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2,617 results on '"Emerging Infectious Diseases"'

1. Lassa Fever Clinical Course and Prognostic Factors in Nigeria (LASCOPE)

Author

Institut National de la Santé Et de la Recherche Médicale, France, University of Oxford, Irrua Specialist Teaching Hospital, Bernhard Nocht Institute for Tropical Medicine, University Hospital, Bordeaux, University of Bordeaux, PACCI Program, Institut de Recherche pour le Developpement, ANRS, Emerging Infectious Diseases, Federal Medical Centre, Owo, European and Developing Countries Clinical Trials Partnership (EDCTP), and Denis Malvy, Professor of Infectious Diseases and Tropical Medicine

Published
2025

5. European Trial Into Mpox Infection (EPOXI)

Author

European Clinical Research Alliance for Infectious Diseases (ECRAID), Universiteit Antwerpen, Erasmus Medical Center, Hospital Universitario La Paz, ANRS, Emerging Infectious Diseases, and Miquel Ekkelenkamp, Clinical Microbiologist

Published
2024

7. International Study on COVID-19 Vaccine to Assess Immunogenicity, Reactogenicity and Efficacy (InVITE) (InVITE)

Author

Institut National de Recherche Biomédicale. Kinshasa, République Démocratique du Congo, Partnership for Clinical Research in Guinea/Partenariat de Recherche Clinique en Guinée (PREGUI), Partnership for Research on Ebola Virus in Liberia (PREVAIL), University Clinical Research Center, Mali, Onom Foundation and Liver Center, Mexican Emerging Infectious Diseases Clinical Research Network, and Ina-Respond

Published
2024

9. Strategic Timing of Antiretroviral Treatment (START)

Author

National Institute of Allergy and Infectious Diseases (NIAID), Copenhagen HIV Programme (CHIP) -- Copenhagen, Denmark, Medical Research Council, Kirby Institute, Washington D.C. Veterans Affairs Medical Center, ANRS, Emerging Infectious Diseases, German Federal Ministry of Education and Research, NEAT - European AIDS Treatment Network, National Health and Medical Research Council, Australia, National Institutes of Health Clinical Center (CC), National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI), National Institute of Mental Health (NIMH), National Institute of Neurological Disorders and Stroke (NINDS), National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Abbott, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme LLC, and Tibotec Pharmaceutical Limited

Published
2024

10. ISTH/ANRS 0409s INTEGRATE Lassa Fever Study

Author

Alliance for International Medical Action, University of Bordeaux, Bernhard Nocht Institute for Tropical Medicine, Federal Medical Centre, Owo, Programme PAC-CI, Site ANRS-MIE de Côte d'Ivoire, Fondation pour la Recherche Scientifique, Benin, Médecins Sans Frontières, Belgium, Alex Ekwueme Federal University Teaching Hospital, Donka Hospital, Conakry, Centre de Recherche Médicale de Lambaréné, University of Hamburg-Eppendorf, Phebe Hospital, Liberia, University of North Carolina, and ANRS, Emerging Infectious Diseases

Published
2024

14. Different Clinical Presentations of Human Rhinovirus Species Infection in Children and Adults in Mexico.

Author

Galindo-Fraga, Arturo, Guerra-de-Blas, Paola del Carmen, Ortega-Villa, Ana M, Mateja, Allyson, Quiñones, Jesus Arturo Ruiz, Cervantes, Pilar Ramos, Barrientos, Fernando Ledesma, Ortiz-Hernández, Ana A, Llamosas-Gallardo, Beatriz, Ramírez-Venegas, Alejandra, Vázquez, Rafael Valdéz, Chepitel, Daniel Noyola, Moreno-Espinosa, Sarbelio, Powers, John H, Guerrero, M Lourdes, Ruiz-Palacios, Guillermo M, Beigel, John H, and Network, for the Mexican Emerging Infectious Diseases

Subjects
INFLUENZA, SYMPTOMS, CLINICAL trial registries, LEUKOCYTES, LACTATE dehydrogenase, VIRUS identification
Abstract

Background Human rhinoviruses (HRVs) are a common cause of influenza-like illness, with the ability to infect the upper and lower respiratory tracts. In this study we aim to describe the clinical and molecular features of HRV infection in Mexican children and adults. Methods We performed a hospital-based, 4-year multicenter prospective observational cohort study of patients with influenza-like illness. Participants who tested positive for HRV were included. We described demographic, clinical, and laboratory characteristics and the association between HRV types, illness severity, and clinical outcomes. Results Of the 5662 subjects recruited, 1473 (26%) had HRV; of those, 988 (67.1%) were adults (≥18 years) and 485 (32.9%) were children. One hundred sixty-seven (11.33%) samples were sequenced; 101 (60.5%) were rhinovirus species A (HRV-A), 22 (13.2%) were rhinovirus species B (HRV-B), and 44 (26.3%) were rhinovirus species C (HRV-C). Among children and adults, 30.5% and 23.5%, respectively, were hospitalized (non–intensive care unit [ICU]). The odds of HRV-C are higher than HRV-A for participants in the ICU (compared to outpatient) and when platelets, lymphocytes, white blood cells, and lactate dehydrogenase are increased. The odds of HRV-C are higher than HRV-A and HRV-B with shortness of breath. The odds of HRV-A are higher than HRV-B, and the odds of HRV-B are higher than HRV-C, when mild symptoms like muscle ache and headache occur. Conclusions Rhinoviruses are a common cause of influenza-like illness. It is necessary to improve the surveillance, testing, and species identification for these viruses to understand different clinical presentations and risk factors associated with worse outcomes. Clinical Trials Registration. NCT01418287. [ABSTRACT FROM AUTHOR]

Published
2022
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15. Brucella effectors NyxA and NyxB target SENP3 to modulate the subcellular localisation of nucleolar proteins

Author

Arthur Louche, Amandine Blanco, Thais Lourdes Santos Lacerda, Lison Cancade-Veyre, Claire Lionnet, Célia Bergé, Monica Rolando, Frédérique Lembo, Jean-Paul Borg, Carmen Buchrieser, Masami Nagahama, Francine C. A. Gérard, Jean-Pierre Gorvel, Virginie Gueguen-Chaignon, Laurent Terradot, Suzana P. Salcedo, Microbiologie moléculaire et biochimie structurale / Molecular Microbiology and Structural Biochemistry (MMSB), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Reproduction et développement des plantes (RDP), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Biologie des Bactéries intracellulaires - Biology of Intracellular Bacteria, Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Meiji Pharmaceutical University, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), SFR Biosciences, Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CB lab was funded by the Institut Pasteur and ANR-10-LABX-62-IBEID for the Legionella experiments. These effectors were discovered under the ERA-Net Pathogenomics grant and the remaining work funded by ANR-15-CE15-0011-01 attributed to Suzana Salcedo. The work was completed with the ANR SNAPshot ANR-21-CE15-0024 attributed to Suzana Salcedo., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-15-CE15-0011,NucPath,Caractérisation du rôle cellulaire de nouveaux effecteurs bactériens ciblant les noyaux des cellules hôtes(2015), ANR-21-CE15-0024,SNAPshot,Détournement du stress nucléaire par les bactéries pathogènes(2021), Laurent, Terradot, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Caractérisation du rôle cellulaire de nouveaux effecteurs bactériens ciblant les noyaux des cellules hôtes - - NucPath2015 - ANR-15-CE15-0011 - AAPG2015 - VALID, Détournement du stress nucléaire par les bactéries pathogènes - - SNAPshot2021 - ANR-21-CE15-0024 - AAPG2021 - VALID, and École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL)

Subjects
[SDV] Life Sciences [q-bio], Multidisciplinary, [SDV]Life Sciences [q-bio], General Physics and Astronomy, General Chemistry, General Biochemistry, Genetics and Molecular Biology
Abstract

The cell nucleus is a primary target for intracellular bacterial pathogens to counteract immune responses and hijack host signalling pathways to cause disease. Here we identify two Brucella abortus effectors, NyxA and NyxB, that interfere with host protease SENP3, and this facilitates intracellular replication of the pathogen. The translocated Nyx effectors directly interact with SENP3 via a defined acidic patch (identified from the crystal structure of NyxB), preventing nucleolar localisation of SENP3 at late stages of infection. By sequestering SENP3, the effectors promote cytoplasmic accumulation of nucleolar AAA-ATPase NVL and ribosomal protein L5 (RPL5) in effector-enriched structures in the vicinity of replicating bacteria. The shuttling of ribosomal biogenesis-associated nucleolar proteins is inhibited by SENP3 and requires the autophagy-initiation protein Beclin1 and the SUMO-E3 ligase PIAS3. Our results highlight a nucleomodulatory function of two Brucella effectors and reveal that SENP3 is a crucial regulator of the subcellular localisation of nucleolar proteins during Brucella infection, promoting intracellular replication of the pathogen.

Published
2023
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16. A large-scale genomic snapshot of Klebsiella spp. isolates in Northern Italy reveals limited transmission between clinical and non-clinical settings

Author

Harry A. Thorpe, Ross Booton, Teemu Kallonen, Marjorie J. Gibbon, Natacha Couto, Virginie Passet, Sebastián López-Fernández, Carla Rodrigues, Louise Matthews, Sonia Mitchell, Richard Reeve, Sophia David, Cristina Merla, Marta Corbella, Carolina Ferrari, Francesco Comandatore, Piero Marone, Sylvain Brisse, Davide Sassera, Jukka Corander, Edward J. Feil, University of Oslo (UiO), University of Bristol [Bristol], Turku University Hospital (TYKS), University of Bath [Bath], Biodiversité et Epidémiologie des Bactéries pathogènes - Biodiversity and Epidemiology of Bacterial Pathogens, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), University of Glasgow, The Wellcome Trust Sanger Institute [Cambridge], Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione 'Istituto Neurologico Nazionale C. Mondino', Università degli Studi di Milano = University of Milan (UNIMI), Università degli Studi di Pavia = University of Pavia (UNIPV), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, This work was funded by the SpARK project, awarded to E.J.F., ‘The rates and routes of transmission of multidrug-resistant Klebsiella clones and genes into the clinic from environmental sources’, which has received funding under the 2016 Joint Programming Initiative on Antimicrobial Resistance call ‘Transmission dynamics’ (medical research council (MRC) reference no. MR/R00241X/1) and by the French Government’s Investissement d’Avenir program Laboratoire d’Excellence ‘Integrative Biology of Emerging Infectious Diseases’ (no. ANR-10-LABX-62-IBEID). J.C. and H.A.T. were funded by the European Research Council grant no. 742158. J.C. and T.K. were funded by the Norwegian Research Council grant no. 271162., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Helsinki Institute for Information Technology, Jukka Corander / Principal Investigator, Department of Mathematics and Statistics, and Department of Computer Science

Subjects
11832 Microbiology and virology, Microbiology (medical), Diversity, Carriage, Genotype, Immunology, Genomics, Cell Biology, Antimicrobial resistance, Applied Microbiology and Biotechnology, Microbiology, Pneumoniae, Association, Carbapenems, Italy, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Klebsiella, Genetics, Animals, Humans, Antibiotic-resistance
Abstract

Genomic analyses of Klebsiella isolates sampled from multiple human, animal and environmental sources in Northern Italy explore Klebsiella population diversity and show that transmission of multidrug-resistant clones between clinical and environmental settings is scarce.The Klebsiella group, found in humans, livestock, plants, soil, water and wild animals, is genetically and ecologically diverse. Many species are opportunistic pathogens and can harbour diverse classes of antimicrobial resistance genes. Healthcare-associated Klebsiella pneumoniae clones that are non-susceptible to carbapenems can spread rapidly, representing a high public health burden. Here we report an analysis of 3,482 genome sequences representing 15 Klebsiella species sampled over a 17-month period from a wide range of clinical, community, animal and environmental settings in and around the Italian city of Pavia. Northern Italy is a hotspot for hospital-acquired carbapenem non-susceptible Klebsiella and thus a pertinent setting to examine the overlap between isolates in clinical and non-clinical settings. We found no genotypic or phenotypic evidence for non-susceptibility to carbapenems outside the clinical environment. Although we noted occasional transmission between clinical and non-clinical settings, our data point to a limited role of animal and environmental reservoirs in the human acquisition of Klebsiella spp. We also provide a detailed genus-wide view of genomic diversity and population structure, including the identification of new groups.

Published
2022
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17. Variants with the N501Y mutation extend SARS-CoV-2 host range to mice, with contact transmission

Author

Sylvie Behillil, Dominique Rousset, Flora Donati, Laurine Levillayer, Grégory Jouvion, Jean Jaubert, Xavier Montagutelli, Vincent Enouf, Mélanie Albert, Sylvie van der Werf, Fabiana Gámbaro, Eduard Baquero Salazar, Etienne Simon-Loriere, Félix A. Rey, Laurine Conquet, Matthieu Prot, Génétique de la souris - Mouse Genetics, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses, Génétique fonctionnelle des maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Virologie Structurale - Structural Virology, École nationale vétérinaire - Alfort (ENVA), 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), Immunologie humorale - Humoral Immunology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Centre National de Référence des virus respiratoires (dont la grippe et le SARS-CoV2) [Paris] (CNR - laboratoire associé), Institut Pasteur de la Guyane, Réseau International des Instituts Pasteur (RIIP), This work was supported by the « URGENCE COVID-19 » fundraising campaign of Institut Pasteur), the French Government’s Investissement d’Avenir program, Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases (Grant No. ANR-10-LABX-62-IBEID), the Agence Nationale de la Recherche (Grant No. ANR-20-COVI-0028-01) and the RECOVER project funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 101003589. ESL acknowledges funding from the INCEPTION programme (Investissements d’Avenir grant ANR-16-CONV-0005)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-20-COVI-0028,HuMoCID,Développement de modèles murins de COVID-19(2020), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), and European Project: 101003589, H2020-SC1-PHE-CORONAVIRUS-2020,RECOVER(2020)

Subjects
Infectivity, Genetics, Mutation rate, variants, reservoir, mice, Rodent, biology, Sars-CoV-2, Host (biology), [SDV]Life Sciences [q-bio], transmission, RNA, host range, Virus, biology.animal, Adaptation, Receptor
Abstract

Receptor recognition is a major determinant of viral host range, as well as infectivity and pathogenesis. Emergences have been associated with serendipitous events of adaptation upon encounters with a novel host, and the high mutation rate of RNA viruses has been proposed to explain their frequent host shifts 1. SARS-CoV-2 extensive circulation in humans has been associated with the emergence of variants, including variants of concern (VOCs) with diverse mutations in the spike and increased transmissibility or immune escape 2. Here we show that unlike the initial virus, VOCs are able to infect common laboratory mice, replicating to high titers in the lungs. This host range expansion is explained in part by the acquisition of changes at key positions of the receptor binding domain that enable binding to the mouse angiotensin-converting enzyme 2 (ACE2) cellular receptor, although differences between viral lineages suggest that other factors are involved in the capacity of SARS-CoV-2 VOCs to infect mice. This abrogation of the species barrier raises the possibility of wild rodent secondary reservoirs and provides new experimental models to study disease pathophysiology and countermeasures.

Published
2023

18. Cytotoxicity of human antibodies targeting the circumsporozoite protein is amplified by 3D substrate and correlates with protection

Author

Aguirre-Botero, Manuela, Wang, Lawrence, Formaglio, Pauline, Aliprandini, Eduardo, Thiberge, Jean-Michel, Schön, Arne, Flores-Garcia, Yevel, Mathis-Torres, Shamika, Flynn, Barbara, da Silva Pereira, Lais, Le Duff, Yann, Hurley, Mathew, Nacer, Adéla, Bowyer, Paul, Zavala, Fidel, Idris, Azza, Francica, Joseph, Seder, Robert, Amino, Rogerio, Infection et Immunité paludéennes - Malaria Infection and Immunity, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), École Doctorale Bio Sorbonne Paris Cité [Paris] (ED562 - BioSPC), Université Sorbonne Paris Cité (USPC)-Université Paris Cité (UPCité), National Institutes of Health [Bethesda] (NIH), Johns Hopkins University (JHU), Johns Hopkins Malaria Research Institute [Baltimore], Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU)-Johns Hopkins University (JHU), National Institute for Biological Standards and Control (NIBSC), Medicines and Healthcare Products Regulatory Agency (MHRA), This work was supported by funds from the Institut Pasteur, the Agence Nationale de la Recherche (ANR, French National Research Agency)/Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – project number SporoSTOP ANR-19-CE15-0027, and the French Government’s Investissement d’Avenir program, Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' – project number ANR-10-LABX-62-IBEID. M.C.A.-B. is funded by the Pasteur - Paris University International PhD Program. A.S. was supported by contract HHSN261200800001E from the National Cancer Institute, NIH. Y.F.-G. and F.Z. thank the Bill and Melinda Gates Foundation and Bloomberg Philanthropies for their continued support. The antibodies provided by the Center for AIDS Reagents repository at the National Institute for Biological Standards and Control, UK (6F8 and 2C4) were produced through the European Commission FP7 European Research Infrastructures for Poverty Related Diseases (EURIPRED) project (INFRA-2012-312661), funded by the European Union’s Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 312661 – EURIPRED. The graphical abstract was created with BioRender.com, We would like to thank the team of the Center for Production and Infection of Anopheles (CEPIA, C2RA, Institut Pasteur) for providing mosquitoes, the staff of Central Animal Facility (C2RA, Institut Pasteur) for animal care, and the team of the Photonic BioImaging platform (UTechS PBI, C2RT, Institut Pasteur) for providing access to the spinning-disk microscope and support., ANR-19-CE15-0027,SporoSTOP,Neutralisation des sporozoïtes de Plasmodium dans la peau de l'hôte(2019), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), and European Project: 312661,EC:FP7:INFRA,FP7-INFRASTRUCTURES-2012-1,EURIPRED(2013)

Subjects
[SDV]Life Sciences [q-bio], [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology
Abstract

International audience; Human monoclonal antibodies (hmAbs) targeting the Plasmodium falciparum circumsporozoite protein (PfCSP) on the sporozoite surface are a promising tool for preventing malaria infection. However, their mechanisms of protection remain unclear. Here, using 13 distinctive PfCSP hmAbs, we provide a comprehensive view of how PfCSP hmAbs neutralize sporozoites in host tissues. Sporozoites are most vulnerable to hmAb-mediated neutralization in the skin. However, rare but potent hmAbs additionally neutralize sporozoites in the blood and liver. Efficient protection in tissues mainly associates with high-affinity and high-cytotoxicity hmAbs inducing rapid parasite loss-of-fitness in the absence of complement and host cells in vitro. A 3D-substrate assay greatly enhances hmAb cytotoxicity and mimics the skin-dependent protection, indicating that the physical stress imposed on motile sporozoites by the skin is crucial for unfolding the protective potential of hmAbs. This functional 3D cytotoxicity assay can thus be useful for downselecting potent anti-PfCSP hmAbs and vaccines.

Published
2023
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19. Epidemiological Evidence of Nosocomial and Zoonotic Transmission of Human T-Cell Leukemia Virus-1 in a Large Survey in a Rural Population of Central Africa

Author

Jill-Léa Ramassamy, Chanceline Bilounga Ndongo, Patrick Nnuka, Maëlle Antunes, Margot Le Mener, Edouard Betsem a Betsem, Richard Njouom, Olivier Cassar, Arnaud Fontanet, Antoine Gessain, Epidémiologie et Physiopathologie des Virus Oncogènes / Oncogenic Virus Epidemiology and Pathophysiology (EPVO (UMR_3569 / U-Pasteur_3)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Ministère de la Santé Publique [Yaoundé, Cameroun], Université de Douala, Université de Yaoundé I, Centre Pasteur du Cameroun, Réseau International des Instituts Pasteur (RIIP), Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Université Paris Cité (UPCité)-Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Paris Cité (UPCité)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), This work was supported by the European Union as part of the EboSursy project (grant number FOOD/2016/379-660 to J. L. R.), and the Institut Pasteur, France and the Centre National de la Recherche Scientifique, UMR 3569, through the Investissement d’Avenir as part of a Laboratoire d’Excellence French research program, Integrative Biology of Emerging Infectious Diseases (grant number ANR10-LBX- 62 IBEID to A. G.). Funding to pay the Open Access publication charges for this article was provided by the European Union., and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)

Subjects
Infectious Diseases, HTLV-1, [SDV]Life Sciences [q-bio], Immunology and Allergy, Cameroon HTLV-1 central Africa cross-sectional survey epidemiology nosocomial zoonoses, epidemiology, nosocomial, Cameroon, central Africa, cross-sectional survey, zoonoses
Abstract

Background Central Africa is one of the largest areas of high endemicity for human T-cell leukemia virus-1 (HTLV-1). However, no preventive measures are yet implemented to reduce its transmission, which can be sexual, from mother-to-child, or through contaminated blood products. Rare zoonotic transmissions from nonhuman primates (NHPs) have also been reported in this region. Here we investigated the HTLV-1 prevalence and associated risk factors in a rural population in Cameroon. Methods From 2019 to 2021, we performed a cross-sectional survey in the eastern region of Cameroon. HTLV-1 infection was first screened by ELISA, then tested by western blot and envelope gene targeted polymerase chain reaction. Risk factors associated with HTLV-1 infection were identified by logistic regression in univariable and multivariable analyses. Results Among 3400 participants, HTLV-1 prevalence was 1.1% (95% confidence interval [CI], .7–1.5). Factors independently associated with HTLV-1 infection were Pygmy ethnicity (adjusted odd ratio [aOR], 2.9; 95% CI, 1.3–6.2), history of surgery (aOR, 6.3; 95% CI, 2.2–17.8), and NHP bite (aOR, 6.6; 95% CI, 2.2–19.8). Conclusions These results suggest both iatrogenic and zoonotic transmission of HTLV-1 in Cameroon. Further studies are needed to assess the risk of nosocomial transmission of HTLV-1, to guide public health authorities in implementing preventive measures to control HTLV-1 transmission.

Published
2022
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20. Estimated protection against COVID-19 based on predicted neutralisation titres from multiple antibody measurements in a longitudinal cohort, France, April 2020 to November 2021

Author

Woudenberg, Tom, Pinaud, Laurie, Garcia, Laura, Tondeur, Laura, Pelleau, Stephane, de Thoisy, Alix, Donnadieu, Françoise, Backovic, Marija, Attia, Mikaël, Hozé, Nathanaël, Duru, Cécile, Koffi, Aymar Davy, Castelain, Sandrine, Ungeheuer, Marie-Noelle, Fernandes Pellerin, Sandrine, Planas, Delphine, Bruel, Timothée, Cauchemez, Simon, Schwartz, Olivier, Fontanet, Arnaud, White, Michael, Epidémiologie et Analyse des Maladies Infectieuses - Infectious Disease Epidemiology and Analytics, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Université Paris Cité (UPCité)-Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Paris Cité (UPCité)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Virologie Structurale - Structural Virology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Modélisation mathématique des maladies infectieuses - Mathematical modelling of Infectious Diseases, Hôpital de Crépy-en-Valois, Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Institut Pasteur [Paris] (IP), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Virus et Immunité - Virus and immunity (CNRS-UMR3569), This work was supported by the Fondation pour la Recherche Médicale (CorPopImm to MW), and the French Government's Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases' (Investissement d'Avenir grant n°ANR-10-LABX-62-IBEID), and INCEPTION programs (Investissement d’Avenir grant ANR-16-CONV-0005), and 'URGENCE COVID-19' fundraising campaign of Institut Pasteur (TooLab project awarded to M.B.). The COVID-Oise cohort is funded by 'Alliance Tous Unis contre le virus' Institut Pasteur, AP-HP and Fondation de France., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), and ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016)

Subjects
seroprevalence, SARS-CoV-2, humoral immunity, sero-epidemiology, viral immunity, COVID-19, antibodies, protection, neutralising antibodies, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; BackgroundThe risk of SARS-CoV-2 (re-)infection remains present given waning of vaccine-induced and infection-acquired immunity, and ongoing circulation of new variants.AimTo develop a method that predicts virus neutralisation and disease protection based on variant-specific antibody measurements to SARS-CoV-2 antigens.MethodsTo correlate antibody and neutralisation titres, we collected 304 serum samples from individuals with either vaccine-induced or infection-acquired SARS-CoV-2 immunity. Using the association between antibody and neutralisation titres, we developed a prediction model for SARS-CoV-2-specific neutralisation titres. From predicted neutralising titres, we inferred protection estimates to symptomatic and severe COVID-19 using previously described relationships between neutralisation titres and protection estimates. We estimated population immunity in a French longitudinal cohort of 905 individuals followed from April 2020 to November 2021.ResultsWe demonstrated a strong correlation between anti-SARS-CoV-2 antibodies measured using a low cost high-throughput assay and antibody response capacity to neutralise live virus. Participants with a single vaccination or immunity caused by infection were especially vulnerable to symptomatic or severe COVID-19. While the median reduced risk of COVID-19 from Delta variant infection in participants with three vaccinations was 96% (IQR: 94–98), median reduced risk among participants with infection-acquired immunity was only 42% (IQR: 22–66).ConclusionOur results are consistent with data from vaccine effectiveness studies, indicating the robustness of our approach. Our multiplex serological assay can be readily adapted to study new variants and provides a framework for development of an assay that would include protection estimates.

Published
2023
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21. Phages against Noncapsulated Klebsiella pneumoniae: Broader Host range, Slower Resistance

Author

Lourenço, Marta, Osbelt, Lisa, Passet, Virginie, Gravey, François, Megrian, Daniela, Strowig, Till, Rodrigues, Carla, Brisse, Sylvain, Biodiversité et Epidémiologie des Bactéries pathogènes - Biodiversity and Epidemiology of Bacterial Pathogens, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Helmholtz Centre for Infection Research (HZI), German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), Dynamique Microbienne associée aux Infections Urinaires et Respiratoires (DYNAMICURE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Microbiologie structurale - Structural Microbiology (Microb. Struc. (UMR_3528 / U-Pasteur_5)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), This work was mainly supported by the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR) project CRISPR-ATTACK (Advancing CRISPR antimicrobials to combat the bacterial pathogen Klebsiella pneumoniae) under the French Agence Nationale de la Recherche grant ANR-18-JAM2-0004-04, S.B. and 01KI1824 to T.S. C.R. was also supported financially by a Pasteur-Roux fellowship by the Institut Pasteur. The BEBP laboratory is supported by the French Government Investissement d’Avenir Program Laboratoire d’Excellence, Integrative Biology of Emerging Infectious Diseases (ANR10LABX62IBEID). T.S. was also supported by the Federal Ministry of Science under the project DF-AMR2:DECOLONIZE (01KI2131), JPI-AMR Germany (01KI1824) as well as by the German Center for Infection Research (DZIF, TTU 06.826)., We thank Olaya Rendueles Garcia and Eduardo Rocha for sharing the mutant strains that were used for the anti-Kd phage isolation. We thank the Biomics Platform, C2RT, Institut Pasteur, Paris, France, supported by France Génomique (ANR-10-INBS-09-09) and IBISA, especially Marc Monot, Elodie Turc, Laure Lemée and Georges Haustant, for the sequencing project management, the preparation of the genomic libraries, and the sequencing. We thank Melanie Hennart for the bioinformatics methodological input and Anne-Marie Wehenkel for the help with the protein analyses. We are grateful to Jin-Town Wang for sharing the strain NTUH-K2044. We thank Quentin Lamy-Besnier, Chiara Crestani, and Olaya Rendueles Garcia for the critical reading of the manuscript., ANR-18-JAM2-0004,CRISPRattacK(2018), and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)

Subjects
Klebsiella pneumoniae, in vivo, bacteriophages, phage therapy, bacteriophage-bacteria interactions, phage resistance, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, genomics, host range, bacteriophage therapy, antimicrobial resistance, noncapsulated mutants, phage-bacteria interactions
Abstract

International audience; Klebsiella pneumoniae (Kp), a human gut colonizer and opportunistic pathogen, is a major contributor to the global burden of antimicrobial resistance. Virulent bacteriophages represent promising agents for decolonization and therapy. However, the majority of anti-Kp phages that have been isolated thus far are highly specific to unique capsular types (anti-K phages), which is a major limitation to phage therapy prospects due to the highly polymorphic capsule of Kp. Here, we report on an original anti-Kp phage isolation strategy, using capsule-deficient Kp mutants as hosts (anti-Kd phages). We show that anti-Kd phages have a broad host range, as the majority are able to infect noncapsulated mutants of multiple genetic sublineages and O-types. Additionally, anti-Kd phages induce a lower rate of resistance emergence in vitro and provide increased killing efficiency when in combination with anti-K phages. In vivo, anti-Kd phages are able to replicate in mouse guts colonized with a capsulated Kp strain, suggesting the presence of noncapsulated Kp subpopulations. The original strategy proposed here represents a promising avenue that circumvents the Kp capsule host restriction barrier, offering promise for therapeutic development.IMPORTANCE Klebsiella pneumoniae (Kp) is an ecologically generalist bacterium as well as an opportunistic pathogen that is responsible for hospital-acquired infections and a major contributor to the global burden of antimicrobial resistance. In the last decades, limited advances have been made in the use of virulent phages as alternatives or complements to antibiotics that are used to treat Kp infections. This work demonstrates the potential value of an anti-Klebsiella phage isolation strategy that addresses the issue of the narrow host range of anti-K phages. Anti-Kd phages may be active in infection sites in which capsule expression is intermittent or repressed or in combination with anti-K phages, which often induce the loss of capsule in escape mutants.

Published
2023
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22. Characterization of Pseudomonas aeruginosa <scp>l,d</scp> -Transpeptidases and Evaluation of Their Role in Peptidoglycan Adaptation to Biofilm Growth

Author

Inès Hugonneau-Beaufet, Jean-Philippe Barnier, Stanislas Thiriet-Rupert, Sylvie Létoffé, Jean-Luc Mainardi, Jean-Marc Ghigo, Christophe Beloin, Michel Arthur, 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), 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), Université Paris Cité (UPCité), Génétique des Biofilms - Genetics of Biofilms, Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the the French National Research Agency (ANR), (grant n°ANR-19-CE15-0006-01 'PeptidoAdapt', Programme AAPG 2019 to MA and JM G). This work was also supported by the French government's Investissement d'Avenir Program, Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases' (grant n°ANR-10-LABX-62-IBEID). S.T.-R was supported by the French National Research Agency (ANR), project EvoTolAB (ANR-18-CE13-0010)., ANR-19-CE15-0006,PeptidoAdapt,Modulation de l'efficacité des antibiotiques par l'adaptation du métabolisme du peptidoglycane à la croissance en biofilm(2019), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), and ANR-18-CE13-0010,EvoTolAB,Evolution et dynamique de dissémination de la tolérance aux antibiotiques dans les biofilms(2018)

Subjects
Microbiology (medical), LD-transpeptidase, Infectious Diseases, General Immunology and Microbiology, Ecology, Physiology, Pseudomonas aeruginosa, Genetics, Cell Biology, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, biofilm
Abstract

International audience; Peptidoglycan is an essential component of the bacterial cell envelope that sustains the turgor pressure of the cytoplasm, determines cell shape, and acts as a scaffold for the anchoring of envelope polymers such as lipoproteins. The final cross-linking step of peptidoglycan polymerization is performed by classical d,d-transpeptidases belonging to the penicillin-binding protein (PBP) family and by l,d-transpeptidases (LDTs), which are dispensable for growth in most bacterial species and whose physiological functions remain elusive. In this study, we investigated the contribution of LDTs to cell envelope synthesis in Pseudomonas aeruginosa grown in planktonic and biofilm conditions. We first assigned a function to each of the three P. aeruginosa LDTs by gene inactivation in P. aeruginosa, heterospecific gene expression in Escherichia coli, and, for one of them, direct determination of its enzymatic activity. We found that the three P. aeruginosa LDTs catalyze peptidoglycan cross-linking (LdtPae1), the anchoring of lipoprotein OprI to the peptidoglycan (LdtPae2), and the hydrolysis of the resulting peptidoglycan-OprI amide bond (LdtPae3). Construction of a phylogram revealed that LDTs performing each of these three functions in various species cannot be assigned to distinct evolutionary lineages, in contrast to what has been observed with PBPs. We showed that biofilm, but not planktonic bacteria, displayed an increase proportion of peptidoglycan cross-links formed by LdtPae1 and a greater extent of OprI anchoring to peptidoglycan, which is controlled by LdtPae2 and LdtPae3. Consistently, deletion of each of the ldt genes impaired biofilm formation and potentiated the bactericidal activity of EDTA. These results indicate that LDTs contribute to the stabilization of the bacterial cell envelope and to the adaptation of peptidoglycan metabolism to growth in biofilm. IMPORTANCE Active-site cysteine LDTs form a functionally heterologous family of enzymes that contribute to the biogenesis of the bacterial cell envelope through formation of peptidoglycan cross-links and through the dynamic anchoring of lipoproteins to peptidoglycan. Here, we report the role of three P. aeruginosa LDTs that had not been previously characterized. We show that these enzymes contribute to resistance to the bactericidal activity of EDTA and to the adaptation of cell envelope polymers to conditions that prevail in biofilms. These results indicate that LDTs should be considered putative targets in the development of drug-EDTA associations for the control of biofilm-related infections.

Published
2023
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23. Plasmodium sporozoite search strategy to locate hotspots of blood vessel invasion

Author

Pauline Formaglio, Marina E. Wosniack, Raphael M. Tromer, Jaderson G. Polli, Yuri B. Matos, Hang Zhong, Ernesto P. Raposo, Marcos G. E. da Luz, Rogerio Amino, Infection et Immunité paludéennes - Malaria Infection and Immunity, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Max Planck Institute for Brain Research, Max-Planck-Gesellschaft, Universidade Federal do Rio Grande do Norte [Natal] (UFRN), Universidade Federal do Paraná (UFPR), Universidade Federal de Pernambuco [Recife] (UFPE), This work was supported by funds from the Institut Pasteur, the Agence National de la Recherche (ANR, French National Research Agency)/Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)—project number SporoSTOP ANR-19-CE15-0027, and the French Government’s Investissement d’Avenir program, Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases—project number ANR-10-LABX-62-IBEID (R.A.), Coordination for the Improvement of Higher Education Personnel (CAPES) – Program for Institutional Internationalization (PRINT) Systems Biology and Omics Sciences Applied to Biosciences and Health grant 88887.311835/2018-00 (M.G.E.L. and R.A.), Conselho National de Desenvolvimento Cientifico e Tecnologico (CNPq) grants 304532/2019-3 (M.G.E.L.) and 305062/2017-4 (E.P.R.), and Fundação de Amparo à Ciência e Tecnologia do Estado de Pernambuco (FACEPE) grant APQ-0602-1.05/14 (E.P.R.)., ANR-19-CE15-0027,SporoSTOP,Neutralisation des sporozoïtes de Plasmodium dans la peau de l'hôte(2019), and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)

Subjects
Multidisciplinary, [SDV]Life Sciences [q-bio], General Physics and Astronomy, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, General Chemistry, General Biochemistry, Genetics and Molecular Biology
Abstract

Plasmodium sporozoites actively migrate in the dermis and enter blood vessels to infect the liver. Despite their importance for malaria infection, little is known about these cutaneous processes. We combine intravital imaging in a rodent malaria model and statistical methods to unveil the parasite strategy to reach the bloodstream. We determine that sporozoites display a high-motility mode with a superdiffusive Lévy-like pattern known to optimize the location of scarce targets. When encountering blood vessels, sporozoites frequently switch to a subdiffusive low-motility behavior associated with probing for intravasation hotspots, marked by the presence of pericytes. Hence, sporozoites present anomalous diffusive motility, alternating between superdiffusive tissue exploration and subdiffusive local vessel exploitation, thus optimizing the sequential tasks of seeking blood vessels and pericyte-associated sites of privileged intravasation.

Published
2023
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24. Epithelial cells maintain memory of prior infection withStreptococcus pneumoniaethrough di-methylation of histone H3

Author

Melanie Hamon, Christine Chevalier, Claudia Chica, Justine Matheau, Michael Connor, Adrien Pain, Chromatine et Infection - Chromatin and Infection, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, École Doctorale Bio Sorbonne Paris Cité [Paris] (ED562 - BioSPC), Université Sorbonne Paris Cité (USPC)-Université Paris Cité (UPCité), Work in the Chromatin and Infection Unit (headed by Melanie Hamon) is supported by the Institut Pasteur, the Agence Nationale de la Recherche (ANR 17 CE12 0007 01 EPIBACTIN),the Fondation pour la Recherche Médicale (FRM608 EQU202003010152), the Fondation iXCore-iXLife, the Don Prix CANETTI 2020, the EMBO Young Investigator Program.M.A.H. is a member of the Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' Agence Nationale de la Recherche (ANR-10-LABX- 62-IBEID). M.G.C. is supported by a Springboard to Independence grant (AirwayStasis) from the French Government’s Investissement d’Avenir program, the Laboratoire d’Excellence ‘‘Integrative Biology of Emerging Infectious Diseases' (ANR-10-LABX-62-605IBEID) and Pasteur-Weizmann research fund. Bioinformatics and Biostatistics Hub is supported by Institut Pasteur., ANR-17-CE12-0007,EpiBactIn,Modifications epigenomiques induites par l'interaction hote-bacteries(2017), and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)

Subjects
Epigenome, Streptococcus pneumoniae, [SDV]Life Sciences [q-bio], bacterial infection, Multiple Factor Analysis, Epigenetics, H3K4me2, Histone modification, Transcriptome
Abstract

Epithelial cells are the first point of contact for bacteria entering the respiratory tract. Streptococcus pneumoniae is an obligate human pathobiont of the nasal mucosa, carried asymptomatically but also the cause of severe pneumonia. The role of the epithelium in maintaining homeostatic interactions or mounting an inflammatory response to invasive S. pneumoniae is currently poorly understood. However, studies have shown that chromatin modifications, at the histone level, induced by bacterial pathogens interfere with the host transcriptional program and promote infection. In this study, we demonstrate that S. pneumoniae actively induces di-methylation of lysine 4 on histone H3 (H3K4me2), which persists for at least 9 days upon clearance of bacteria with antibiotics. We show that infection establishes a unique epigenetic program affecting the transcriptional response of epithelial cells, rendering them more permissive upon secondary infection. Our results establish H3K4me2 as a unique modification induced by infection, distinct from H3K4me3, which localizes to enhancer regions genome-wide. Therefore, this study reveals evidence that bacterial infection leaves a memory in epithelial cells after bacterial clearance, in an epigenomic mark, thereby altering cellular responses for subsequent infection.

Published
2023
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25. Climate change and vector-borne diseases: a multi-omics approach of temperature-induced changes in the mosquito

Author

Bellone, Rachel, Lechat, Pierre, Mousson, Laurence, Gilbart, Valentine, Piorkowski, Géraldine, Bohers, Chloé, Merits, Andres, Kornobis, Etienne, Reveillaud, Julie, Paupy, Christophe, Vazeille, Marie, Martinet, Jean-Philippe, Madec, Yoann, de Lamballerie, Xavier, Dauga, Catherine, Failloux, Anna-Bella, Arbovirus et Insectes Vecteurs - Arboviruses and Insect Vectors, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Collège Doctoral, Sorbonne Université (SU), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, 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), University of Tartu, 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), Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Université Paris Cité (UPCité)-Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-Université Paris Cité (UPCité)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM)-HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), This work was supported by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 731060 (Infravec2, Research Infrastructures for the control of vector-borne diseases), the Laboratoire d’Excellence ‘Integrative Biology of Emerging Infectious Diseases’ (grant n°ANR-10-LABX-62-IBEID) and the European Union’s Horizon 2020 research and innovation programme under ZIKAlliance grant agreement No 734548., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), and European Project: 734548,ZIKAlliance(2016)

Subjects
chikungunya, [SDV]Life Sciences [q-bio], Temperature, General Medicine, Aedes albopictus
Abstract

Background Climate change and globalization contribute to the expansion of mosquito vectors and their associated pathogens. Long spared, temperate regions have had to deal with the emergence of arboviruses traditionally confined to tropical regions. Chikungunya virus (CHIKV) was reported for the first time in Europe in 2007, causing a localized outbreak in Italy, which then recurred repeatedly over the years in other European localities. This raises the question of climate effects, particularly temperature, on the dynamics of vector-borne viruses. The objective of this study is to improve the understanding of the molecular mechanisms set up in the vector in response to temperature. Methods We combine three complementary approaches by examining Aedes albopictus mosquito gene expression (transcriptomics), bacterial flora (metagenomics) and CHIKV evolutionary dynamics (genomics) induced by viral infection and temperature changes. Results We show that temperature alters profoundly mosquito gene expression, bacterial microbiome and viral population diversity. We observe that (i) CHIKV infection upregulated most genes (mainly in immune and stress-related pathways) at 20°C but not at 28°C, (ii) CHIKV infection significantly increased the abundance of Enterobacteriaceae Serratia marcescens at 28°C and (iii) CHIKV evolutionary dynamics were different according to temperature. Conclusion The substantial changes detected in the vectorial system (the vector and its bacterial microbiota, and the arbovirus) lead to temperature-specific adjustments to reach the ultimate goal of arbovirus transmission; at 20°C and 28°C, the Asian tiger mosquito Ae. albopictus was able to transmit CHIKV at the same efficiency. Therefore, CHIKV is likely to continue its expansion in the northern regions and could become a public health problem in more countries than those already affected in Europe.

Published
2023
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26. Enhanced neutralization escape to therapeutic monoclonal antibodies by SARS-CoV-2 omicron sub-lineages

Author

Franck Touret, Emilie Giraud, Jérôme Bourret, Flora Donati, Jaouen Tran-Rajau, Jeanne Chiaravalli, Frédéric Lemoine, Fabrice Agou, Etienne Simon-Lorière, Sylvie van der Werf, Xavier de Lamballerie, 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), Criblage chémogénomique et biologique (Plateforme) - Chemogenomic and Biological Screening Platform (PF-CCB), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR - laboratoire coordonnateur), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses, This work was performed in the framework of the Preclinical Study Group of the French agency for emerging infectious diseases (ANRS-MIE). It was supported by the ANRS-MIE (BIOVAR and PRI projects of the EMERGEN research program) and by the European Commission (European Virus Archive Global project (EVA GLOBAL, grant agreement No 871029) of the Horizon 2020 research and innovation program). The SVDW and ESL laboratories acknowledge funding from the European Commission (RECOVER project, grant agreement No 101003589) of the Horizon 2020 research and innovation program and by the French Government's Investissement d'Avenir program, Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases' (grant n°ANR-10-LABX-62-IBEID). The SVDW lab acknowledges funding from Santé publique France (the French national public health agency), the 'Enhancing Whole Genome Sequencing (WGS) and/or Reverse Transcription Polymerase Chain Reaction (RT-PCR) national infrastructures and capacities to respond to the COVID-19 pandemic in the European Union and European Economic Area' Grant Agreement ECDC/HERA/2021/007 ECD. 12221, and the Caisse nationale d’assurance maladie (Cnam), the national health insurance funds. The ESL laboratory acknowledges funding from the INCEPTION program (Investissements d’Avenir grant ANR-16-CONV-0005), the NIH PICREID program (Award Number U01AI151758)., We thank Pr B.Lina for providing the SARS-CoV-2 BA.2, BA.5, and XBB strains. We thank Rayane Amaral and Camille Placidi-Italia for the technical help regarding the molecular biology experiments and the cell culture. We thank Dr Cecile Baronti for her help and expertise regarding BSL3 experiments at UVE. We thank the staff of the National Reference Center for technical help, the team of the Mutualized Platform of Microbiology (P2M) at Institut Pasteur for help with sequencing and bioinformaticians of the Bioinformatics Hub at Institut Pasteur for help with sequence analysis. We are indebted to Dr. H. Mouquet (Institut Pasteur, Paris, France) for providing the Bebtelovimab/LY-Cov1404 antibody. We thank the public and private laboratories for providing specimens and aknowledge the EMERGEN genomic surveillance consortium. We acknowledge the authors, originating and submitting laboratories of the sequences from GISAID and GenBank., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), European Project: 871029,H2020,H2020-INFRAIA-2019-1,EVA-GLOBAL(2020), and European Project: 101003589, H2020-SC1-PHE-CORONAVIRUS-2020,RECOVER(2020)

Subjects
Multidisciplinary, [SDE]Environmental Sciences
Abstract

SummaryThe landscape of SARS-CoV-2 variants dramatically diversified with the simultaneous appearance of multiple sub-variants originating from BA.2, BA.4 and BA.5 Omicron sub-lineages. They harbor a specific set of mutations in the spike that can make them more evasive to therapeutic monoclonal antibodies. In this study, we compared the neutralizing potential of monoclonal antibodies against the Omicron BA.2.75.2, BQ.1, BQ.1.1 and XBB variants, with a pre-Omicron Delta variant as a reference. Sotrovimab retains some activity against BA.2.75.2, BQ.1 and XBB as it did against BA.2/BA.5, but is less active against BQ.1.1. Within the Evusheld/AZD7442 cocktail, Cilgavimab lost all activity against all subvariants studied, resulting in loss of Evusheld activity. Finally, Bebtelovimab, while still active against BA.2.75, also lost all neutralizing activity against BQ.1, BQ.1.1 and XBB variants.

Published
2023
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27. The Capsule Increases Susceptibility to Last-Resort Polymyxins, but Not to Other Antibiotics, in Klebsiella pneumoniae

Author

Francesca D’Angelo, Eduardo P. C. Rocha, Olaya Rendueles, Génomique évolutive des Microbes / Microbial Evolutionary Genomics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), F.D. was funded by an ANR (Agence National de la Recherche) JCJC grant (ANR 18 CE12 0001 01 ENCAPSULATION) awarded to O.R. The laboratory is funded by a Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' grant (ANR-10-LABX-62-IBEID) and the FRM (EQU201903007835)., We thank Jean-Marc Ghigo and Christophe Beloin for plasmid pKOBEG199 and the original KmFRT cassette, and we thank Didier Mazel for the gift of plasmid pMPIII, containing a flippase to excise kanamycin resistance, necessary for building the Δcps mutant in K. pneumoniae CIP 52.145. We are grateful to Manuel Ares Arroyo and Javier Pizarro Cerda for critical reading of the manuscript and to the Microbial Evolutionary Genomics lab for helpful discussions., ANR-18-CE12-0001,ENCAPSULATION,Le rôle évolutif des capsules dans l'adaptation bactérienne(2018), and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)

Subjects
Pharmacology, antimicrobial compounds, Infectious Diseases, multidrug resistance, capsule, Klebsiella, [SDV]Life Sciences [q-bio], Pharmacology (medical), colistin, ESKAPE pathogen
Abstract

International audience; The extracellular capsule is a virulence factor present in many facultative pathogens, but its role in antimicrobial resistance remains controversial. To shed light on this debate, we tested six antibiotics on four Klebsiella pneumoniae species complex strains. Noncapsulated strains exhibited increased tolerance to polymyxins, but not to other antibiotics, as measured using the MIC. Our results urge caution on the use of therapeutic agents that target the capsule and may result in selection for its inactivation.

Published
2023
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28. Escherichia coli Aggregates Mediated by Native or Synthetic Adhesins Exhibit Both Core and Adhesin-Specific Transcriptional Responses

Author

Yankel Chekli, Rebecca J. Stevick, Etienne Kornobis, Valérie Briolat, Jean-Marc Ghigo, Christophe Beloin, Génétique des Biofilms - Genetics of Biofilms, Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Biomics (plateforme technologique), This work was supported by grants from the French Government’s Investissement d’Avenir program, Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases (grant no. ANR-10-LABX-62-IBEID) and by the Fondation pour la Recherche Médicale (grant no. DEQ20180339185). Y.C. was supported by a MENESR (Ministère Français de l’Education Nationale, de l’Enseignement Supérieur et de la Recherche) fellowship. R.J.S. was supported by a grant from the Philippe Foundation. Biomics Platform -C2RT- was supported by France Génomique (grant no. ANR-10-INBS-09-09) and IBISA., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), and ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010)

Subjects
Microbiology (medical), tolerance, stress tolerance, General Immunology and Microbiology, Ecology, Physiology, [SDV]Life Sciences [q-bio], E. coli, antigen 43, stress response, Cell Biology, nanobodies, anaerobia, bacterial physiology, Infectious Diseases, Escherichia coli, aggregates, Genetics, Ag43
Abstract

International audience; Bacteria can rapidly tune their physiology and metabolism to adapt to environmental fluctuations. In particular, they can adapt their lifestyle to the close proximity of other bacteria or the presence of different surfaces. However, whether these interactions trigger transcriptomic responses is poorly understood. We used a specific setup of E. coli strains expressing native or synthetic adhesins mediating bacterial aggregation to study the transcriptomic changes of aggregated compared to nonaggregated bacteria. Our results show that, following aggregation, bacteria exhibit a core response independent of the adhesin type, with differential expression of 56.9% of the coding genome, including genes involved in stress response and anaerobic lifestyle. Moreover, when aggregates were formed via a naturally expressed E. coli adhesin (antigen 43), the transcriptomic response of the bacteria was more exaggerated than that of aggregates formed via a synthetic adhesin. This suggests that the response to aggregation induced by native E. coli adhesins could have been finely tuned during bacterial evolution. Our study therefore provides insights into the effect of self-interaction in bacteria and allows a better understanding of why bacterial aggregates exhibit increased stress tolerance.IMPORTANCE The formation of bacterial aggregates has an important role in both clinical and ecological contexts. Although these structures have been previously shown to be more resistant to stressful conditions, the genetic basis of this stress tolerance associated with the aggregate lifestyle is poorly understood. Surface sensing mediated by different adhesins can result in various changes in bacterial physiology. However, whether adhesin-adhesin interactions, as well as the type of adhesin mediating aggregation, affect bacterial cell physiology is unknown. By sequencing the transcriptomes of aggregated and nonaggregated cells expressing native or synthetic adhesins, we characterized the effects of aggregation and adhesin type on E. coli physiology.

Published
2023
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29. Bacterial capsular polysaccharides with antibiofilm activity share common biophysical and electrokinetic properties

Author

Joaquín Bernal-Bayard, Jérôme Thiebaud, Marina Brossaud, Audrey Beaussart, Céline Caillet, Yves Waldvogel, Laetitia Travier, Sylvie Létoffé, Thierry Fontaine, Bachra Rokbi, Philippe Talaga, Christophe Beloin, Noëlle Mistretta, Jérôme F. L. Duval, Jean-Marc Ghigo, Génétique des Biofilms - Genetics of Biofilms, Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universidad de Sevilla / University of Sevilla, Sanofi Pasteur [Marcy-l'Étoile, France], Laboratoire Interdisciplinaire des Environnements Continentaux (LIEC), Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Terre et Environnement de Lorraine (OTELo), Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Interactions cerveau-immunité - Brain-immune communication, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 842629,Salmofish, Duval, Jerome, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, and Tracing T3SS effectors in vivo during Salmonella infection in the zebrafish model - Salmofish - 0000-00-00 - 0000-00-00 - 842629 - VALID

Subjects
[SDV] Life Sciences [q-bio], Multidisciplinary, [SDV]Life Sciences [q-bio], [CHIM] Chemical Sciences, General Physics and Astronomy, [CHIM]Chemical Sciences, General Chemistry, General Biochemistry, Genetics and Molecular Biology
Abstract

Bacterial biofilms are surface-attached communities that are difficult to eradicate due to a high tolerance to antimicrobial agents. The use of non-biocidal surface-active compounds to prevent the initial adhesion and aggregation of bacterial pathogens is a promising alternative to antibiotic treatments and several antibiofilm compounds have been identified, including some capsular polysaccharides released by various bacteria. However, the lack of chemical and mechanistic understanding of the activity of these high-molecular-weight polymers limits their use for control of biofilm formation. Here, we screened a collection of 32 purified capsular polysaccharides and identified seven new compounds with non-biocidal activity against biofilms formed by Escherichia coli and/or Staphylococcus aureus. We analyzed the polysaccharide mobility under applied electric field conditions and showed that active and inactive polysaccharide polymers display distinct electrokinetic properties and that all active macromolecules shared high intrinsic viscosity features. Based on these characteristics, we identified two additional antibiofilm capsular polysaccharides with high density of electrostatic charges and their permeability to fluid flow. Our study therefore provides insights into key biophysical properties discriminating active from inactive polysaccharides. This characterization of a specific electrokinetic signature for polysaccharides displaying antibiofilm activity opens new perspectives to identify or engineer non-biocidal surface-active macromolecules to control biofilm formation in medical and industrial settings.Significance statementSome bacteria produce non-biocidal capsular polysaccharides that reduce the adhesion of bacterial pathogens to surfaces. Due to a lack of molecular and structural definition, the basis of their antiadhesion activity is unknown, thus hindering their prophylactic use for biofilm control. Here, we identified nine new active compounds and compared their composition, structure and biophysical properties with other inactive capsular polysaccharides. Despite the absence of specific molecular motif, we demonstrate that all active polysaccharides share common electrokinetic properties that distinguish them from inactive polymers. This characterization of the biophysical properties of antibiofilm bacterial polysaccharide provides key insights to engineer non-biocidal and bio-inspired surface-active compounds to control bacterial adhesion in medical and industrial settings.

Published
2023
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30. The E2 glycoprotein holds key residues for Mayaro virus adaptation to the urban Aedes aegypti mosquito

Author

Ferdinand Roesch, Chelsea Cereghino, Lucia Carrau, Alexandra Hardy, Helder Ribeiro-Filho, Annabelle Henrion Lacritick, Cassandra Koh, Jeffrey Marano, Tyler Bates, Pallavi Rai, Christina Chuong, Shamima Akter, Thomas Vallet, Hervé Blanc, Truitt Elliot, Anne M. Brown, Pawel Michalak, Tanya LeRoith, Jesse Bloom, Rafael Elias Marques, Maria-Carla Saleh, Marco Vignuzzi, James Weger-Lucarelli, Virginia Tech [Blacksburg], Populations virales et Pathogenèse - Viral Populations and Pathogenesis, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), New York University Langone Medical Center (NYU Langone Medical Center), NYU System (NYU), Centro Nacional de Pesquisa em Energia e Materiais = Brazilian Center for Research in Energy and Materials (CNPEM), Virus et Interférence ARN - Viruses and RNA Interference, George Mason University [Fairfax], Program of Genetics, Bioinformatics, and Computational Biology [Blacksburg] (GBCB), University of Haifa [Haifa], Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Howard Hughes Medical Institute [Chevy Chase] (HHMI), Howard Hughes Medical Institute (HHMI), This work was funded by the DARPA PREEMPT program administered through DARPA Cooperative Agreement HR001118S0017, this funding was awarded to M-C.S., M.V, and J.W-L. This work also received funding from Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases (grant ANR-10-LABX-62-IBEID) to M-C.S. and M.V. Further support was provided by startup funds awarded to J.W-L by the Virginia-Maryland College of Veterinary Medicine and a grant from the One Health Research Funding Program awarded to J.W-L and P.M., and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)

Subjects
Virology, Immunology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Genetics, Parasitology, Molecular Biology, Microbiology
Abstract

International audience; Adaptation to mosquito vectors suited for transmission in urban settings is a major driver in the emergence of arboviruses. To better anticipate future emergence events, it is crucial to assess their potential to adapt to new vector hosts. In this work, we used two different experimental evolution approaches to study the adaptation process of an emerging alphavirus, Mayaro virus (MAYV), to Ae. aegypti, an urban mosquito vector of many other arboviruses. We identified E2-T179N as a key mutation increasing MAYV replication in insect cells and enhancing transmission after escaping the midgut of live Ae. aegypti. In contrast, this mutation decreased viral replication and binding in human fibroblasts, a primary cellular target of MAYV in humans. We also showed that MAYV E2-T179N generates reduced viremia and displays less severe tissue pathology in vivo in a mouse model. We found evidence in mouse fibroblasts that MAYV E2-T179N is less dependent on the Mxra8 receptor for replication than WT MAYV. Similarly, exogenous expression of human apolipoprotein receptor 2 and Mxra8 enhanced WT MAYV replication compared to MAYV E2-T179N. When this mutation was introduced in the closely related chikungunya virus, which has caused major outbreaks globally in the past two decades, we observed increased replication in both human and insect cells, suggesting E2 position 179 is an important determinant of alphavirus host-adaptation, although in a virus-specific manner. Collectively, these results indicate that adaptation at the T179 residue in MAYV E2 may result in increased vector competence-but coming at the cost of optimal replication in humans-and may represent a first step towards a future emergence event.Author summary: Mosquito-borne viruses must replicate in both mosquito and vertebrate hosts to be maintained in nature successfully. When viruses that are typically transmitted by forest dwelling mosquitoes enter urban environments due to deforestation or travel, they must adapt to urban mosquito vectors to transmit effectively. For mosquito-borne viruses, the need to also replicate in a vertebrate host like humans constrains this adaptation process. Towards understanding how the emerging alphavirus, Mayaro virus, might adapt to transmission by the urban mosquito vector, Ae. aegypti, we used natural evolution approaches to identify several viral mutations that impacted replication in both mosquito and vertebrate hosts. We show that a single mutation in the receptor binding domain of E2 increased transmission by Ae. aegypti after bypassing the midgut infection barrier but simultaneously reduced replication and pathology in a mouse model. Mechanistic studies suggested that this mutation decreases the dependence of MAYV on human Mxra8 and the putative MAYV receptor human ApoER2 during replication. This suggests MAYV with this mutation alone is unlikely to be maintained in a natural transmission cycle between mosquitoes and humans. Understanding the adaptive potential of emerging viruses is critical to preventing future pandemics.

Published
2023
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32. An ancient divide in outer membrane tethering systems in bacteria suggests a mechanism for the diderm-to-monoderm transition

Author

Jerzy Witwinowski, Anna Sartori-Rupp, Najwa Taib, Nika Pende, To Nam Tham, Daniel Poppleton, Jean-Marc Ghigo, Christophe Beloin, Simonetta Gribaldo, Biologie Évolutive de la Cellule Microbienne - Evolutionary Biology of the Microbial Cell, Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plateforme BioImagerie Ultrastructurale – Ultrastructural BioImaging Platform (UTechS UBI), Institut Pasteur [Paris] (IP), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Génétique des Biofilms - Genetics of Biofilms, This work was supported by funding from the French National Research Agency (ANR) (no. Fir-OM ANR-16-CE12-0010), the Institut Pasteur’s Programmes Transversaux de Recherche (no. PTR 39-16), the French government’s Investissement d’Avenir Program, Laboratoire d’Excellence’s Integrative Biology of Emerging Infectious Diseases (grant no. ANR-10-LABX-62-IBEID) and the Fondation pour la Recherche Médicale (grant no. DEQ20180339185). N.P. is funded by a Pasteur-Roux Postdoctoral Fellowship from the Institut Pasteur. We thank A. Jiménez-Fernández for help with Veillonella genetics techniques. We thank the UTechS Photonic BioImaging (Imagopole), C2RT, Institut Pasteur (Paris, France) and the France BioImaging infrastructure network supported by the ANR (no. ANR-10–INSB–04, Investments for the Future), and the Région Ile-de-France (program Domaine d’Intérêt Majeur-Malinf) for the use of the Zeiss LSM 780 Elyra PS1 microscope. We thank S. Tachon from the NanoImaging Core facility of the Center for Technological Resources and Research of Institut Pasteur for assistance with the tomography acquisitions at the Titan Krios microscope. We thank the French Government Programme Investissements d’Avenir France BioImaging (FBI, no. ANR-10-INSB-04-01) for equipment support. We thank M. Nilges and the Equipex CACSICE (Centre d’analyse de systèmes complexes dans les environnements complexes) for providing the Falcon II direct detector. We thank the IT department at Institut Pasteur, Paris, for providing computational and storage services (TARS cluster)., ANR-16-CE12-0010,Fir-OM,Firmicutes avec une membrane externe: vers des nouveaux modeles d'étude de la transition monodermes/didermes(2016), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), and ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010)

Subjects
Microbiology (medical), Bacteria, MESH: Peptidoglycan, Lipoproteins, Immunology, MESH: Periplasm, Peptidoglycan, Cell Biology, MESH: Lipoproteins, [SDV.BID.SPT]Life Sciences [q-bio]/Biodiversity/Systematics, Phylogenetics and taxonomy, Gram-Positive Bacteria, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Applied Microbiology and Biotechnology, Microbiology, MESH: Gram-Positive Bacteria, MESH: Bacteria, Periplasm, Genetics, MESH: Phylogeny, Phylogeny
Abstract

International audience; Recent data support the hypothesis that Gram-positive bacteria (monoderms) arose from Gram-negative ones (diderms) through loss of the outer membrane (OM), but how this happened remains unknown. As tethering of the OM is essential for cell envelope stability in diderm bacteria, its destabilization may have been involved in this transition. In the present study, we present an in-depth analysis of the four known main OM-tethering systems across the Tree of Bacteria (ToB). We show that the presence of such systems follows the ToB with a bimodal distribution matching the deepest phylogenetic divergence between Terrabacteria and Gracilicutes. Whereas the lipoprotein peptidoglycan-associated lipoprotein (Pal) is restricted to the Gracilicutes, along with a more sporadic occurrence of OmpA, and Braun's lipoprotein is present only in a subclade of Gammaproteobacteria, diderm Terrabacteria display, as the main system, the OmpM protein. We propose an evolutionary scenario whereby OmpM represents a simple, ancestral OM-tethering system that was later replaced by one based on Pal after the emergence of the Lol machinery to deliver lipoproteins to the OM, with OmpA as a possible transition state. We speculate that the existence of only one main OM-tethering system in the Terrabacteria would have allowed the multiple OM losses specifically inferred in this clade through OmpM perturbation, and we provide experimental support for this hypothesis by inactivating all four ompM gene copies in the genetically tractable diderm Firmicute Veillonella parvula. High-resolution imaging and tomogram reconstructions reveal a non-lethal phenotype in which vast portions of the OM detach from the cells, forming huge vesicles with an inflated periplasm shared by multiple dividing cells. Together, our results highlight an ancient shift of OM-tethering systems in bacterial evolution and suggest a mechanism for OM loss and the multiple emergences of the monoderm phenotype from diderm ancestors.

Published
2022
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33. Impact of non-pharmaceutical interventions, weather, vaccination, and variants on COVID-19 transmission across departments in France

Author

Juliette Paireau, Marie-Laure Charpignon, Sophie Larrieu, Clémentine Calba, Nathanaël Hozé, Pierre-Yves Boëlle, Rodolphe Thiebaut, Mélanie Prague, Simon Cauchemez, Direction des maladies infectieuses - Infectious Diseases Division [Saint-Maurice], Santé publique France - French National Public Health Agency [Saint-Maurice, France], Modélisation mathématique des maladies infectieuses - Mathematical modelling of Infectious Diseases, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), MIT Institute for Data, Systems, and Society [Cambridge, MA] (IDSS), Massachusetts Institute of Technology (MIT), Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Statistics In System biology and Translational Medicine (SISTM), Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)- 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)-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), Santé publique France Nouvelle-Aquitaine [Bordeaux], Santé publique France Provence-Alpes-Côte d'azur et Corse - Provence-Alps-French Riviera and Corsica [Marseille], Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), We acknowledge financial support from the Investissement d’Avenir program, the Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases program (grant ANR-10-LABX-62-IBEID), Santé publique France, the INCEPTION project (PIA/ANR16-CONV-0005), the European Union’s Horizon 2020 research and innovation program under grants 101003589 (RECOVER) and 874735 (VEO), AXA, Groupama, the French Agency for Research on AIDS and Emerging Infectious Diseases via the EMERGEN project (ANRS0151), and the National Research Agency (ANR) through the ANR-Flash call for COVID-19 (grant ANR-20-COVI-0018)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), ANR-20-COVI-0018,TheraCoV,Dynamique virale au niveau individuel et populationnel : implications pour l'optimisation des stratégies antivirales(2020), European Project: 101003589, H2020-SC1-PHE-CORONAVIRUS-2020,RECOVER(2020), and European Project: 874735,H2020-SC1-2019-Single-Stage-RTD,VEO(2020)

Subjects
variants, Infectious Diseases, SARS-CoV-2, COVID-19, reproduction number, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, vaccination, non-pharmaceutical interventions, climate, multivariable regression model
Abstract

Background Multiple factors shape the temporal dynamics of the COVID-19 pandemic. Quantifying their relative contributions is key to guide future control strategies. Our objective was to disentangle the individual effects of non-pharmaceutical interventions (NPIs), weather, vaccination, and variants of concern (VOC) on local SARS-CoV-2 transmission. Methods We developed a log-linear model for the weekly reproduction number (R) of hospital admissions in 92 French metropolitan departments. We leveraged (i) the homogeneity in data collection and NPI definitions across departments, (ii) the spatial heterogeneity in the timing of NPIs, and (iii) an extensive observation period (14 months) covering different weather conditions, VOC proportions, and vaccine coverage levels. Findings Three lockdowns reduced R by 72.7% (95% CI 71.3–74.1), 70.4% (69.2–71.6) and 60.7% (56.4–64.5), respectively. Curfews implemented at 6/7 pm and 8/9 pm reduced R by 34.3% (27.9–40.2) and 18.9% (12.04–25.3), respectively. School closures reduced R by only 4.9% (2.0–7.8). We estimated that vaccination of the entire population would have reduced R by 71.7% (56.4–81.6), whereas the emergence of VOC (mainly Alpha during the study period) increased transmission by 44.6% (36.1–53.6) compared with the historical variant. Winter weather conditions (lower temperature and absolute humidity) increased R by 42.2% (37.3–47.3) compared to summer weather conditions. Additionally, we explored counterfactual scenarios (absence of VOC or vaccination) to assess their impact on hospital admissions. Interpretation Our study demonstrates the strong effectiveness of NPIs and vaccination and quantifies the role of weather while adjusting for other confounders. It highlights the importance of retrospective evaluation of interventions to inform future decision-making.

Published
2023
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34. Competition between lysogenic and sensitive bacteria is determined by the fitness costs of the different emerging phage-resistance strategies

Author

Olaya Rendueles, Jorge AM de Sousa, Eduardo PC Rocha, Génomique évolutive des Microbes / Microbial Evolutionary Genomics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), ANR JCJC (Agence national de recherche) grant [ANR 18 CE12-0001 01 ENCAPSULATION]Laboratoire d’Excellence ‘Integrative Biology of Emerging Infectious Diseases’ (grant ANR-10-LABX-62-IBEID)FRM [EQU201903007835], ANR-18-CE12-0001,ENCAPSULATION,Le rôle évolutif des capsules dans l'adaptation bactérienne(2018), and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)

Subjects
General Immunology and Microbiology, General Neuroscience, General Medicine, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, General Biochemistry, Genetics and Molecular Biology
Abstract

Many bacterial genomes carry prophages whose induction can eliminate competitors. In response, bacteria may become resistant by modifying surface receptors, by lysogenization, or by other poorly known processes. All these mechanisms affect bacterial fitness and population dynamics. To understand the evolution of phage resistance, we co-cultivated a phage-sensitive strain (BJ1) and a polylysogenic Klebsiella pneumoniae strain (ST14) under different phage pressures. The population yield remained stable after 30 days. Surprisingly, the initially sensitive strain remained in all populations and its frequency was highest when phage pressure was strongest. Resistance to phages in these populations emerged initially through mutations preventing capsule biosynthesis. Protection through lysogeny was rarely observed because the lysogens have increased death rates due to prophage induction. Unexpectedly, the adaptation process changed at longer time scales: the frequency of capsulated cells in BJ1 populations increased again because the production of the capsule was fine-tuned, reducing the ability of phage to absorb. Contrary to the lysogens, these capsulated-resistant clones are pan-resistant to a large panel of phages. Intriguingly, some clones exhibited transient non-genetic resistance to phages, suggesting an important role of phenotypic resistance in coevolving populations. Our results show that interactions between lysogens and sensitive strains are shaped by antagonistic co-evolution between phages and bacteria. These processes may involve key physiological traits, such as the capsule, and depend on the time frame of the evolutionary process. At short time scales, simple and costly inactivating mutations are adaptive, but in the long term, changes drawing more favorable trade-offs between resistance to phages and cell fitness become prevalent.

Published
2023
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35. MacSyFinder v2: Improved modelling and search engine to identify molecular systems in genomes

Author

Bertrand Néron, Eduardo Rocha, Rémi Denise, Marie Touchon, Sophie Abby, Charles Coluzzi, Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Génomique évolutive des Microbes / Microbial Evolutionary Genomics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University College Cork (UCC), Translational Innovation in Medicine and Complexity / Recherche Translationnelle et Innovation en Médecine et Complexité - UMR 5525 (TIMC ), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA), EPCR lab acknowledges funding from the INCEPTION project (ANR-16-CONV-0005), Equipe FRM(Fondation pour la Recherche Médicale): EQU201903007835, and Laboratoire d’Excellence IBEIDIntegrative Biology of Emerging Infectious Diseases (ANR-10-LABX-62-IBEID). SSA received financial supportfrom the CNRS and TIMC lab (INSIS 'starting grant') and the French National Research Agency,'Investissements d’avenir' program ANR-15-IDEX-02, ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), and ANR-15-IDEX-0002,UGA,IDEX UGA(2015)

Subjects
[SDV]Life Sciences [q-bio], [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM]
Abstract

Complex cellular functions are usually encoded by a set of genes in one or a few organized genetic loci in microbial genomes. Macromolecular System Finder (MacSyFinder) is a program that uses these properties to model and then annotate cellular functions in microbial genomes. This is done by integrating the identification of each individual gene at the level of the molecular system. We hereby present a major release of MacSyFinder (version 2) coded in Python 3. The code was improved and rationalized to facilitate future maintainability. Several new features were added to allow more flexible modelling of the systems. We introduce a more intuitive and comprehensive search engine to identify all the best candidate systems and sub-optimal ones that respect the models' constraints. We also introduce the novel macsydata companion tool that enables the easy installation and broad distribution of the models developed for MacSyFinder (macsy-models) from GitHub repositories. Finally, we have updated and improved MacSyFinder popular models: TXSScan to identify protein secretion systems, TFFscan to identify type IV filaments, CONJscan to identify conjugative systems, and CasFinder to identify CRISPR associated proteins. MacSyFinder and the updated models are available at: https://github.com/gem-pasteur/macsyfinder and https://github.com/macsy-models.

Published
2023
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36. Complete Genome Sequences of Bioluminescent Staphylococcus aureus Strains Xen31 and Xen36, Derived from Two Clinical Isolates

Author

Océane Blaise, Clarisse Leseigneur, Thomas Cokelaer, Elena Capuzzo, Nadira Frescaline, Olivier Dussurget, Yersinia, Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Transfusion Sanguine des Armées (CTSA), Service de Santé des Armées, Laboratoire de Physique des Plasmas (LPP), Observatoire de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École polytechnique (X)-Sorbonne Université (SU)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Biomics (plateforme technologique), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, We acknowledge funding from Institut Pasteur, Direction Générale de l’Armement, l’Agence Innovation Défense (AID), l’Agence Nationale de la Recherche (ANR-17-CE18-0011-02 and ANR-21-ASM1-0001-02), and Université Paris Cité and CNRS. O.B. was supported by an Ecole Polytechnique/AID doctoral fellowship. E.C. was supported by an Institut Pasteur/AID doctoral fellowship.The Yersinia Research Unit is a member of the Laboratory of Excellence Integrative Biology of Emerging Infectious Diseases (ANR-LBX-62-IBEID)., ANR-17-CE18-0011,NADKiller,NADK : une nouvelle cible bactérienne pour le développement d'antibiotiques(2017), ANR-21-ASM1-0001,NOVOPLASM,Un axe NOVateur pOur cicatriser les brûlures sevères infectées par l'application de PLASMa froid(2021), and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)

Subjects
Immunology and Microbiology (miscellaneous), [SDV]Life Sciences [q-bio], Genetics, Molecular Biology
Abstract

Here, we report complete genome sequences of two clinical isolates of Staphylococcus aureus , namely, Xen31 and Xen36, which have been genetically modified to express an optimized Photorhabdus luminescens luciferase operon. Xen31 and Xen36 are bioluminescent strains used widely for investigation of bacterial pathogenesis, drug discovery, and development of novel therapies.

Published
2023
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37. Intermittent antibiotic treatment of bacterial biofilms favors the rapid evolution of resistance

Author

Masaru Usui, Yutaka Yoshii, Stanislas Thiriet-Rupert, Jean-Marc Ghigo, Christophe Beloin, Rakuno Gakuen University, Génétique des Biofilms - Genetics of Biofilms, Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the French National Research Agency (ANR), project EvolTolAB (ANR-18-CE13-0010), by the French government’s Investissement d’Avenir Program, Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (grant n°ANR-10-LABX-62-IBEID) and by the Fondation pour la Recherche Médicale (grant DEQ20180339185). S.T.-R was supported by the French National Research Agency (ANR), project EvolTolAB (ANR-18-CE13-0010)., ANR-18-CE13-0010,EvoTolAB,Evolution et dynamique de dissémination de la tolérance aux antibiotiques dans les biofilms(2018), and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)

Subjects
MESH: Escherichia coli, MESH: Anti-Bacterial Agents, [SDV]Life Sciences [q-bio], MESH: Drug Resistance, Bacterial, Medicine (miscellaneous), MESH: Aminoglycosides, MESH: Biofilms, General Agricultural and Biological Sciences, General Biochemistry, Genetics and Molecular Biology
Abstract

The rise of antibiotic resistance in bacterial pathogens is a major health concern and the determinants of this emergence are actively studied. By contrast, although biofilms are an important cause of infections due to their high tolerance to a broad range of antimicrobials, much less is known on the development of antibiotic resistance within the biofilm environment, an issue potentially aggravating the current antibiotic crisis. Here, we compared the occurrence of resistance mutations in pathogenic Escherichia coli planktonic and biofilm populations exposed to clinically relevant cycles of lethal treatments with the aminoglycoside antibiotic amikacin. This experimental evolution approach revealed that mutations in sbmA and fusA are rapidly selected in biofilm but not in planktonic populations. The apparition of these bona fide resistance —and not tolerance— mutations is favored by the biofilm preexisting tolerance and high mutation rate. Moreover, we showed that while fusA mutations displayed a high fitness cost in planktonic conditions, these mutations were maintained in biofilms, a phenomenon further possibly amplified by the selection of fimH mutations favoring biofilm formation itself. Our study therefore provides new insights into the dynamic evolution of antibiotic resistance in biofilms, which could lead to clinically practical antibiotic regimen limiting biofilm-associated infections, while mitigating the emergence of worrisome antibiotic resistance mutations.

Published
2023
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38. High-throughput functional profiling of the human fungal pathogen Candida albicans genome

Author

Murielle Chauvel, Sophie Bachellier-Bassi, Anne-Marie Guérout, Keunsook K. Lee, Corinne Maufrais, Emmanuelle Permal, Juliana Pipoli Da Fonseca, Sadri Znaidi, Didier Mazel, Carol A. Munro, Christophe d’Enfert, Melanie Legrand, 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), Plasticité du Génome Bactérien - Bacterial Genome Plasticity (PGB), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK., NGeneBio [Seoul, Corée du sud], Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Biomics (plateforme technologique), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP), This work was financially supported by a Biomedical Resources grant from the Wellcome Trust (The Candida albicans ORFeome project, 088858/Z/09/Z to CAM and CD), the European Commission (FINSysB, PITN-GA-2008-214004 to CD), and the Agence Nationale de la Recherche (KANJI, ANR-08-MIE-033-01 to CD, CANDICOL, ANR-10-01 to CD). CAM would like to acknowledge support from a Royal Society Leverhulme Trust Senior Research Fellowship (SRF∖R1∖180115). We acknowledge support from the French Government’s Investissement d’Avenir program (Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases, ANR-10-LABX-62-IBEID)., ANR-08-MIEN-0033,KANJI,Colonisation et invasion de la muqueuse digestive par le champignon pathogène de l'homme Candida albicans(2008), ANR-10-PATH-0008,CANDICOL(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), and European Project: 214004,PEOPLE,FP7-PEOPLE-2007-1-1-ITN,FINSYSB(2008)

Subjects
[SDV]Life Sciences [q-bio], Candida albicans, overexpression mutants, ORFeome, General Medicine, Large-scale systematic studies, Bar-seq, Molecular Biology, Microbiology, Candida albicans ORFeome Overexpression mutants Bar-seq Large-scale systematic studies, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology
Abstract

International audience; Candida albicans is a major fungal pathogen of humans. Although its genome has been sequenced more than two decades ago, there are still over 4300 uncharacterized C. albicans genes. We previously generated an ORFeome as well as a collection of destination vectors to facilitate overexpression of C. albicans ORFs. Here, we report the construction of ~2500 overexpression mutants and their evaluation by in vitro spotting on rich medium and in a liquid pool experiment in rich medium, allowing the identification of genes whose overexpression has a fitness cost. The candidates were further validated at the individual strain level. This new resource allows large-scale screens in different growth conditions to be performed routinely. Altogether, based on the concept of identifying functionally related genes by cluster analysis, the availability of this overexpression mutant collection will facilitate the character- ization of gene functions in C. albicans.

Published
2023
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39. Yersiniomics, a Multi-Omics Interactive Database for Yersinia Species

Author

Pierre Lê-Bury, Karen Druart, Cyril Savin, Pierre Lechat, Guillem Mas Fiol, Mariette Matondo, Christophe Bécavin, Olivier Dussurget, Javier Pizarro-Cerdá, Yersinia, Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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)-Université Paris Cité (UPCité), Centre National de Référence de la Peste et autres Yersinioses - National Reference Center Plague and Yersinioses (CNR), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut de pharmacologie moléculaire et cellulaire (IPMC), 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 National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), The project received funding from Institut Pasteur, Agence de l’Innovation de Défense (AID-DGA), Université Paris Cité, CNRS, LabEX Integrative Biology of Emerging Infectious Diseases (ANR-10-LBX-62-IBEID), Fondation pour la Recherche Médicale (FDT202204015222), and the Inception program (Investissement d’Avenir grant ANR-16-CONV-0005). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication, We thank Eric D. Merkley for sharing Pacific Northwest National Laboratory data sets. We are grateful to all members of the Yersinia research unit and the French national reference center for plague and other yersiniosis for insightful discussions., and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)

Subjects
Microbiology (medical), General Immunology and Microbiology, Ecology, Physiology, proteome, synteny, Cell Biology, multi-omics, Yersinia, Infectious Diseases, Genetics, [CHIM]Chemical Sciences, RNA-Seq, microarray, genome, transcriptome, database, mass spectrometry
Abstract

International audience; The genus Yersinia includes a large variety of nonpathogenic and life-threatening pathogenic bacteria, which cause a broad spectrum of diseases in humans and animals, such as plague, enteritis, Far East scarlet-like fever (FESLF), and enteric redmouth disease. Like most clinically relevant microorganisms, Yersinia spp. are currently subjected to intense multi-omics investigations whose numbers have increased extensively in recent years, generating massive amounts of data useful for diagnostic and therapeutic developments. The lack of a simple and centralized way to exploit these data led us to design Yersiniomics, a web-based platform allowing straightforward analysis of Yersinia omics data. Yersiniomics contains a curated multi-omics database at its core, gathering 200 genomic, 317 transcriptomic, and 62 proteomic data sets for Yersinia species. It integrates genomic, transcriptomic, and proteomic browsers, a genome viewer, and a heatmap viewer to navigate within genomes and experimental conditions. For streamlined access to structural and functional properties, it directly links each gene to GenBank, the Kyoto Encyclopedia of Genes and Genomes (KEGG), UniProt, InterPro, IntAct, and the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and each experiment to Gene Expression Omnibus (GEO), the European Nucleotide Archive (ENA), or the Proteomics Identifications Database (PRIDE). Yersiniomics provides a powerful tool for microbiologists to assist with investigations ranging from specific gene studies to systems biology studies. IMPORTANCE The expanding genus Yersinia is composed of multiple nonpathogenic species and a few pathogenic species, including the deadly etiologic agent of plague, Yersinia pestis. In 2 decades, the number of genomic, transcriptomic, and proteomic studies on Yersinia grew massively, delivering a wealth of data. We developed Yersiniomics, an interactive web-based platform, to centralize and analyze omics data sets on Yersinia species. The platform allows user-friendly navigation between genomic data, expression data, and experimental conditions. Yersiniomics will be a valuable tool to microbiologists.

Published
2023
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40. Determinants of Chikungunya and O’nyong-Nyong Virus Specificity for Infection of Aedes and Anopheles Mosquito Vectors

Author

Solène Cottis, Adrien A. Blisnick, Anna-Bella Failloux, Kenneth D. Vernick, Génétique et Génomique des Insectes Vecteurs - Genetics and Genomics of Insect Vectors, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Ecole Doctorale Complexité du Vivant (ED515), Sorbonne Université (SU), Arbovirus et Insectes Vecteurs - Arboviruses and Insect Vectors, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), This work received financial support to KDV from the Agence Nationale de la Recherche, #ANR-19-CE35-0004 ArboVec, National Institutes of Health, NIAID #AI145999, and French Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' #ANR-10-LABX-62-IBEID, and to ABF from the Agence Nationale de la Recherche, #ANR-19-CE35-0004 ArboVec, and French Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' #ANR-10-LABX-62-IBEID., ANR-19-CE35-0004,ArboVEC,Barrières d'hôtes dans la spécificité des interactions entre moustiques vecteurs et arbovirus(2019), and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)

Subjects
chikungunya virus, Infectious Diseases, Aedes, Virology, [SDV]Life Sciences [q-bio], Anopheles, vector specificity, host-pathogen interactions, o'nyong-nyong virus
Abstract

International audience; Mosquito-borne diseases caused by viruses and parasites are responsible for more than 700 million infections each year. Anopheles and Aedes are the two major vectors for, respectively, malaria and arboviruses. Anopheles mosquitoes are the primary vector of just one known arbovirus, the alphavirus o’nyong-nyong virus (ONNV), which is closely related to the chikungunya virus (CHIKV), vectored by Aedes mosquitoes. However, Anopheles harbor a complex natural virome of RNA viruses, and a number of pathogenic arboviruses have been isolated from Anopheles mosquitoes in nature. CHIKV and ONNV are in the same antigenic group, the Semliki Forest virus complex, are difficult to distinguish via immunodiagnostic assay, and symptomatically cause essentially the same human disease. The major difference between the arboviruses appears to be their differential use of mosquito vectors. The mechanisms governing this vector specificity are poorly understood. Here, we summarize intrinsic and extrinsic factors that could be associated with vector specificity by these viruses. We highlight the complexity and multifactorial aspect of vectorial specificity of the two alphaviruses, and evaluate the level of risk of vector shift by ONNV or CHIKV.

Published
2023
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41. Identification and characterization of thousands of bacteriophage satellites across bacteria

Author

Jorge A Moura de Sousa, Alfred Fillol-Salom, José R Penadés, Eduardo P C Rocha, Génomique évolutive des Microbes / Microbial Evolutionary Genomics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Imperial College London, We acknowledge funding from Equipe FRM (Fondation pour la Recherche Médicale): EQU201903007835, Laboratoire d’Excellence IBEID Integrative Biology of Emerging Infectious Diseases [ANR LBX-62 IBEID AAP BOURSE S2I ROCHA]. This work used the computational and storage services (TARS cluster) provided by the IT department at Institut Pasteur, Paris., We thank Kim Seed for comments and suggestions on earlier versions of the manuscript, Graham Hatfull for helpful discussion regarding the PhiRv1 and PhiRv2 elements in M. tuberculosis, and Bertrand Néron and Fabien Mareuil from the Institut Pasteur’s Bioinformatics and Biostatistics Hub for help in the development of the Docker and Galaxy version of SatelliteFinder., and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)

Subjects
Horizontal Gene Transfer, [SDV.BID.EVO]Life Sciences [q-bio]/Biodiversity/Populations and Evolution [q-bio.PE], Mobile Genetic Elements, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, Comparative Genomics, Phage Satellites, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Abstract

Bacteriophage-bacteria interactions are affected by phage satellites, elements that exploit phages for transfer between bacterial cells. Satellites can encode defense systems, antibiotic resistance genes, and virulence factors, but their number and diversity are unknown for lack of a tool to identify them. We developed a flexible and updateable program to identify satellites in bacterial genomes – SatelliteFinder – and use it to identify the best described families: P4-like, phage inducible chromosomal islands (PICI), capsid-forming PICI, and phage-inducible chromosomal island-like elements (PLE). We vastly expanded the number of described elements to ∼5000, finding hundreds of bacterial genomes with two different families of satellites, and dozens of Escherichia coli genomes with three. Most satellites were found in Proteobacteria and Firmicutes, but some are in novel taxa such as Actinobacteria. We characterized the gene repertoires of satellites, which are variable in size and composition, and their genomic organization, which is very conserved. With the partial exception of PICI and cfPICI, there are few homologous core genes between families of satellites, and even fewer homologous to phages. Hence, phage satellites are ancient, diverse, and probably evolved multiple times independently. Occasionally, core genes of a given family of satellites are found in another, suggesting gene flow between different satellites. Given the many elements found in spite of our conservative approach, the many bacteria infected by phages that still lack known satellites, and the recent proposals for novel families, we speculate that we are at the beginning of the discovery of massive numbers and types of satellites. SatelliteFinder is accessible for the community as a Galaxy service at https://galaxy.pasteur.fr/root?tool_id=toolshed.pasteur.fr/repos/fmareuil/satellitefinder/SatelliteFinder/0.9

Published
2023
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42. Assessing vector competence of mosquitoes from northeastern France to West Nile virus and Usutu virus

Author

Jean-Philippe Martinet, Chloé Bohers, Marie Vazeille, Hubert Ferté, Laurence Mousson, Bruno Mathieu, Jérôme Depaquit, Anna-Bella Failloux, Arbovirus et Insectes Vecteurs - Arboviruses and Insect Vectors, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), 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), Institut de Parasitologie et de Pathologie Tropicale (IPPTS), Université de Strasbourg (UNISTRA), Centre Hospitalier Universitaire de Reims (CHU Reims), This study was funded by the ANSES APR-EST Grant N° 2020/01/129 (JPM, JD, BM, ABF) and the Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases' (grant n°ANR-10-LABX-62-IBEID) (ABF)., and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)

Subjects
[SDV]Life Sciences [q-bio]
Abstract

West Nile virus (WNV) and Usutu virus (USUV) are two arthropod-borne viruses that circulate in mainland France. Assessing vector competence has only been conducted so far with mosquitoes from southern France while an increasingly active circulation of WNV and USUV has been reported in the last years. The main vectors are mosquitoes of theCulexgenus and the common mosquitoCulex pipiens. Here, we measure the vector competence of five mosquito species (Aedes rusticus, Aedes albopictus, Anopheles plumbeus, Culex pipiensandCuliseta longiareolata) present in northeastern France. Field-collected populations were exposed to artificial infectious blood meal containing WNV or USUV and examined at different days post-infection. We show that (i)Cx. pipienstransmitted WNV and USUV, (ii)Ae. rusticusonly WNV, and (iii) unexpectedly,Ae. albopictustransmitted both WNV and USUV. Less surprising,An. plumbeuswas not competent for both viruses. Combined with data on distribution and population dynamics, these assessments of vector competence will help in developing a risk map and implementing appropriate prevention and control measures.Author summaryWest Nile virus (WNV) and Usutu virus (USUV) are on the rise in Europe and in France. WNV is reported in France as early as the 1960s in the Camargue and USUV more recently, in 2015 in eastern France. The re-emergence of WNV infections in the Camargue is associated with an expansion towards the North which is also favorable to maintain a viral transmission cycle. USUV frequently co-circulates with WNV sharing the same mosquito vectors.Culex pipiens, able to feed on birds and humans, is considered to be the main vector in France. Our study is the first to investigate the vector competence to WNV and USUV of five different mosquito species collected in northeastern France. We ascertain that FrenchCx. pipiensmosquitoes are competent to both WNV and USUV. More surprisingly, the mosquitoAedes albopictusfrom northeastern France was able to transmit WNV and USUV. Based on our result, we propose that surveillance of mosquitoes combined with viral detections must be implemented in northeastern France to allow early viral detection and timely intervention to prevent outbreaks of these two neurological diseases.

Published
2023
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43. Geographic distribution, clinical epidemiology and genetic diversity of the human oncogenic retrovirus HTLV-1 in Africa, the world’s largest endemic area

Author

Antoine Gessain, Jill-Léa Ramassamy, Philippe V. Afonso, Olivier Cassar, Epidémiologie et Physiopathologie des Virus Oncogènes / Oncogenic Virus Epidemiology and Pathophysiology (EPVO (UMR_3569 / U-Pasteur_3)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), The French government’s 'Investissement d’Avenir' Program, Laboratoire d’Excellence (LabEx): 'Integrative Biology of Emerging Infectious Diseases' (ANR-10-LBX-62-IBEID) and the European Union as part of the EboSursy project (FOOD/2016/379-660)., and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)

Subjects
MESH: ATL, [SDV]Life Sciences [q-bio], Immunology, MESH: HAM/TSP, MESH: Africa, MESH: Epidemiology, MESH: Genetic variability, HTLV-1, ATL, Africa, genetic variability, MESH: HTLV-1, Immunology and Allergy, epidemiology, HAM/TSP
Abstract

The African continent is considered the largest high endemic area for the oncogenic retrovirus HTLV-1 with an estimated two to five million infected individuals. However, data on epidemiological aspects, in particular prevalence, risk factors and geographical distribution, are still very limited for many regions: on the one hand, few large-scale and representative studies have been performed and, on the other hand, many studies do not include confirmatory tests, resulting in indeterminate serological results, and a likely overestimation of HTLV-1 seroprevalence. For this review, we included the most robust studies published since 1984 on the prevalence of HTLV-1 and the two major diseases associated with this infection in people living in Africa and the Indian Ocean islands: adult T-cell leukemia (ATL) and tropical spastic paraparesis or HTLV-1-associated myelopathy (HAM/TSP). We also considered most of the book chapters and abstracts published at the 20 international conferences on HTLV and related viruses held since 1985, as well as the results of recent meta-analyses regarding the status of HTLV-1 in West and sub-Saharan Africa. Based on this bibliography, it appears that HTLV-1 distribution is very heterogeneous in Africa: The highest prevalences of HTLV-1 are reported in western, central and southern Africa, while eastern and northern Africa show lower prevalences. In highly endemic areas, the HTLV-1 prevalence in the adult population ranges from 0.3 to 3%, increases with age, and is highest among women. In rural areas of Gabon and the Democratic Republic of the Congo (DRC), HTLV-1 prevalence can reach up to 10-25% in elder women. HTLV-1-associated diseases in African patients have rarely been reported in situ on hospital wards, by local physicians. With the exception of the Republic of South Africa, DRC and Senegal, most reports on ATL and HAM/TSP in African patients have been published by European and American clinicians and involve immigrants or medical returnees to Europe (France and the UK) and the United States. There is clearly a huge underreporting of these diseases on the African continent. The genetic diversity of HTLV-1 is greatest in Africa, where six distinct genotypes (a, b, d, e, f, g) have been identified. The most frequent genotype in central Africa is genotype b. The other genotypes found in central Africa (d, e, f and g) are very rare. The vast majority of HTLV-1 strains from West and North Africa belong to genotype a, the so-called ‘Cosmopolitan’ genotype. These strains form five clades roughly reflecting the geographic origin of the infected individuals. We have recently shown that some of these clades are the result of recombination between a-WA and a-NA strains. Almost all sequences from southern Africa belong to Transcontinental a-genotype subgroup.

Published
2023
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44. Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria

Author

Jérémie Rosain, Anna-Lena Neehus, Jérémy Manry, Rui Yang, Jérémie Le Pen, Wassim Daher, Zhiyong Liu, Yi-Hao Chan, Natalia Tahuil, Özden Türel, Mathieu Bourgey, Masato Ogishi, Jean-Marc Doisne, Helena M. Izquierdo, Takayoshi Shirasaki, Tom Le Voyer, Antoine Guérin, Paul Bastard, Marcela Moncada-Vélez, Ji Eun Han, Taushif Khan, Franck Rapaport, Seon-Hui Hong, Andrew Cheung, Kathrin Haake, Barbara C. Mindt, Laura Pérez, Quentin Philippot, Danyel Lee, Peng Zhang, Darawan Rinchai, Fatima Al Ali, Manar Mahmoud Ahmad Ata, Mahbuba Rahman, Jessica N. Peel, Søren Heissel, Henrik Molina, Yasemin Kendir-Demirkol, Rasheed Bailey, Shuxiang Zhao, Jonathan Bohlen, Mathieu Mancini, Yoann Seeleuthner, Marie Roelens, Lazaro Lorenzo, Camille Soudée, María Elvira Josefina Paz, María Laura González, Mohamed Jeljeli, Jean Soulier, Serge Romana, Anne-Sophie L’Honneur, Marie Materna, Rubén Martínez-Barricarte, Mathieu Pochon, Carmen Oleaga-Quintas, Alexandre Michev, Mélanie Migaud, Romain Lévy, Marie-Alexandra Alyanakian, Flore Rozenberg, Carys A. Croft, Guillaume Vogt, Jean-François Emile, Laurent Kremer, Cindy S. Ma, Jörg H. Fritz, Stanley M. Lemon, András N. Spaan, Nicolas Manel, Laurent Abel, Margaret R. MacDonald, Stéphanie Boisson-Dupuis, Nico Marr, Stuart G. Tangye, James P. Di Santo, Qian Zhang, Shen-Ying Zhang, Charles M. Rice, Vivien Béziat, Nico Lachmann, David Langlais, Jean-Laurent Casanova, Philippe Gros, Jacinta Bustamante, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hannover Medical School [Hannover] (MHH), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Institut de Recherche en Infectiologie de Montpellier (IRIM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Yong Loo Lin School of Medicine [Singapore], Hospital del Niño Jesus, San Miguel de Tucumán, Bezmiâlem Vakıf Üniversitesi, McGill University = Université McGill [Montréal, Canada], Immunité Innée - Innate Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Curie [Paris], University of North Carolina System (UNC), Garvan Institute of medical research, The University of Sydney, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Universidad de Antioquia = University of Antioquia [Medellín, Colombia], East China Normal University [Shangaï] (ECNU), Sidra Medicine [Doha, Qatar], 'Juan Pedro Garrahan' National Hospital of Pediatrics, Buenos Aires, 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 Cochin [AP-HP], Hopital Saint-Louis [AP-HP] (AP-HP), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Hôpital Ambroise Paré [AP-HP], Université de Montpellier (UM), Howard Hughes Medical Institute (HHMI), The Laboratory of Human Genetics of Infectious Diseases is supported in part by grants from Inserm, Paris Cité University, the St. Giles Foundation, The Rockefeller University, the Center for Clinical and Translational Science (UL1TR001866), the National Center for Research Resources and the National Center for Advancing Sciences, the National Institutes of Health (NIH), (R01AI095983, R01AI088364, R01AI163029, and U19AI162568), the National Institute of Allergy and Infectious Diseases, 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 ANRS Nord-Sud (ANRS-COV05), ANRS (ECTZ170784-ANRS0073), GENVIR (ANR-20-CE93-003), GENMSMD (ANR-16-CE17-0005-01), AABIFNCOV (ANR-20-CO11-0001), GenMIS-C (ANR-21-COVR-0039), SUNLIVE (ANR-19-CE15-0012-01), MAFMACRO (ANR-22-CE92-0008) grants, Ecos-NORD (ECOS N°C19S01), the Fisher Center for Alzheimer's Research Foundation, the Meyer Foundation, the JPB Foundation, the European Union’s Horizon 2020 research and innovation program (824110, EASI-Genomics), the Square Foundation, Grandir–Fonds de solidarité pour l’Enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, the French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), and REACTing-INSERM. The Laboratory of Virology and Infectious Disease was supported in part by the NIH (R01AI091707-10 to C.M.R.). J.L.P. was supported by the Francois Wallace Monahan Postdoctoral Fellowship at The Rockefeller University and the European Molecular Biology Organization Long-Term Fellowship (ALTF 380-2018). N. Marr was supported by Sidra Medicine and the Qatar National Research Fund (NPRP9-251-3-045). The Yale Center for Mendelian Genomics (UM1HG006504) was funded by the National Human Genome Research Institute, the Yale GSP Coordinating Center (U24 HG008956), and the Yale High-Performance Computing Center (S10OD018521). This research was partly supported by Calcul Québec, Compute Canada Canadian Institutes of Health Research (CIHR) Project Grant to D. Langlais. (#168959) and a CIHR Foundation Grant (to P.G.). D. Langlais was also supported by an FRQS Chercheur-Boursier Junior 1 Award and the Calgary Foundation for Innovation John R. Evans Leaders Fund. P.G. is supported by a Distinguished James McGill Professorship award from McGill University. S.M.L is supported by the NIH: R01-AI103083 and R01-AI150095. J.R. was supported by poste d’accueil Inserm'. J.R., P.B., and T.L.V were supported by the MD-PhD program of the Imagine Institute by the Bettencourt Schueller Foundation. N.L received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (852178 grant), German Research Foundation,(DFG) under Germany’s Excellence Strategy—EXC 2155—project number 390874280 and REBIRTH 'Förderung aus Mitteln des Niedersächsischen Vorab'. A.-L.N. was supported by the international PhD program of the Imagine Institute, by the Bettencourt Schueller Foundation and the fin de thèse FRM program (FDT202204015102). R.Y. was supported by the Sackler Center for Biomedicine and Nutrition, the Shapiro-Silverberg Fund for the Advancement of Translational Research at the Center for Clinical and Translational Science of the Rockefeller University, and the Research Grant Program from the Immune Deficiency Foundation. D. Lee. was supported by FRMfellowship (FDM202006011282). C.S.M was supported by an Early-Mid Career Research Fellowship from the Department of Health of the New South Wales Government of Australia. S.G.T was supported by an NHMRC Leadership 3 Investigator Grant (1176665) and NHMRC grant (1113904). M.O. was supported by the David Rockefeller Graduate Program, the Funai Foundation for Information Technology, the Honjo International Scholarship Foundation, and the New York Hideyo Noguchi Memorial Society. This work was supported by grants from ANRS (ECTZ118797), Sidaction (20-2-AEQ-12822-2), and FRM (EQU202103012774) to N. Manel, and H.I. was supported by fellowships from Institut Curie, Seneca Foundation (20941/PD/18), and ANRS (ECTZ171453). A.N.S. was supported in part by the European Union’s Horizon 2020 research and innovation program (789645 Marie Sklodowska-Curie grant). Y.-H.C. is supported by an A∗STAR International Fellowship. J. Bohlen is an EMBO postdoctoral fellow. We thank the NIH Tetramer Core Facility (NTCF) for providing the 5-OP-RU-loaded MR1 tetramer, which was developed jointly with Dr. James McCluskey, Dr. Jamie Rossjohn, and Dr. David Fairlie., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), 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), ANR-21-COVR-0039,GenMIS-C,Recherche des Déficits immunitaires innées monogéniques prédisposant au syndrome inflammatoire multisystémique chez l'enfant.(2021), ANR-19-CE15-0012,SUNLIVE,Variabilité structurale et fonctionnelle des lipides complexes chez les mycobactéries : de l'assemblage de la paroi à la physiopathologie et virulence(2019), ANR-22-CE92-0008,MAFMACRO,Genetic predisposition and the role of myeloid cells in the susceptibility to mycobacterial infection(2022), European Project: 824110,H2020-INFRAIA-2018-1,EASI-Genomics(2019), and TÜREL, ÖZDEN

Subjects
inborn errors of immunity, Temel Bilimler, [SDV]Life Sciences [q-bio], interferon-stimulated gene, Life Sciences, Molecular Biology and Genetics, Genel Biyokimya, Genetik ve Moleküler Biyoloji, IRF1, General Biochemistry, Genetics and Molecular Biology, Mycobacterium, macrophages, interferon-γ, Yaşam Bilimleri, viruses, Cytogenetic, Natural Sciences, Moleküler Biyoloji ve Genetik, Sitogenetik
Abstract

Inborn errors of human IFN-γ-dependent macrophagic immunity underlie mycobacterial diseases, whereas inborn errors of IFN-α/β-dependent intrinsic immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria and related intramacrophagic pathogens. These children have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2, which is life-threatening in individuals with impaired IFN-α/β immunity. In leukocytes or fibroblasts stimulated in vitro, IRF1-dependent responses to IFN-γ are, both quantitatively and qualitatively, much stronger than those to IFN-α/β. Moreover, IRF1-deficient mononuclear phagocytes do not control mycobacteria and related pathogens normally when stimulated with IFN-γ. By contrast, IFN-α/β-dependent intrinsic immunity to nine viruses, including SARS-CoV-2, is almost normal in IRF1-deficient fibroblasts. Human IRF1 is essential for IFN-γ-dependent macrophagic immunity to mycobacteria, but largely redundant for IFN-α/β-dependent antiviral immunity.

Published
2023
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45. 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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46. The Pga59 cell wall protein is an amyloid forming protein involved in adhesion and biofilm establishment in the pathogenic yeast Candida albicans

Author

Thierry Mourer, Mennat El Ghalid, Gérard Pehau-Arnaudet, Brice Kauffmann, Antoine Loquet, Sébastien Brûlé, Vitor Cabral, Christophe d’Enfert, Sophie Bachellier-Bassi, 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), Plateforme BioImagerie Ultrastructurale – Ultrastructural BioImaging Platform (UTechS UBI), Institut Pasteur [Paris] (IP), Biologie Moléculaire Structurale et Processus Infectieux (CNRS UMR3528), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Soutien à la Recherche de l'Institut Européen de Chimie Biologique, Université Sciences et Technologies - Bordeaux 1 (UB)-Institut Européen de Chimie et de Biologie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), 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), Biophysique Moléculaire (plateforme) - Molecular Biophysics (platform), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), T.M. is a recipient of the Pasteur-Cantarini postdoctoral fellowship from the Institut Pasteur. M.E.G. was supported by Institut Pasteur Action Initiative Concertée Mycologie and V.C. was the recipient of a PhD fellowship from the European Commission (FINSysB, PITN-GA-2008-21400). The research work was conducted in the laboratory of C.dE. is supported by the French Government’s Investissement d’Avenir programme (Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases, ANR-10-LABX-62-IBEID). This work has benefited from the Biophysical and Structural Chemistry Platform at IECB, CNRS UAR 3033, INSERM US001. We thank both UBI and PBI Core facilities from Institut Pasteur, and we are grateful for support for equipment from the French Government Programme Investissements d’Avenir France BioImaging (FBI, N° ANR-10-INSB-04-01)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), and European Project: 214004,PEOPLE,FP7-PEOPLE-2007-1-1-ITN,FINSYSB(2008)

Subjects
[SDV]Life Sciences [q-bio], Applied Microbiology and Biotechnology, Microbiology, Biotechnology
Abstract

The human commensal fungus Candida albicans can attach to epithelia or indwelling medical devices and form biofilms, that are highly tolerant to antifungal drugs and can evade the immune response. The cell surface protein Pga59 has been shown to influence adhesion and biofilm formation. Here, we present evidence that Pga59 displays amyloid properties. Using electron microscopy, staining with an amyloid fibre-specific dye and X-ray diffraction experiments, we showed that the predicted amyloid-forming region of Pga59 is sufficient to build up an amyloid fibre in vitro and that recombinant Pga59 can also adopt a cross-β amyloid fibre architecture. Further, mutations impairing Pga59 amyloid assembly led to diminished adhesion to substrates and reduced biofilm production. Immunogold labelling on amyloid structures extracted from C. albicans revealed that Pga59 is used by the fungal cell to assemble amyloids within the cell wall in response to adhesion. Altogether, our results suggest that Pga59 amyloid properties are used by the fungal cell to mediate cell-substrate interactions and biofilm formation.

Published
2023
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47. The c‐di‐ <scp>AMP</scp> ‐binding protein <scp>CbpB</scp> modulates the level of <scp>ppGpp</scp> alarmone in Streptococcus agalactiae

Author

Giovanni Covaleda‐Cortés, Ariel Mechaly, Terry Brissac, Heike Baehre, Laura Devaux, Patrick England, Bertrand Raynal, Sylviane Hoos, Myriam Gominet, Arnaud Firon, Patrick Trieu‐Cuot, Pierre Alexandre Kaminski, Biologie des Bactéries pathogènes à Gram-positif - Biology of Gram-Positive Pathogens, Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Cristallographie (Plateforme) - Crystallography (Platform), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hannover Medical School [Hannover] (MHH), Biophysique Moléculaire (plateforme) - Molecular Biophysics (platform), This work was supported by grants from the French Government ‘Laboratory of Excellence - Integrative Biology of Emerging Infectious Diseases’ (LabEx IBEID, grant number ANR-10-LABX-62-IBEID to PTC), the Fondation pour la Recherche Médicale (FRM grant number DEQ20181039599 to PTC)., We acknowledge SOLEIL for provision of synchrotron radiation facilities, and we thank the staff of beamlines PROXIMA-1 and PROXIMA-2A for assistance. The authors are grateful to the Staff of the Crystallography platform at the Institut Pasteur for robot-driven crystallization screenings. We acknowledge Eduard Baquero Salazar for his help during the early stage of this work. We also acknowledge the help of Mariette Matondo and Thibault Chaze from the Proteomics facility of Institut Pasteur., and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)

Subjects
CbpB protein, Cyclic diadenosine monophosphate (c‐di‐AMP), [SDV]Life Sciences [q-bio], X‐ray crystallography & binding, Streptococcus, Cell Biology, Potassium homeostasis, CBS domain, Molecular Biology, Biochemistry
Abstract

International audience; Cyclic di-AMP is an essential signaling molecule in Gram-positive bacteria. This second messenger regulates the osmotic pressure of the cell by interacting directly with the regulatory domains, either RCK_C or CBS domains, of several potassium and osmolyte uptake membrane protein systems. Cyclic di-AMP also targets stand-alone CBS domain proteins such as DarB in Bacillus subtilis and CbpB in Listeria monocytogenes. We show here that the CbpB protein of Group B Streptococcus binds c-di-AMP with a very high affinity. Crystal structures of CbpB reveal the determinants of binding specificity and significant conformational changes occurring upon c-di-AMP binding. Deletion of the cbpB gene alters bacterial growth in low potassium conditions most likely due to a decrease in the amount of ppGpp caused by a loss of interaction between CbpB and Rel, the GTP/GDP pyrophosphokinase.

Published
2023
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48. Discovery of Bis-Imidazoline Derivatives as New CXCR4 Ligands

Author

Zhicheng Zhou, Isabelle Staropoli, Anne Brelot, Peggy Suzanne, Aurélien Lesnard, Fanny Fontaine, Serge Perato, Sylvain Rault, Olivier Helynck, Fernando Arenzana-Seisdedos, Jana Sopkova-de Oliveira Santos, Bernard Lagane, Hélène Munier-Lehmann, Philippe Colin, Pathogénie Virale - Viral Pathogenesis, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Etudes et de Recherche sur le Médicament de Normandie (CERMN), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Chimie et Biocatalyse, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), 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), This research was funded by Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur, Agence Nationale de Recherche sur le SIDA et les hépatites Virales (ANRS- MIE) and Institut Carnot Pasteur MI, Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (Grant ANR-10-LABEX-62-IBEID). Z.Z. and P.C. were supported by a research fellowship from ANRS-MIE., and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)

Subjects
CXCR4, [SDV]Life Sciences [q-bio], Organic Chemistry, Pharmaceutical Science, therapeutic target, antagonist, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, CXCL12, HIV-1 infection, Analytical Chemistry, bis-imidazoline, Chemistry (miscellaneous), Drug Discovery, Molecular Medicine, Physical and Theoretical Chemistry
Abstract

International audience; The chemokine receptor CXCR4 and its ligand CXCL12 regulate leukocyte trafficking, homeostasis and functions and are potential therapeutic targets in many diseases such as HIV-1 infection and cancers. Here, we identified new CXCR4 ligands in the CERMN chemical library using a FRET-based high-throughput screening assay. These are bis-imidazoline compounds comprising two imidazole rings linked by an alkyl chain. The molecules displace CXCL12 binding with submicromolar potencies, similarly to AMD3100, the only marketed CXCR4 ligand. They also inhibit anti-CXCR4 mAb 12G5 binding, CXCL12-mediated chemotaxis and HIV-1 infection. Further studies with newly synthesized derivatives pointed out to a role of alkyl chain length on the bis-imidazoline properties, with molecules with an even number of carbons equal to 8, 10 or 12 being the most potent. Interestingly, these differ in the functions of CXCR4 that they influence. Site-directed mutagenesis and molecular docking predict that the alkyl chain folds in such a way that the two imidazole groups become lodged in the transmembrane binding cavity of CXCR4. Results also suggest that the alkyl chain length influences how the imidazole rings positions in the cavity. These results may provide a basis for the design of new CXCR4 antagonists targeting specific functions of the receptor.

Published
2023
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49. Microbiota-induced active translocation of peptidoglycan across the intestinal barrier dictates its within-host dissemination

Author

Richard Wheeler, Paulo André Dias Bastos, Olivier Disson, Aline Rifflet, Ilana Gabanyi, Julia Spielbauer, Marion Bérard, Marc Lecuit, Ivo Gomperts Boneca, Biologie et Génétique de la Paroi bactérienne - Biology and Genetics of Bacterial Cell Wall, Institut Pasteur [Paris] (IP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Perception et Mémoire / Perception and Memory, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Microenvironnement et Immunité - Microenvironment and Immunity, Animalerie Centrale (plateforme) - Central Animal Facility (platform) (C2RA), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Centre National de Référence Listeria - National Reference Center Listeria (CNR), Centre collaborateur de l'OMS Listeria / WHO Collaborating Centre Listeria (CC-OMS / WHO-CC), Institut Pasteur [Paris] (IP)-Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This project has received funding from the Institut Carnot Pasteur Microbes & Santé, and the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no 665807. A.R. and I.G.B. laboratory were supported by Investissement d’Avenir program, Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (ANR-10-LABX-62-IBEID). I.G.B. laboratory was also supported by the Investissement d’Avenir program (RHU Torino Lumière ANR-16-RHUS-0008), by the French National Research Agency (ANR-16-CE15-0021) and by R&D grants from Danone and MEIJI. Additional funding was provided by DIM1Health., We thank the UTechS PBI, a member of the France–BioImaging infrastructure network supported by the French National Research Agency (ANR-10–INSB–04, Investments for the future) for microscope usage and assistance. We thank the members of the Centre for Gnotobiology Platform of the Institut Pasteur (especially Thierry Angélique, Eddie Maranghi, Martine Jacob, and Marisa Gabriela Lopez Dieguez), and of the Institut Pasteur Central Animal Facility for all their assistance with animal studies. P.A.D.B. was part of the Pasteur-Paris University International PhD Program., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), ANR-16-RHUS-0008,LUMIERE,LUMIERE(2016), ANR-16-CE15-0021,PG-Brain,Modulation de l'activité du cerveau par le peptidoglycan bactérien(2016), and European Project: 665807,H2020,H2020-MSCA-COFUND-2014,PASTEURDOC(2015)

Subjects
Multidisciplinary, gut microbiota, systemic trafficking, [SDV.BA]Life Sciences [q-bio]/Animal biology, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], peptidoglycan, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Abstract

International audience; Peptidoglycan, the major structural polymer forming the cell wall of bacteria, is an important mediator of physiological and behavioral effects in mammalian hosts. These effects are frequently linked to its translocation from the intestinal lumen to host tissues. However, the modality and regulation of this translocation across the gut barrier has not been precisely addressed. In this study, we characterized the absorption of peptidoglycan across the intestine and its systemic dissemination. We report that peptidoglycan has a distinct tropism for host organs when absorbed via the gut, most notably by favoring access to the brain. We demonstrate that intestinal translocation of peptidoglycan occurs through a microbiota-induced active process. This process is regulated by the parasympathetic pathway via the muscarinic acetylcholine receptors. Together, this study reveals fundamental parameters concerning the uptake of a major microbiota molecular signal from the steady-state gut.

Published
2023
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50. Impact of Green Gold Nanoparticle Coating on Internalization, Trafficking, and Efficiency for Photothermal Therapy of Skin Cancer

Author

Clément Bonamy, Sabrina Pesnel, Maroua Ben Haddada, Olivier Gorgette, Christine Schmitt, Anne-Laure Morel, Nathalie Sauvonnet, Torskal [Sainte-Clotilde, La Réunion], Intracellular Trafficking and Tissue Homeostasis, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Plate-forme de bioimagerie ultrastructurale - Ultrastructural BioImaging Core Facility, We thank ASSU 2000 for supporting NS. We are grateful for support for UBI equipment from the French Government Programme Investissements d’Avenir France BioImaging (FBI, N° ANR-10-INSB-04-01) and the French gouvernement (Agence Nationale de la Recherche) Investissement d’Avenir programme, Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (ANR-10-LABX-62-IBEID)., ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)

Subjects
General Chemical Engineering, [SDV]Life Sciences [q-bio], [CHIM]Chemical Sciences, General Chemistry
Abstract

International audience; Skin cancer is a global health issue and mainly composed of melanoma and nonmelanoma cancers. For the first clinical proof of concept on humans, we decided to study good prognosis skin cancers, i.e., carcinoma basal cell. In UE, the first-line treatment remains surgical resection, healing most of the tumors, but presents aesthetic disadvantages with a high reoccurrence rate on exposed areas. Moreover, the therapeutic indications could extend to melanoma and metastasis, which is a different medical strategy that could combine this treatment. Indeed, patients with late-stage melanoma are in a therapeutic impasse, despite recent targeted and immunological therapies. Photothermal therapy using gold nanoparticles is the subject of many investigations due to their strong potential to treat cancers by physical, thermal destruction. We developed gold nanoparticles synthesized by green chemistry (gGNPs), using endemic plant extract from Reunion Island, which have previously showed their efficiency at a preclinical stage. Here, we demonstrate that these gGNPs are less cytotoxic than gold nanoparticles synthesized by Turkevich’s method. Furthermore, our work describes the optimization of gGNP coating and stabilization, also taking into consideration the gGNP path in cells (endocytosis, intracellular trafficking, and exocytosis), their specificity toward cancerous cells, their cytotoxicity, and their in vivo efficiency. Finally, based on the metabolic switch of cancerous cells overexpressing Glut transporters in skin cancers, we demonstrated that glucose-stabilized gGNP (gGNP@G) enables a quick internalization, fourfold higher in cancerous cells in contrast to healthy cells with no side cytotoxicity, which is particularly relevant to target and treat cancer.

Published
2023
Full Text
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