE. S.G.T. is supported by Investigator and Program Grants awarded by the National Health and Medical Research Council of Australia and a UNSW Sydney COVID Rapid Response Initiative Grant. L.I. reported funding from Regione Lombardia, Italy (project “Risposta immune in pazienti con COVID-19 e co-morbidità”). L.I. and G. L. Marseglia reported funding from Regione Lombardia, Italy (project Risposta immune in pazienti con COVID-19 e co-morbidità). This research was partially supported by the Instituto de Salud Carlos III (COV20/0968). J.R.H. reported funding from Biomedical Advanced Research and Development Authority HHSO10201600031C. S.O. reports funding Research Program on Emerging and Re-emerging Infectious Diseases from Japan Agency for Medical Research and Development, AMED (grant number JP20fk0108531). G.G. was supported by ANR Flash COVID-19 program and SARS-CoV-2 Program of the Faculty of Medicine from Sorbonne University iCOVID programs. The Three-City (3C) Study was conducted under a partnership agreement among the INSERM, the Victor Segalen Bordeaux 2 University, and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study was also supported by the Caisse Nationale d’Assurance Maladie des Travailleurs Salariés, Direction générale de la Santé, Mutuelle Générale de l’Education Nationale (MGEN), Institut de la Longévité, Conseils Régionaux of Aquitaine and Bourgogne, Fondation de France, and Ministry of Research–INSERM Programme “Cohortes et collections de données biologiques”. S. Debette was supported by the University of Bordeaux Initiative of Excellence. P.K.G. reports funding from the National Cancer Institute, NIH, under contract no. 75N91019D00024, task order no. 75N91021F00001. J.W. is supported by an FWO Fundamental Clinical Mandate (1833317N). Sample processing at IrsiCaixa was possible thanks to the crowdfunding initiative YoMeCorono. Work at Vall d’Hebron was also partly supported by research funding from Instituto de Salud Carlos III grant PI17/00660 cofinanced by the European Regional Development Fund (ERDF). C.R.-G. and colleagues of the Canarian Health System Sequencing Hub were supported by the Instituto de Salud Carlos III (COV20_01333 and COV20_01334, Spanish Ministry for Science and Innovation RTC-2017-6471-1; AEI/FEDER, UE), Fundación DISA (OA18/017 and OA20/024), and Cabildo Insular de Tenerife (CGIEU0000219140 and “Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19”). C.M.B. is supported by a MSFHR Health Professional-Investigator Award. P.Q.H. and L.H. were funded by the European Union’s Horizon 2020 research and innovation program (ATAC, 101003650). Work at Y.-L.L.’s laboratory in the University of Hong Kong (HKU) was supported by the Society for the Relief of Disabled Children. MBBS/PhD study of D.L. in HKU was supported by the Croucher Foundation. J.L.F. was supported in part by the Coopération Scientifique France-Colciencias (ECOS-Nord/COLCIENCIAS/MEN/ICETEX (806-2018) and Colciencias contract 713-2016 (code 111574455633)]. A.K. was in part supported by grants NU20-05-00282 and NV18-05-00162 issued by the Czech Health Research Council and Ministry of Health, Czech Republic. L.P. was funded by Program Project COVID-19 OSR-UniSR and Ministero della Salute (COVID-2020-12371617). I.M. is a Senior Clinical Investigator at the Research Foundation–Flanders and is supported by the CSL Behring Chair of Primary Immunodeficiencies; by the KU Leuven C1 grant C16/18/007; by a VIB-GC PID grant; by the FWO frants G0C8517N, G0B5120N, and G0E8420N; and by the Jeffrey Modell Foundation. I.M. has received funding under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 948959). E.A. received funding from the Hellenic Foundation for Research and Innovation (INTERFLU, no. 1574). M.Vi received funding from the São Paulo Research Foundation (FAPESP) (grant number 2020/09702-1) and JBS SA (grant number 69004). The NH-COVAIR study group consortium was supported by a grant from the Meath Foundation

Published
2021
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37. Cryptococcus extracellular vesicles properties and their use as vaccine platforms

Author

Juliana Rizzo, Sarah Sze Wah Wong, Anastasia D. Gazi, Frédérique Moyrand, Thibault Chaze, Pierre‐Henri Commere, Sophie Novault, Mariette Matondo, Gérard Péhau‐Arnaudet, Flavia C. G. Reis, Matthijn Vos, Lysangela R. Alves, Robin C. May, Leonardo Nimrichter, Marcio L. Rodrigues, Vishukumar Aimanianda, Guilhem Janbon, Biologie des ARN des Pathogènes fongiques - RNA Biology of Fungal Pathogens, Institut Pasteur [Paris] (IP), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Plateforme BioImagerie Ultrastructurale – Ultrastructural BioImaging Platform (UTechS UBI), Spectrométrie de Masse pour la Biologie – Mass Spectrometry for Biology (UTechS MSBio), Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Fundação Oswaldo Cruz / Oswaldo Cruz Foundation (FIOCRUZ), Réseau International des Instituts Pasteur (RIIP), Plateforme technologique Nanoimagerie / Nanoimaging Technological Platform, University of Birmingham [Birmingham], Universidade Federal do Rio de Janeiro (UFRJ), This work was supported by a CAPES COFECUB grant n°39712ZK (to GJ, MLR, LA and LN). JR was supported by the CAPES-COFECUB Franco-Brazilian Research Exchange Program (88887.357947/2019-00) and by a Pasteur-Roux-Cantarini fellowship of Institut Pasteur. SSWW was supported by CEFIPRA/ANR-DFG-AfuINF grant and Pasteur-Roux-Cantarini postdoctoral fellowship. VA was supported by ANR-DFG AfuINF and Indo-French Centre for the Promotion of Advanced Research (CEFIPRA, Grant No5403-1) grants. Jean-Marie Winter from the NanoImaging Core at Institut Pasteur is acknowledged for his support image acquisition. The NanoImaging Core was created with the help of a grant from the French Government's ‘Investissements d'Avenir’ program (EQUIPEX CACSICE – 'Centre d'analyse de systèmes complexes dans les environnements complexes', ANR-11-EQPX-0008). The Falcon II equipping the F20 microscope at the UBI used during this study was also financed by the Equipex CACSICE (grant number ANR-11-EQPX-0008). M.L.R. is supported by grants from the Brazilian Ministry of Health (grant 440015/2018-9), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, grants 405520/2018-2 and 301304/2017-3), and Fiocruz (grants VPPCB-007-FIO-18 and VPPIS-001-FIO18)MLR, JR, and FCGR also acknowledge support from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, finance code 001) and the Instituto Nacional de Ciência e Tecnologia de Inovação em Doenças de Populações Negligenciadas (INCT-IDPN)., and ANR-11-EQPX-0008,CACSICE,Centre d'analyse de systèmes complexes dans les environnements complexes(2011)

Subjects
QH573-671, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Cryptococcus, fungal infections, vaccine, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Cryo‐EM, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Cytology, extracellular vesicles, Research Articles, Research Article, mannoproteins, Cryo-EM
Abstract

International audience; Whereas extracellular vesicle (EV) research has become commonplace in different biomedical fields, this field of research is still in its infancy in mycology. Here we provide a robust set of data regarding the structural and compositional aspects of EVs isolated from the fungal pathogenic species Cryptococcus neoformans, C. deneoformans and C. deuterogattii . Using cutting-edge methodological approaches including cryogenic electron microscopy and cryogenic electron tomography, proteomics, and flow cytometry, we revisited cryptococcal EV features and suggest a new EV structural model, in which the vesicular lipid bilayer is covered by mannoprotein-based fibrillar decoration, bearing the capsule polysaccharide as its outer layer. About 10% of the EV population is devoid of fibrillar decoration, adding another aspect to EV diversity. By analyzing EV protein cargo from the three species, we characterized the typical Cryptococcus EV proteome. It contains several membrane-bound protein families, including some Tsh proteins bearing a SUR7/PalI motif. The presence of known protective antigens on the surface of Cryptococcus EVs, resembling the morphology of encapsulated virus structures, suggested their potential as a vaccine. Indeed, mice immunized with EVs obtained from an acapsular C. neoformans mutant strain rendered a strong antibody response in mice and significantly prolonged their survival upon C. neoformans infection.

Published
2021
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38. Evaluation of a new Histoplasma spp. reverse transcriptase quantitative PCR assay

Author

Alanio, Alexandre, Gits-Muselli, Maud, Lanternier, Fanny, Sturny-Leclère, Aude, Benazra, Marion, Hamane, Samia, Rodrigues, Anderson Messias, Garcia-Hermoso, Dea, Lortholary, Olivier, Dromer, Françoise, Bretagne, Stéphane, French Mycoses Study Group, The, Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris] (IP), Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Federal University of Sao Paulo (Unifesp), The authors report no funding for this study., The French mycoses study group is composed of: Marine Gosset Woimant, Geneviève blanchard (Centre Hospitaler de Pontoise, Pontoise), Souad Silhadi (Centre Hospitalier de Chambéry, Chambéry), Nicolas Vignier, Aurelia Pitsch, Kaoutar Jidar (Centre Hospitalier de Melun, Melun), Nicolas Traversier (Centre Hospitalier Felix Guyon, La Réunion), Didier Poisson, Claire Lecointre (Centre Hospitalier Régional d'Orléans, Orléans), Françoise Foulet, Françoise Botterel, Nawel Ait Ammar, Amsellem (CHU Henri Mondor, Créteil), Frederic Gabriel (CHU de Bordeau-GH Pellegrin, Bordeaux), Philipe Poirier (CHU de Clermont Ferrand, Clermont-Ferrand), Marjorie Cornu, Severine Loridant (CHU de Lille, Lille), Florent Morio, David Boutoille, Fakhri Jeddi (CHU de Nantes, Nantes), Lilia Hasseine (CHU de Nice, Nice), Rachida Ouissa (CHU de Pointe à Pitre, Guadeloupe), Dominique Toubas (CHU de Reims, Reims), Eric Bailly, Guillaume Désoubeaux (CHU deTours), Emily Ronez (Hôpital Ambroise Paré, Boulogne), Guillaume Foulon, Sebastien Lefrançois (Hôpital Américain, Neuilly), Christine Bonnal (Hôpital Bichat, Paris), André Paugam, Maxime Dougados (Hôpital Cochin, Paris), Marine Desroches (Hôpital d'Instruction des Armées Percy, Clamart), Hélène Barazzutti, Nicolas Paleiron (Hôpital d'Instruction des Armées, Toulon), Meja rabodonirina (Hôpital de la Croix Rousse, Lyon), Emilie Catherinot, Emilie Cardot-Martin, Chrisian Hiesse, Hélène Salvator (Hôpital Foch, Suresnes), Claire Aguilar, Anne Gigandon, Thomas de Montpreville (Hôpital Marie Lannelongue, Le Plessis-Robinson), Marie-Elisabeth Bougnoux, Emilie Sitterlé (Hôpital Necker Enfants Malades, Paris), Arnaud Fekkar, Sébastien Imbert, Alexandre Bleibtreu (Hôpital Pité Salpétrière), Yaye Senghor (Hôpital Saint Joseph, Paris), Blandine Denis, Jean-Michel Molina, Geoffroy Liegeon, Anne-Lise Munnier, Marion Malphettes (Hôpital Saint Louis, Paris), Julie Denis (Hôpitaux Civils de Strasbourg, Strasbourg), Alain Berlioz-Arthaud (Institut Pasteur de Bangui, Bangui, République centrafricaine), Franciska Lange (Centre Hospitalier Sallanches-Chamonix, Sallanches), Myriam Chiaruzzi, Loic Epelboin (Centre Hospitalier Andrée Rosemon, Cayenne, Guyane Française), The authors are grateful to the technical staff of the mycology-parasitology laboratory at Hospital Saint Louis, Paris, France for handling specimens and performing this assay routinely, in particular, Elodie Da Silva, Thierry Pautet, Dieyenaba Siby-Diakite, Sarah seng and Julie Bui, who performed optimization experiments., Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Université de Paris (UP), Institut Pasteur [Paris], and Institut Pasteur [Paris]-CHU Necker - Enfants Malades [AP-HP]

Subjects
Whole blood, qPCR, quantification cycle, whole nucleic acids, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, reverse transcriptase, bacterial infections and mycoses, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, Histoplasmosis, fungal load, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology
Abstract

International audience; Laboratory diagnosis of histoplasmosis is based on various methods including microscopy, culture, antigen and DNA detection of Histoplasma capsulatum var. capsulatum (Hcc) or H. capsulatum var. duboisii (Hcd). To improve sensitivity of existing quantitative PCR assays, we developed a new reverse transcriptase qPCR (RTqPCR) assay allowing amplification of whole nucleic acids of Histoplasma spp.. and validated on suspected cases.The limit of detection was 20 copies and the specificity against 114 fungal isolates/species was restricted to Histoplasma spp.. Whole nucleic acids of 1,319 prospectively collected consecutive samples from 907 patients suspected of histoplasmosis were tested routinely between May 2015 and May 2019 in parallel with standard diagnostic procedures performed in parallel. 44 had proven histoplasmosis due to Hcc (n=40) or Hcd (n=4) infections. RTqPCR was positive in 43/44 patients (97.7% sensitivity), in at least one specimen. Nine out of 863 cases (99% specificity) were RTqPCR positive and therefore classified as possible cases. RTqPCR was positive in 13/30 (43.3%) blood tested in proven cases. A positive RTqPCR in blood was significantly associated with Hcc progressive disseminated histoplasmosis with a positive RTqPCR in 92.3% of the immunocompromised patients with disseminated disease. This new Histoplasma RTqPCR assay enabling amplification of hcc and hcd is highly sensitive and allows the diagnosis of histoplasmosis advantageously from blood and BAL.

Published
2021
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39. Mainly Post-Transplant Factors Are Associated with Invasive Aspergillosis after Allogeneic Stem Cell Transplantation: A Study from the Surveillance des Aspergilloses Invasives en France and Société Francophone de Greffe de Moelle et de Thérapie Cellulaire

Author

Karine Sitbon, Regis Peffault de la Tour, Sylvie Bastuji-Garin, Olivier Lortholary, Stéphane Bretagne, Sébastien Maury, Catherine Cordonnier, Christine Robin, Nicole Raus, CCSD, Accord Elsevier, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre National de Référence des Mycoses invasives et antifongiques - Mycologie moléculaire (CNRMA), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Mycologie moléculaire - Molecular Mycology, Société Française de Greffe de Moelle et de Thérapie Cellulaire, Saint-Denis, France, Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Paris Descartes University, Université Paris Descartes - Paris 5 (UPD5), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Clinical Epidemiology and Ageing : Geriatrie Soins Primaires et Santé Publique (CEpiA), The SAIF program was supported by acspecific grant from Institut de Veille Sanitaire, 94410, Saint-Maurice, France., The authors are grateful to the microbiology and clinical staff from the French Mycosis Study Group who actively participated in the SAIF network. They are also grateful to the clinicians and data managers of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) centers who provided data for this study., Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-CHU Necker - Enfants Malades [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], CHU Necker - Enfants Malades [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut Pasteur [Paris]

Subjects
Adult, Male, medicine.medical_specialty, Neutropenia, medicine.medical_treatment, Graft vs Host Disease, Hematopoietic stem cell transplantation, Disease, Aspergillosis, 03 medical and health sciences, Invasive fungal infection, 0302 clinical medicine, Recurrence, Risk Factors, Internal medicine, medicine, Humans, Prospective Studies, Registries, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Societies, Medical, Retrospective Studies, Transplantation, business.industry, Hematopoietic Stem Cell Transplantation, Hematology, Middle Aged, Allografts, medicine.disease, Control subjects, [SDV.MP.MYC] Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Post transplant, Allogeneic stem cell transplantation, 3. Good health, Europe, surgical procedures, operative, 030220 oncology & carcinogenesis, Acute Disease, Female, Stem cell, business, 030215 immunology
Abstract

International audience; Invasive aspergillosis (IA) occurs in up to 23% of allogeneic hematopoietic stem cell transplantation (HSCT) patients. Although transplant procedures have changed over time, more late cases of IA are being observed. The objective of this study was to identify the pre-and post-transplant factors of IA in a large cohort of HSCT patients mainly transplanted with reduced-intensity conditioning. This multicenter, case-control study was carried out using data collected between 2005 and 2010 by the Surveillance des Aspergilloses Invasives en France program (Institut Pasteur, Paris) and the European Society for Blood and Marrow Transplantation ProMISe registry. Four control subjects without IA were individually matched to each case based on the center, patient age, and year of the transplant. We identified 185 cases of probable and proven IA and 651 control subjects. The median date of IA after the transplant was 133 days, with 35 cases (19%) of early IA (before day 40), 33 cases (18%) of late IA (days 40 to 100), and 117 cases (63%) cases of very late IA (after day 100). In the multivariate analysis early IA was significantly associated with a lack of engraftment, whereas late and very late IA were significantly associated with more than grade II acute graft-versus-host disease (GVHD); very late IA was also significantly associated with relapse and secondary neutropenia. Two-thirds of IA cases occurred more than 100 days after HSCT with different risk factors from those occurring earlier. Prophylactic strategies should consider the specific risk factors for late and very late IA, especially GVHD, relapse after transplant, and secondary neutropenia.

Published
2019
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40. Proteomic Analysis of Humoral Immune Components in Bronchoalveolar Lavage of Patients Infected or Colonized by Aspergillus fumigatus

Author

Dellière, Sarah, Duchateau, Magalie, Wong, Sarah Sze Wah, Giai Gianetto, Quentin, Guegan, Hélène, Matondo, Mariette, Gangneux, Jean-Pierre, Aimanianda, Vishukumar, Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Parasitologie et Mycologie (Parasito-Myco - ST LOUIS PARIS), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Plateforme de Protéomique / Proteomics platform, Spectrométrie de Masse pour la Biologie – Mass Spectrometry for Biology (UTechS MSBio), Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), This work was supported by ANR-FUNHYDRO (ANR-16S-CE110020-01) grant., ANR-16-CE11-0020,FUNHYDRO,Amyloïdes fonctionnels formés par les hydrophobines du pathogène fongique Aspergillus fumigatus(2016), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut Pasteur [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Giai Gianetto, Quentin, and Amyloïdes fonctionnels formés par les hydrophobines du pathogène fongique Aspergillus fumigatus - - FUNHYDRO2016 - ANR-16-CE11-0020 - AAPG2016 - VALID

Subjects
Male, Proteome, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, proteomics, humoral immunity, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], RNA, Ribosomal, 28S, Humans, bronchoalveolar lavage, aspergillosis, Protein Interaction Maps, skin and connective tissue diseases, complement system, Aged, Aspergillus fumigatus, RNA, Fungal, Complement System Proteins, Middle Aged, Immunity, Innate, Immunity, Humoral, Pulmonary Alveoli, Case-Control Studies, Perspective, Host-Pathogen Interactions, pentraxin-3, Cytokines, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, sense organs, Bronchoalveolar Lavage Fluid
Abstract

Humoral immune components have been individually studied in the context of interaction of host with Aspergillus fumigatus, a major airborne fungal pathogen. However, a global view of the multitude and complex nature of humoral immune components is needed to bring new insight into host-Aspergillus interaction. Therefore, we undertook comparative proteomic analysis of the bronchoalveolar lavage fluid collected from individuals infected or colonized with A. fumigatus versus controls, to identify those alveolar humoral components affected upon A. fumigatus infection. Complement proteins C1q, C8 beta-chain, factor-H, ficolin-1, ficolin-2, mannan binding lectin serine peptidase 2, pentraxin-3 and the surfactant protein-D were identified as the major humoral immune components affected by A. fumigatus infection and colonization. Based on this observation, we hypothesize that crosstalk between these humoral components is essential during host-Aspergillus interaction giving new specific leads to study for better understanding the pathogenesis. Furthermore, the affected humoral components could be potential diagnostic markers of A. fumigatus infection or colonization.

Published
2021
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41. Increased sensitivity of a new commercial reverse transcriptase-quantitative PCR for the detection of Pneumocystis jirovecii in respiratory specimens

Author

Alexandre Alanio, Maud Gits-Muselli, Stéphane Bretagne, Samia Hamane, Nesrine Aissaoui, Sarah Dellière, Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris] (IP), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and Institut Pasteur [Paris]

Subjects
Adult, Male, diagnosis, Respiratory System, Opportunistic Infections, Pneumocystis pneumonia, Pneumocystis carinii, Real-Time Polymerase Chain Reaction, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, Sensitivity and Specificity, law.invention, Extractor, 03 medical and health sciences, law, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, medicine, Pneumocystis jirovecii, Humans, Respiratory system, Polymerase chain reaction, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, 030304 developmental biology, Aged, 0303 health sciences, biology, 030306 microbiology, business.industry, Reverse Transcriptase Polymerase Chain Reaction, Pneumonia, Pneumocystis, General Medicine, Middle Aged, medicine.disease, biology.organism_classification, Virology, Reverse transcriptase, 3. Good health, mitochondria, Pneumonia, real time PCR, Infectious Diseases, Real-time polymerase chain reaction, Female, business
Abstract

Optimal sensitivity to detect low Pneumocystis loads is of importance to take individual and collective measures to avoid evolution towards Pneumocystis pneumonia and outbreaks in immunocompromised patients. This study compares two qPCR procedures, a new automated RTqPCR using the GeneLEAD VIII extractor/thermocycler (GLVIII; ∼2.2 h workflow) and a previously validated in-house qPCR assays (IH; ∼5 h workflow) both targeting mtSSU and mtLSU for detecting P. jirovecii in 213 respiratory samples. GLVIII was found to be more sensitive than IH, detecting eight more specimens. Bland-Altman analysis between the two procedures showed a Cq bias of 1.17 ± 0.07 in favor of GLVIII. Lay Summary The fungus Pneumocystis needs to be detected early in respiratory samples to prevent pneumonia in immunocompromised hosts. We evaluated a new commercial RTqPCR on 213 respiratory samples to detect Pneumocystis and found it more sensitive and faster than our routine sensitive in-house qPCR assay.

Published
2021
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42. Prospective comparison of (1,3)-beta-D-glucan detection using colorimetric and turbidimetric assays for diagnosing invasive fungal disease

Author

Stéphane Bretagne, Anne Bergeron, Sophie Touratier, Samia Hamane, Nicolas Guigue, Alexandre Alanio, Maud Gits-Muselli, Blandine Denis, Institut Pasteur [Paris], Mycologie moléculaire - Molecular Mycology, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pasteur [Paris] (IP), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Adult, Male, Fusariosis, medicine.medical_specialty, Single sample, Aspergillosis, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, Sensitivity and Specificity, Gastroenterology, Prospective comparison of colorimetric and turbidimetric 1→3)-β-D-glucan assays (1→3)-β-D-glucan, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Internal medicine, medicine, Pneumocystosis, Humans, Prospective Studies, 030212 general & internal medicine, colorimetric assay, Diagnostic Techniques and Procedures, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, (1→3)-β-D-glucan, 0303 health sciences, biology, 030306 microbiology, business.industry, Immunoturbidimetry, General Medicine, Middle Aged, medicine.disease, Predictive value, Fungal antigen, 3. Good health, invasive fungal disease, Infectious Diseases, 1,3-Beta-glucan synthase, Invasive fungal disease, Mycoses, biology.protein, Colorimetry, Female, Proteoglycans, turbidimetric assay, business, Invasive Fungal Infections
Abstract

Serum (1→3)-β-D-glucan (BDG), an pan fungal antigen, is detected in some invasive fungal diseases (IFDs). We compared two commercial kits, the Fungitell assay (FA) (colorimetric) and the Wako assay (WA) (turbidimetric) over a 4-month period to prospectively test 171 patients who mainly had hematological conditions (62%) and experienced episodes (n = 175) of suspected invasive fungal infection. Twenty-three episodes due to BDG-producing fungi were diagnosed (pneumocystosis, n = 12; invasive aspergillosis, n = 5; candidemia, n = 3; invasive fusariosis, n = 2; hepato-splenic candidiasis, n = 1). Both assays provided similar areas under the curves (AUC = 0.9). Using the optimized positivity thresholds (≥120 pg/ml for FA and ≥ 4 pg/ml for WA), the sensitivity and specificity were 81.8% (CI95: 61.5–92.7), 94.8% (90.1–97.3) for FA and 81.8% (61.5–92.7), 95.4% (90.9–97.8) for WA. Negative predictive value was 97.3% (93.3–99.0) for both tests. If the manufacturer's positivity threshold (≥11 pg/ml) was applied, the WA sensitivity decreased to 50%. Among 71 patients with bacterial infections, 21.1% were FA-positive and 5.6% were WA-positive (p < 10−2). The WA performed similarly as compared to the FA with an optimized cutoff value. The WA is a single sample test that is clinically relevant when a prompt therapeutic decision is required. Lay Summary Serum (1→3)-β-D-glucan testing is dominated by two kits including Fungitell colorimetric assay (FA) and the Wako turbidimetric assay (WA). We compared them prospectively and observed that they both perform similarly when selecting their optimal threshold (≥120 pg/ml for FA and ≥ 4 pg/ml for WA).

Published
2021
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43. Earliest case of Candida auris infection imported in 2007 in Europe from India prior to the 2009 description in Japan

Author

Marie Desnos-Ollivier, Stéphane Bretagne, Arnaud Fekkar, Mycologie moléculaire - Molecular Mycology, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris], Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de parasitologie - mycologie [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris Diderot - Paris 7 (UPD7), Laboratoire de Parasitologie-Mycologie [CHU Saint Louis, Paris], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by Institut Pasteur and Santé Publique France., We thank the Mutualized Platform for Microbiology (P2M, Institut Pasteur, Paris, France) for whole genome sequencing., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Centre d'Immunologie et des Maladies Infectieuses (CIMI), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AUGUSTE, Christèle, Service de Parasitologie - Mycologie [CHU Pitié-Salpétrière], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Whole genome sequencing, 0303 health sciences, whole genome sequencing, 030306 microbiology, short tandem repeat, Outbreak, India, Biology, Candida auris, Virology, [SDV.MP.MYC] Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, 3. Good health, Multiple drug resistance, Europe, 03 medical and health sciences, Emerging pathogen, Infectious Diseases, Clade, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology
Abstract

International audience; Candida auris is an emerging pathogen frequently associated with multidrug resistance and involved in many worldwide outbreaks. We here report the first European imported case in France due to isolate belonging of the South Indian clade I and the importance of prevention measure to avoid fungal spreading.

Published
2021
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44. Azoles susceptibility profiles of more than 9,000 clinical yeast isolates belonging to 40 common and rare species

Author

Olivier Lortholary, Françoise Dromer, Stéphane Bretagne, Marie Desnos-Ollivier, Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Service des Maladies infectieuses et tropicales [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Parasitologie-Mycologie [CHU Saint Louis, Paris], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université Paris Cité (UPCité), Institut Pasteur and Santé Publique France., Members of the French Mycoses Study group who contributed to the data are in alphabetical order of the cities, all the French microbiologists and mycologists who sent isolates for characterization of unusual antifungal susceptibility profiles or to contribute to the ongoing surveillance program on the epidemiology of invasive fungal infections in France (YEASTS and RESSIF programs): N. Brieu (CH Aix), T. Chouaki, C. Damiani, A. Totet (CHU Amiens, J. P. Bouchara, M. Pihet (CHU Angers), S. Bland (CH Annecy), V. Blanc (CH Antibes), S. Branger (CH Avignon), A. P. Bellanger, L. Million (CHU Besançon), C. Plassart (CH Beauvais), I. Poilane (hôpital Jean Verdier, Bondy), I. Accoceberry, L. Delhaes, F. Gabriel (CH Bordeaux), A. L. Roux, V. Sivadon-Tardy (hôpital Ambroise Paré, Boulogne Billancourt), F. Laurent (CH, Bourg en Bresse), S. Legal, E. Moalic, G. Nevez, D. Quinio (CHU Brest), M. Cariou (CH Bretagne Sud), J. Bonhomme (CHU, Caen), B. Podac (CH, Chalon sur Saône), S. Lechatch (CH, Charleville-Mézières), C. Soler (hopital d’Instruction des armées, Clamart), P. Poirier, C. Nourrisson (CHU, Clermont Ferrand), O. Augereau (CH, Colmar), N. Fauchet (CHIC, Créteil), F. Dalles (CHU, Dijon), P. Cahen (CMC, Foch), N. Desbois, C. Miossec (CHU, Fort de France), J. L. Hermann (hôpital Raymond Poincaré, Garches), M. Cornet, D. Maubon, H. Pelloux (CHU, Grenoble), M. Nicolas (CHU,Guadeloupe), C. Aznar, D. Blanchet, J. F. Carod, M. Demar, (CHU, Guyane), A. Angoulvant (hôpital Bicêtre, le Kremlin Bicêtre), C. Ciupek (CH, Le Mans), A. Gigandon (hôpital Marie Lannelongue, Le Plessis Robinson), B. Bouteille (CH Limoges), E. Frealle, B. Sendid (CHU Lille), D. Dupont, J. Menotti, F. Persat, M. Wallon (CHU, Lyon), C. Cassagne, S. Ranque (CHU, Marseille), T. Benoit-Cattin, L. Collet (CH Mayotte), A. Fiacre (CH Meaux), N. Bourgeois, L. Lachaud (CHU, Montpellier), M. Machouart (CHU, Nancy), P. Lepape, F. Morio (CHU, Nantes), O. Moquet (CH, Nevers), S. Lefrançois (hôpital Américain, Neuilly), M. Sasso (CHU, Nimes), F. Reibel (GH, Nord-Essone), M. Gari-Toussaint, L. Hasseine (CHU Nice), L. Bret, D. Poisson (CHR Orléans), S. Brun (hôpital Avicenne, Paris), C. Bonnal, S. Houze (hôpital Bichat, Paris), A. Paugam (hôpital Cochin, Paris), E. Dannaoui (HEGP, Paris), N. Ait-Ammar, F. Botterel, R. Chouk (CHU Henri Mondor, Paris), M. E. Bougnoux, E. Sitterle (hôpital Necker, Paris), A. Fekkar, R. Piarroux (hôpital Pitié Salpêtrière, Paris), J. Guitard, C. Hennequin (hôpital St Antoine, Paris), M. Gits-Muselli, S. Hamane (hôpital Saint Louis, Paris), S. Bonacorsi, P. Mariani (hôpital Robert Debré, Paris), D. Moissenet (hôpital Trousseau, Paris), A. Minoza, E. Perraud, M. H. Rodier (CHU Poitiers), G. Colonna (CH, Porto Vecchio), D. Toubas (CHU Reims), J. P. Gangneux, F. Robert-Gangneux (CHU Rennes), O. Belmonte, G. Hoarau, M. C. Jaffar Bandjee, J. Jaubert, S. Picot, N. Traversier (CHU Réunion), L. Favennec, G. Gargala (CHU, Rouen), C. Tournus (CH, St Denis), H. Raberin (CHU, St Etienne), V. Letscher Bru (CHU, Strasbourg), S. Cassaing (CHU, Toulouse), P. Patoz (CH Tourcoing), E. Bailly, G. Desoubeaux (CHU Tours), F. Moreau (CH Troyes), P. Munier (CH Valence), E. Mazars (CH Valenciennes), O. Eloy (CH Versailles), E. Chachaty (Institut Gustave Roussy, Villejuif), and members of the NRCMA (Institut Pasteur, Paris): A. Boullié, C. Gautier, V. Geolier, C. Blanc, D. Hoinard and D. Raoux-Barbot for technical help, and K. Boukris-Sitbon, F. Lanternier, A. Alanio, D. Garcia-Hermoso for their expertise and contribution to the surveillance programs., Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and Université de Paris (UP)

Subjects
Serotype, Azoles, Antifungal Agents, Microbial Sensitivity Tests, Candida parapsilosis, Rhodotorula mucilaginosa, Pichia, Microbiology, Candida tropicalis, 03 medical and health sciences, 0302 clinical medicine, Drug Resistance, Fungal, Pharmacology (medical), 030212 general & internal medicine, Candida albicans, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Pharmacology, chemistry.chemical_classification, 0303 health sciences, biology, Candida glabrata, 030306 microbiology, Broth microdilution, Rhodotorula, biology.organism_classification, 3. Good health, Infectious Diseases, chemistry, Susceptibility, Saccharomycetales, Azole, France
Abstract

Invasive yeast infections represent a major global public health issue, and only few antifungal agents are available. Azoles are one of the classes of antifungals used for treatment of invasive candidiasis. The determination of antifungal susceptibility profiles using standardized methods is important to identify resistant isolates and to uncover the potential emergence of intrinsically resistant species. Here, we report data on 9,319 clinical isolates belonging to 40 pathogenic yeast species recovered in France over 17 years. The antifungal susceptibility profiles were all determined at the National Reference Center for Invasive Mycoses and Antifungals based on the EUCAST broth microdilution method. The centralized collection and analysis allowed us to describe the trends of azole susceptibility of isolates belonging to common species, confirming the high susceptibility for Candida albicans (n = 3,295), Candida tropicalis (n = 641), and Candida parapsilosis (n = 820) and decreased susceptibility for Candida glabrata (n = 1,274) and Pichia kudriavzevii (n = 343). These profiles also provide interesting data concerning azole susceptibility of Cryptococcus neoformans species complex, showing comparable MIC distributions for the three species but lower MIC(50)s and MIC(90)s for serotype D (n = 208) compared to serotype A (n = 949) and AD hybrids (n = 177). Finally, these data provide useful information for rare and/or emerging species, such as Clavispora lusitaniae (n = 221), Saprochaete clavata (n = 184), Meyerozyma guilliermondii complex (n = 150), Candida haemulonii complex (n = 87), Rhodotorula mucilaginosa (n = 55), and Wickerhamomyces anomalus (n = 36).

Published
2021
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45. Cryptococcus gattii in Patients with Lymphoid Neoplasms: An Illustration of Evolutive Host–Fungus Interactions

Author

Olivier Paccoud, Marie-Elisabeth Bougnoux, Marie Desnos-Ollivier, Bruno Varet, Olivier Lortholary, Fanny Lanternier, Service des Maladies infectieuses et tropicales [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de Parasitologie-Mycologie, Service de Microbiologie [Hôpital Necker-Enfants-Malades, Paris], Assistance Publique - Hôpitaux de Paris, Université de Paris (UP), Mycologie moléculaire - Molecular Mycology, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris], Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)

Subjects
lymphoid neoplasms, lcsh:Biology (General), cryptococcosis, ibrutinib, chronic lymphocytic leukemia, Cryptococcus gattii, Review, haematological malignancy, lcsh:QH301-705.5, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology
Abstract

International audience; Recent outbreaks of Cryptococcus gattii (CG) infections in North America have sparked renewed interest in the pathogenic potential of CG, and have underscored notable differences with Cryptococcus neoformans in terms of geographic distribution, pathogen virulence, and host susceptibility. While cases of CG are increasingly reported in patients with a wide variety of underlying conditions, only very few have been reported in patients with lymphoid neoplasms. Herein, we report a case of autochthonous CG meningitis in a patient receiving ibrutinib for chronic lymphocytic leukemia in France, and review available data on the clinical epidemiology of CG infections in patients with lymphoid neoplasms. We also summarise recent data on the host responses to CG infection, as well as the potential management pitfalls associated with its treatment in the haematological setting. The clinical epidemiology, clinical presentation, and course of disease during infections caused by CG involve complex interactions between environmental exposure to CG, infecting genotype, pathogen virulence factors, host susceptibility, and host immune responses. Future treatment guidelines should address the challenges associated with the management of antifungal treatments in the onco-haematological setting and the potential drug-drug interactions.

Published
2021
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46. Central nervous system candidiasis beyond neonates: Lessons from a nationwide study

Author

Berengere Gruson, Taieb Chouaki, Xavier Cazals, Olivier Lortholary, Claire Rivoisy, Marie-Elisabeth Bougnoux, Fanny Lanternier, Louis Bernard, Fabrice Chrétien, Grégory Jouvion, Agnès Lefort, Guillaume Desoubeaux, Marie Desnos-Ollivier, Hélène Chaussade, Service des Maladies infectieuses et tropicales [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de neuroradiologie [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Histopathologie humaine et Modèles animaux, Institut Pasteur [Paris] (IP), Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Parasitologie-Mycologie, Service de Microbiologie [Hôpital Necker-Enfants-Malades, Paris], Assistance Publique - Hôpitaux de Paris, Université Paris Cité (UPCité), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), CHU Amiens-Picardie, French Mycosis Study Group: The following investigators participated in data collection: Florence Ader, and Florence Persat (Centre Hospitalo-Universitaire, Lyon), Marlène Amara and Noémie Degunzburg (Centre Hospitalier, Versailles), Eric Bailly (Centre Hospitalo-Universitaire, Tours), Julie Bonhomme (Centre Hospitalo-Universitaire, Caen), Nathalie Bourgeois, Anne-Sophie Brunel, and Laurence Lachaud (Centre Hospitalo-Universitaire, Montpellier), Damier Bouhour (Centre Hospitalier, Bourg en Bresse), Laure Chaput and Frédéric Pene (Hôpital Cochin, Paris), Emmanuel Chatelus, Aurélien Guffroy, and Valérie Letscher-Bru (Centre Hospitalo-Universitaire, Strasbourg), Arnaud Fekkar (Hôpital de La Pitié-Salpêtrière, Paris), Eglantine Haustraetee and Renaud Verdon (Centre Hospitalo-Universitaire, Caen) Christophe Hennequin and Jean-Rémi Lavillegrand (Hôpital Saint-Antoine, Paris), Benoît Henry, Stéphane Jaureguiberry, and Véronique Morel (Hôpital de La Pitié-Salpêtrière, Paris), Julien Jaubert, Julie Mathieu-Streit, andML Xelot (Centre Hospitalo-Universitaire, Saint Denis de la Réunion), Yoann Zerbib (Centre Hospitalo-Universitaire, CHU Amiens)., Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), UF de Génétique moléculaire [CHU Trousseau], Desnos-Ollivier, Marie, Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Institut Pasteur [Paris], Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Paris (UP), and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Gastroenterology, Young Adult, 03 medical and health sciences, central nervous system fungal infections, 0302 clinical medicine, Cerebrospinal fluid, Risk Factors, Internal medicine, medicine, Humans, Endocarditis, hematologic neoplasms, 030212 general & internal medicine, Risk factor, Child, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Aged, Retrospective Studies, Candida, Aged, 80 and over, 0303 health sciences, medicine.diagnostic_test, 030306 microbiology, Lumbar puncture, business.industry, Candidiasis, inherited CARD9 deficiency, Retrospective cohort study, General Medicine, Middle Aged, Disseminated Candidiasis, medicine.disease, Magnetic Resonance Imaging, [SDV.MP.MYC] Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, 3. Good health, Infectious Diseases, Infective endocarditis, Epidemiological Monitoring, endocarditis, Female, France, business, Meningitis
Abstract

Though candidiasis is the most frequent invasive fungal infection, Candida spp. central nervous system (CNS) infections are rare but severe. To further describe clinico-patho-radiological presentations of this entity, we report a retrospective study from January 2005 to December 2018 including patients aged ≥ 28 days with proven or probable CNS candidiasis in France. Twenty-four patients were included. Seventeen patients (70%) had CNS localization secondary to disseminated candidiasis (10 with hematologic malignancies [HM]; the seven other patients had infective endocarditis [IE]). Among patients with HM, seven previously had lumbar puncture for intrathecal chemotherapy, the three others had IE. Among patients with disseminated infection, magnetic resonance imaging (MRI) evidenced meningitis (17%), micro-abscesses (58%), or vascular complications (67%). Seven patients (30%) had isolated CNS involvement related to neurosurgery (n = 2), CARD9 deficiency (n = 2), intravenous drug use, diabetes mellitus, or no identified predisposing condition (n = 1 each). All evaluated patients with isolated CNS involvement had meningitis on cerebrospinal fluid (CSF) and intracranial hypertension. For the latter patients, MRI evidenced meningitis (71%) or abscesses (57%). Among all patients, cerebrospinal fluid (CSF) culture grew Candida spp. in 31% of cases. CSF βDGlucan or mannan Ag were positive in respectively 86% and 80% of cases. Mortality attributed to CNS candidiasis was 42%: 53% in case of disseminated infection (70% for HM) and 14% in case of localized infection. CNS candidiasis are isolated or occur during disseminated infection in patients with HM and lumbar puncture for intrathecal chemotherapy or during IE. Clinical, radiological finding and outcome highly vary according to CNS localized versus disseminated candidiasis. Lay Summary Candida is a yeast and is the most common cause of fungal infections worldwide. Candida central nervous system (CNS) infections are rare, severe, and poorly described. We report a retrospective study from January 2005 to December 2018 including patients aged ≥ 28 days with proven or probable CNS candidiasis in France. Twenty-four patients were included (14 men, median age 51 years). Seventeen patients had CNS localization secondary to disseminated candidiasis from blood to CNS (10 with hematologic malignancies [HM], the seven other patients had infective endocarditis [IE]). Seven patients had isolated CNS involvement related to neurosurgery (n = 2), CARD9 deficiency (n = 2), intravenous drug use (n = 1), diabetes mellitus (n = 1), or no identified risk factor (n = 1). During Candida CNS infections, brain lesions were meningitis abscesses or vascular complications. Cerebrospinal fluid (CSF) culture grew Candida spp. in 31% of cases. Forty-two percent of patients died from infection: 53% in case of disseminated infection (70% for HM) and 14% in case of localized infection.

Published
2021
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47. New clinical algorithm including fungal biomarkers to better diagnose probable invasive pulmonary aspergillosis in ICU

Author

Jean-Christophe Navellou, Stéphane Bretagne, Gaël Piton, Laurence Millon, Joffrey Hamam, Emeline Scherer, Anne-Pauline Bellanger, Hadrien Winiszewski, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Libourne, Service de parasitologie et mycologie [CHRU de Besançon], Laboratoire Chrono-environnement (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), None, Members of the Collaborative RESSIF group: Eric Bailly (CHU de Tours, Tours, France), Anne Isabelle Bertozi (CHU de Toulouse, Toulouse, France), Julie Bonhomme (CHU Caen, Caen, France), Bernard Bouteille (CHU de Limoges, Limoges, France), Cedric Bretonnière (CHU de Nantes, Nantes, France), Sophie Cassaing (CHU de Toulouse, Toulouse, France), Taieb Chouaki (CHU Amiens, Amiens, France), Olivier Cointault (CHU de Toulouse, Toulouse, France), Pierre Delobel (CHU de Toulouse, Toulouse, France), Odile Eloy (CH de Versailles, Versailles, France), Stanislas Faguer (CHU de Toulouse, Toulouse, France), Jerome Guinard (CH Orléans, Orléans, France), Thierry Lepoivre (CHU de Nantes, Nantes, France), Valerie Letscher-Bru (CHU de Strasbourg, Strasbourg, France), Bertrand Marcheix (CHU de Toulouse, Toulouse, France), Alida Minoza (CHU de Poitiers, Poitiers, France), Florent Morio (CHU de Nantes, Nantes, France), Celine Nourisson (CHU Clermont-Ferrand, Clermont-Ferrand, France), André Paugam (CHU Cochin, Paris, France), Hélène Raberin (CHU St-Etienne, St Etienne, France), Beatrice Riu (CHU de Toulouse, Toulouse, France)., Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
medicine.medical_specialty, Population, Critical Care and Intensive Care Medicine, Aspergillosis, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Anesthesiology, Internal medicine, medicine, Aspergillus qPCR, Intensive care unit, 030212 general & internal medicine, Prospective cohort study, education, skin and connective tissue diseases, Mycosis, Fungal biomarkers, education.field_of_study, business.industry, Research, lcsh:Medical emergencies. Critical care. Intensive care. First aid, Cancer, lcsh:RC86-88.9, medicine.disease, 3. Good health, respiratory tract diseases, Clinical algorithm, 030228 respiratory system, Biomarker (medicine), Invasive aspergillosis, Galactomannan antigen, [SDV.IB]Life Sciences [q-bio]/Bioengineering, business
Abstract

Background The classification of invasive pulmonary aspergillosis (IPA) issued by the European Organization for the Research and Treatment of Cancer/Mycoses Study Group Education and Research Consortium (EORTC/MSGERC) is used for immunocompromised patients. An alternative algorithm adapted to the intensive care unit (ICU) population has been proposed (AspICU), but this algorithm did not include microbial biomarkers such as the galactomannan antigen and the Aspergillus quantitative PCR. The objective of the present pilot study was to evaluate a new algorithm that includes fungal biomarkers (BM-AspICU) for the diagnosis of probable IPA in an ICU population. Patients and methods Data from 35 patients with pathology-proven IPA according to European Organization for the Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSGERC)-2008 criteria were extracted from the French multicenter database of the Invasive Fungal Infections Surveillance Network (RESSIF). The patients were investigated according to the AspICU algorithm, and the BM-AspICU algorithm in analyzing the clinical, imaging, and biomarker data available in the records, without taking into account the pathology findings. Results Eight patients had to be excluded because no imaging data were recorded in the database. Among the 27 proven IPAs with complete data, 16 would have been considered as putative IPA with the AspICU algorithm and 24 would have been considered as probable IPA using the new algorithm BM-AspICU. Seven out of the 8 patients with probable BM-AspICU IPA (and not classified with the AspICU algorithm) had no host factors and no Aspergillus-positive broncho-alveolar lavage fluid (BALF) culture. Three patients were non-classifiable with any of the two algorithms, because they did not have any microbial criteria during the course of the infection, and diagnosis of proven aspergillosis was done using autopsy samples. Conclusion Inclusion of biomarkers could be effective to identify probable IPA in the ICU population. A prospective study is needed to validate the routine application of the BM-AspICU algorithm in the ICU population.

Published
2021
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48. Different repartition of the cryptic species of black aspergilli according to the anatomical sites in human infections, in a French University hospital

Author

Sophie Touratier, Dea Garcia-Hermoso, Maud Gits-Muselli, Samia Hamane, Louise Bondeelle, Stéphane Bretagne, Blandine Denis, Elisa Cherpin, Benjamin Verillaud, Alexandre Alanio, Laboratoire de Parasitologie-Mycologie [CHU Saint Louis, Paris], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de Référence Mycologie et Antifongiques-Mycologie Moléculaire (CNRMA), Institut Pasteur [Paris] (IP), Université Paris Cité (UPCité), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Département Otorhinolaryngologie, Hôpital Lariboisière Saint-Louis Fernand Widal, Assistance Publique-Hôpitaux de Paris (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Maladies infectieuses, Hopital Lariboisière Saint-Louis Fernand Widal, Assistance Publique-Hôpitaux de Paris (AP-HP), Service de pneumologie [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Cité (UPCité), Pharmacie, Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), The authors thank all the clinicians who cared for the patients and all the laboratory staff and more specifically Cécile Gautier for technical assistance regarding culture of strains and MIC determinations. We are also indebted to Françoise Dromer for her helpful comments to the manuscript., AUGUSTE, Christèle, Institut Pasteur [Paris], Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP)

Subjects
Species complex, Veterinary medicine, otomycosis, Otomycosis, Aspergillosis, 03 medical and health sciences, Aspergillus welwitschiae, medicine, Animals, Humans, Ear canal, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, 030304 developmental biology, 0303 health sciences, Aspergillus, invasive aspergillosis, biology, 030306 microbiology, Aspergillus niger, General Medicine, medicine.disease, biology.organism_classification, [SDV.MP.MYC] Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Hospitals, Infectious Diseases, Aspergillus vadensis, medicine.anatomical_structure, Aspergillus tubingensis, Black aspergilli
Abstract

Black aspergilli of the section Nigri are rarely differentiated at the species level when originating from human specimens. We wondered whether some cryptic species could be more frequently observed in some clinical entities. We analyzed the 198 black isolates consecutively collected from the external ear canal (EEC; n = 66), respiratory specimens (n = 99), and environment (n = 33). DNA was extracted and species identification was performed upon the partial calmodulin gene. We identified by decreasing frequency: Aspergillus welwitschiae (35.3%), Aspergillus tubingensis (34.3%), Aspergillus niger (17.2%), Aspergillus luchuensis (4%), Aspergillus aff. welwitschiae (3%), Aspergillus neoniger (2%), Aspergillus piperis (1.5%), Aspergillus japonicus (1.0%), Aspergillus vadensis (0.5%), and two Aspergillus tubingensis clade (1%). The distribution of the three main cryptic species was different between EEC and respiratory samples (P Lay summary We analyzed 198 black aspergilli isolates collected from different samples type to determine their species identification. We observe a different distribution of species between ear canal and respiratory samples (P

Published
2021
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49. Interlaboratory evaluation of Mucorales PCR assays for testing serum specimens: A study by the fungal PCR Initiative and the Modimucor study group

Author

Rocchi, S, Scherer, E, Mengoli, C, Alanio, A, Botterel, F, Bougnoux, M, Bretagne, S, Cogliati, M, Cornu, M, Dalle, Frédéric, Damiani, Céline, Denis, J, Fuchs, S, Gits-Muselli, M, Hagen, F, Halliday, C, Hare, R, Iriart, Xavier, Klaassen, C, Lackner, M, Lengerova, M, Letscher-Bru, V, Morio, F, Nourrisson, C, Posch, W, Sendid, B, Springer, J, Willinger, B, White, P, Barnes, R, Cruciani, M, Donnelly, J, Loeffler, J, Millon, L, Service de parasitologie et mycologie [CHRU de Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Laboratoire Chrono-environnement (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Università degli Studi di Padova = University of Padua (Unipd), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris] (IP), Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpitaux Universitaire Saint-Louis, Lariboisière, Fernand-Widal, Université Paris Cité (UPCité), Université Paris-Est Créteil Val-de-Marne - Faculté de médecine (UPEC Médecine), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), École nationale vétérinaire - Alfort (ENVA), CHU Henri Mondor [Créteil], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Biologie et Pathogénicité fongiques (BPF), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP), Università degli Studi di Milano = University of Milan (UNIMI), Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Laboratoire de parasitologie mycologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Vin Aliment Microbiologie et Stress (VAlMiS), Procédés Alimentaires et Microbiologiques (PAM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Procédés Alimentaires et Microbiologiques [Dijon] (PAM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université Bourgogne Franche-Comté [COMUE] (UBFC)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoire de parasitologie et de mycologie médicales [CHU Amiens], CHU Amiens-Picardie, Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Laboratoire de Parasitologie et de Mycologie Médicale [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Leopold Franzens Universität Innsbruck - University of Innsbruck, UFR Médecine [Santé] - Université Paris Cité (UFR Médecine UPCité), Univ Utrecht, Westerdijk Fungal Biodivers Inst, Fungal Physiol, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands, Partenaires INRAE, University Medical Center [Utrecht], Shanghai Key Laboratory of Molecular Medical Mycology, Changzheng Hospital, Second Military Medical University, Statens Serum Institut [Copenhagen], Service de Parasitologie et Mycologie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Innsbruck Medical University = Medizinische Universität Innsbruck (IMU), University Hospital Brno, CHU Strasbourg, Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Clermont-Ferrand, University Hospital Wuerzburg / Universitäts­klinikum Würzburg, Medizinische Universität Wien = Medical University of Vienna, Public Health Wales [Cardiff, Royaume uni], University of Texas Health Science Center at San Antonio [San Antonio, Tx, USA], This work was supported by a grant from the French Ministry of Health PHRC (Projet Hospitalier de Recherche Clinique) national-ModiMucor 2014-A00580-47., Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Génomique évolutive, modélisation et santé (CNRS-UMR2000), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Cité - UFR Médecine [Santé] (UPCité UFR Médecine), CHU Henri Mondor, Biologie des ARN des Pathogènes fongiques - RNA Biology of Fungal Pathogens, Institut Pasteur [Paris]-Université Paris Cité (UPCité), University of Innsbruck, Service de Parasitologie et Mycologie, CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie et Pathogénicité fongiques - Fungal Biology and Pathogenicity (BPF), Institut Pasteur [Paris]-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Padova Medical School, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Université Paris Cité - UFR Médecine Paris Centre [Santé] (UPC Médecine Paris Centre), Université Paris Cité (UPC), Institut Pasteur [Paris]-Université Paris Cité (UPC), and Università degli Studi di Milano [Milano] (UNIMI)

Subjects
standardization, MESH: Clinical Laboratory Techniques / instrumentation, MESH: Humans, MESH: Mucorales / genetics, Mucorales PCR, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, circulating DNA, MESH: Molecular Diagnostic Techniques / standards, MESH: Observer Variation, MESH: Mucormycosis / blood, MESH: Reproducibility of Results, MESH: France, interlaboratory assay, MESH: Real-Time Polymerase Chain Reaction / standards, MESH: Hospitals, University / statistics & numerical data, MESH: Clinical Laboratory Techniques / standards, MESH: DNA, Fungal / genetics, MESH: Clinical Laboratory Techniques / methods, MESH: Mucormycosis / diagnosis, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Interlaboratory evaluations of Mucorales qPCR assays were developed to assess the reproducibility and performance of methods currently used. The participants comprised 12 laboratories from French university hospitals (nine of them participating in the Modimucor study) and 11 laboratories participating in the Fungal PCR Initiative. For panel 1, three sera were each spiked with DNA from three different species (Rhizomucor pusillus, Lichtheimia corymbifera, Rhizopus oryzae). For panel 2, six sera with three concentrations of R. pusillus and L. corymbifera (1, 10, and 100 genomes/ml) were prepared. Each panel included a blind negative-control serum. A form was distributed with each panel to collect results and required technical information, including DNA extraction method, sample volume used, DNA elution volume, qPCR method, qPCR template input volume, qPCR total reaction volume, qPCR platform, and qPCR reagents used. For panel 1, assessing 18 different protocols, qualitative results (positive or negative) were correct in 97% of cases (70/72). A very low interlaboratory variability in Cq values (SD = 1.89 cycles) were observed. For panel 2 assessing 26 different protocols, the detection rates were high (77-100%) for 5/6 of spiked serum. There was a significant association between the qPCR platform and performance. However, certain technical steps and optimal combinations of factors may also impact performance. The good reproducibility and performance demonstrated in this study support the use of Mucorales qPCR as part of the diagnostic strategy for mucormycosis.

Published
2021
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50. A Short-Tandem-Repeat Assay (MmySTR) for Studying Genetic Variation in Madurella mycetomatis

Author

Annelies Verbon, Bertrand Nyuykonge, Ahmed H. Fahal, Sybren de Hoog, Willemien H A Zandijk, Kimberly Eadie, Sarah A. Ahmed, Wendy W. J. van de Sande, Marie Desnos-Ollivier, Corné H. W. Klaassen, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Radboud University Medical Center [Nijmegen], Canisius-Wilhelmina Hospital [Nijmegen, The Netherlands], University of Khartoum, Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris] (IP), Mycetoma Research Center [Khartoum] (MRC), Medical Microbiology & Infectious Diseases, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and Institut Pasteur [Paris]

Subjects
0301 basic medicine, Microbiology (medical), 030106 microbiology, Population, Biology, microsatellites, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Tandem repeat, Genotype, Multiplex polymerase chain reaction, Typing, education, Genotyping, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Genetics, education.field_of_study, Madurella mycetomatis, biology.organism_classification, short tandem repeats, 3. Good health, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], 030104 developmental biology, genotyping, MmySTR, Microsatellite, mycetoma
Abstract

International audience; Madurella mycetomatis is the major causative agent of eumycetoma, a neglected tropical infection characterized by painless subcutaneous lesions, inflammation, and grains draining from multiple sinuses. To study the epidemiology of mycetoma, a robust discriminatory typing technique is needed. We describe the use of a short-tandem-repeat assay (MmySTR) for genotyping of M. mycetomatis isolates predominantly from Sudan. Eleven microsatellite markers (3 dinucleotides, 4 trinucleotide repeats, and 4 tetranucleotide repeats) were selected from the M. mycetomatis MM55 genome using the Tandem Repeats Finder software. PCR amplification primers were designed for each microsatellite marker using primer3 software and amplified in a multicolor multiplex PCR approach. To establish the extent of genetic variation within the population, a collection of 120 clinical isolates from different regions was genotyped with this assay. The 11 selected MmySTR markers showed a large genotypic heterogeneity. From a collection of 120 isolates, 108 different genotypes were obtained. Simpson’s diversity index (D) value for individual markers ranged from 0.081 to 0.881, and the combined panel displayed an overall D value of 0.997. The MmySTR assay demonstrated high stability, reproducibility, and specificity. The MmySTR assay is a promising new typing technique that can be used to genotype isolates of M. mycetomatis. Apart from the possible contribution of host factors, the genetic diversity observed among this group of isolates might contribute to the different clinical manifestations of mycetoma. We recommend that the MmySTR assay be used to establish a global reference database for future study of M. mycetomatis isolates.

Published
2021
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