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1. Nasopharyngeal and serological anti SARS-CoV-2 IgG/IgA responses in COVID-19 patients

Author

Bernadette Crescenzo-Chaigne, Sylvie Behillil, Vincent Enouf, Nicolas Escriou, Stephane Petres, Marie Noelle Ungeheuer, Jade Ghosn, Sarah Tubiana, Lila Bouadma, Sylvie van der Werf, and Caroline Demeret

Subjects
SARS CoV, Mucosal Immunity, Serology, Infectious and parasitic diseases, RC109-216
Abstract

Background: The systemic antibody responses to SARS-CoV-2 in COVID-19 patients has been extensively studied. However, less is known about the mucosal responses in the upper airways, the site of initial SARS-CoV-2 replication. Methods: The IgG and IgA antibody responses were analysed in plasma and nasopharyngeal swabs from the first four confirmed COVID-19 patients in France. Two were pauci-symptomatic while two developed severe disease. We characterized their antibody profiles by using an in-house ELISA to detect antibodies directed against SARS-CoV-2 Nucleoprotein and Spike. Results: Anti-N IgG and IgA antibodies were detected in the NPS of severe patients only. The levels of antibodies in the plasma markedly differed amongst the patients. The most distinctive features are a strong anti-N IgG response in the severe patient who recovered, and a high anti-N IgA response specifically detected in the fatal case of COVID-19. Conclusions: Anti-N IgG and IgA antibodies are detected in NPS only for severe patients, with levels related to serological antibodies. The severe patients showed different antibody profiles in the plasma, notably regarding the IgA and IgG response to the N antigen, that may reflect different disease outcome. By contrast, pauci-symptomatic patients did not exhibit any mucosal antibodies in NSP, which is associated with a low or absent serological response against both N and S.

Published
2021
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2. Broad range molecular detection methods identify only Borrelia spp. in erythema migrans biopsies and blood of tick-bitten patients

Author

Philippe Pérot, Laura Tondeur, Sara Moutailler, Delphine Chrétien, Nicole Corre-Catelin, Muriel Vayssier-Taussat, Marc Eloit, Catherine Chirouze, Céline Cazorla, Laurence Arowas, Elisabeth Botelho-Nevers, Pascale Frey-Klett, Arnaud Fontanet, Clémence Galon, Karine Lacombe, Véronique Perronne, Valentine Piquard, Marie Préau, Costanza Puppo, Marie-Noelle Ungeheuer, and Ayla Zayoud

Subjects
Ticks, Lyme disease, Erythema migrans, Metagenomics, RT-PCR, Pathogen discovery, Medicine (General), R5-920
Abstract

In this multicenter study conducted in France, we challenged the hypothesis of the transmission of pathogens other than Borrelia spp. in 22 patients developing erythema migrans following a tick bite. Using a combination of high-throughput microfluidic PCRs and agnostic metagenomics on skin biopsies and blood samples, no microorganisms other than Borrelia spp. was found.

Published
2024
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3. Age-associated gut microbiota impairs hippocampus-dependent memory in a vagus-dependent manner

Author

Damien Rei, Soham Saha, Marianne Haddad, Anna Haider Rubio, Blanca Liliana Perlaza, Marion Berard, Marie-Noelle Ungeheuer, Harry Sokol, and Pierre-Marie Lledo

Subjects
Aging, Neuroscience, Medicine
Abstract

Aging is known to be associated with hippocampus-dependent memory decline, but the underlying causes of this age-related memory impairment remain highly debated. Here, we show that fecal microbiota transplantation (FMT) from aged, but not young, animal donors into young mice is sufficient to trigger profound hippocampal alterations, including astrogliosis, decreased adult neurogenesis, decreased novelty-induced neuronal activation, and impairment in hippocampus-dependent memory. Furthermore, similar alterations were reported when mice were subjected to an FMT from aged human donors. To decipher the mechanisms involved in mediating these microbiota-induced effects on brain function, we mapped the vagus nerve–related (VN-related) neuronal activity patterns and report that aged FMT animals showed a reduction in neuronal activity in the ascending-VN output brain structure, whether under basal condition or after VN stimulation. Targeted pharmacogenetic manipulation of VN-ascending neurons demonstrated that the decrease in vagal activity is detrimental to hippocampal functions. In contrast, increasing vagal ascending activity alleviated the adverse effects of aged mouse FMT on hippocampal functions and had a promnesic effect in aged mice. Thus, pharmacogenetic VN stimulation is a potential therapeutic strategy to lessen microbiota-dependent age-associated impairments in hippocampal functions.

Published
2022
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4. Are International Units of Anti-HBs Antibodies Always Indicative of Hepatitis B Virus Neutralizing Activity?

Author

Yada Aronthippaitoon, Nathan Szerman, Nicole Ngo-Giang-Huong, Syria Laperche, Marie-Noelle Ungeheuer, Camille Sureau, Woottichai Khamduang, and Catherine Gaudy-Graffin

Subjects
HBV vaccine, anti-HBs international units, anti-HBs neutralizing activity, HBV infectivity neutralization, Medicine
Abstract

Objective: Anti-HBs antibodies are elicited upon hepatitis B vaccination, and concentrations above 10 mIU/mL are considered protective. Our aim was to assess the relationship between IU/mL of anti-HBs and neutralization activity. Methods: Immunoglobulins G (IgGs) were purified from individuals who received a serum-derived vaccine (Group 1), a recombinant vaccine, Genevac-B or Engerix-B (Group 2), or who recovered from acute infection (Group 3). IgGs were tested for anti-HBs, anti-preS1, and anti-preS2 antibodies and for their neutralizing activity in an in vitro infection assay. Results: Anti-HBs IUs/mL value did not strictly correlate with neutralization activity. The Group 1 antibodies demonstrated a greater neutralizing activity than those of Group 2. Anti-preS1 antibodies were detected in Groups 1 and 3, and anti-preS2 in Group 1 and Group 2/Genhevac-B, but the contribution of anti-preS antibodies to neutralization could not be demonstrated. Virions bearing immune escape HBsAg variants were less susceptible to neutralization than wild-type virions. Conclusion. The level of anti-HBs antibodies in IUs is not sufficient to assess neutralizing activity. Consequently, (i) an in vitro neutralization assay should be included in the quality control procedures of antibody preparations intended for HB prophylaxis or immunotherapy, and (ii) a greater emphasis should be placed on ensuring that vaccine genotype/subtype matches with that of the circulating HBV.

Published
2023
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5. Asymptomatic and symptomatic SARS-CoV-2 infections elicit polyfunctional antibodies

Author

Jérémy Dufloo, Ludivine Grzelak, Isabelle Staropoli, Yoann Madec, Laura Tondeur, François Anna, Stéphane Pelleau, Aurélie Wiedemann, Cyril Planchais, Julian Buchrieser, Rémy Robinot, Marie-Noelle Ungeheuer, Hugo Mouquet, Pierre Charneau, Michael White, Yves Lévy, Bruno Hoen, Arnaud Fontanet, Olivier Schwartz, and Timothée Bruel

Subjects
SARS-CoV-2, ADCC, complement, asymptomatic, antibody, Medicine (General), R5-920
Abstract

Summary: Many SARS-CoV-2-infected individuals remain asymptomatic. Little is known about the extent and quality of their antiviral humoral response. Here, we analyze antibody functions in 52 asymptomatic infected individuals, 119 mildly symptomatic, and 21 hospitalized patients with COVID-19. We measure anti-spike immunoglobulin G (IgG), IgA, and IgM levels with the S-Flow assay and map IgG-targeted epitopes with a Luminex assay. We also evaluate neutralization, complement deposition, and antibody-dependent cellular cytotoxicity (ADCC) using replication-competent SARS-CoV-2 or reporter cell systems. We show that COVID-19 sera mediate complement deposition and kill infected cells by ADCC. Sera from asymptomatic individuals neutralize the virus, activate ADCC, and trigger complement deposition. Antibody levels and functions are lower in asymptomatic individuals than they are in symptomatic cases. Antibody functions are correlated, regardless of disease severity. Longitudinal samplings show that antibody functions follow similar kinetics of induction and contraction. Overall, asymptomatic SARS-CoV-2 infection elicits polyfunctional antibodies neutralizing the virus and targeting infected cells.

Published
2021
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6. Complement-dependent mpox-virus-neutralizing antibodies in infected and vaccinated individuals

Author

Mathieu Hubert, Florence Guivel-Benhassine, Timothée Bruel, Françoise Porrot, Delphine Planas, Jessica Vanhomwegen, Aurélie Wiedemann, Sonia Burrel, Stéphane Marot, Romain Palich, Gentiane Monsel, Harouna Diombera, Sébastien Gallien, Jose Luis Lopez-Zaragoza, William Vindrios, Fabien Taieb, Sandrine Fernandes-Pellerin, Maurine Delhaye, Hélène Laude, Laurence Arowas, Marie-Noelle Ungeheuer, Laurent Hocqueloux, Valérie Pourcher, Thierry Prazuck, Anne-Geneviève Marcelin, Jean-Daniel Lelièvre, Christophe Batéjat, Yves Lévy, Jean-Claude Manuguerra, and Olivier Schwartz

Subjects
Virology, Parasitology, Microbiology
Published
2023

7. SHERLOCK4HAT: A CRISPR-based tool kit for diagnosis of Human African Trypanosomiasis

Author

Núria Sima, Annick Dujeancourt-Henry, Blanca Liliana Perlaza, Marie-Noelle Ungeheuer, Brice Rotureau, Lucy Glover, Biologie moléculaire des Trypanosomes - Trypanosome Molecular Biology, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Biologie cellulaire des Trypanosomes - Trypanosome Cell Biology, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut Pasteur de Guinée, Réseau International des Instituts Pasteur (RIIP), Institut Pasteur (PTR-175 SHERLOCK4HAT), French Government's Investissement d’Avenir program Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases (LabEx IBEID), and Agence Nationale pour la Recherche (ANR-PRC 2021 SherPa)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), and ANR-21-CE17-0022,SherPa,Développement d'une plateforme SHERLOCK pour la détection polyvalente des parasites trypanosomatidés.(2021)

Subjects
Trypanosomiasis, African, [SDV]Life Sciences [q-bio], Trypanosoma brucei gambiense, HAT, Humans, Animals, Diagnostic, Trypanosoma brucei, General Medicine, General Biochemistry, Genetics and Molecular Biology, SHERLOCK
Abstract

To achieve elimination of Human African Trypanosomiasis (HAT) caused by Trypanosoma brucei gambiense (gHAT), the development of highly sensitive diagnostics is needed. We have developed a CRISPR based diagnostic for HAT using SHERLOCK (Specific High-sensitivity Enzymatic Reporter unLOCKing) that is readily adaptable to a field-based setting.We adapted SHERLOCK for the detection of T. brucei species. We targeted 7SLRNA, TgSGP and SRA genes and tested SHERLOCK against RNA from blood, buffy coat, dried blood spots (DBS), and clinical samples.The pan-Trypanozoon 7SLRNA and T. b. gambiense-specific TgSGP SHERLOCK assays had a sensitivity of 0.1 parasite/μL and a limit of detection 100 molecules/μL. T. b. rhodesiense-specific SRA had a sensitivity of 0.1 parasite/μL and a limit of detection of 10 molecules/μL. TgSGP SHERLOCK and SRA SHERLOCK detected 100% of the field isolated strains. Using clinical specimens from the WHO HAT cryobank, the 7SLRNA SHERLOCK detected trypanosomes in gHAT samples with 56.1%, 95% CI [46.25-65.53] sensitivity and 98.4%, 95% CI [91.41-99.92] specificity, and rHAT samples with 100%, 95% CI [83.18-100] sensitivity and 94.1%, 95% CI [80.91-98.95] specificity. The species-specific TgSGP and SRA SHERLOCK discriminated between the gambiense/rhodesiense HAT infections with 100% accuracy.The 7SLRNA, TgSGP and SRA SHERLOCK discriminate between gHAT and rHAT infections, and could be used for epidemiological surveillance and diagnosis of HAT in the field after further technical development.Institut Pasteur (PTR-175 SHERLOCK4HAT), French Government's Investissement d'Avenir program Laboratoire d'Excellence Integrative Biology of Emerging Infectious Diseases (LabEx IBEID), and Agence Nationale pour la Recherche (ANR-PRC 2021 SherPa).

Published
2022

8. The nexus between telomere length and lymphocyte count in seniors hospitalized with COVID-19

Author

Carlos Labat, Ezra Susser, Sylvie Gautier, Marie Noelle Ungeheuer, Daniel Levy, Simon Toupance, Christine Perret-Guillaume, Abraham Aviv, Simon Verhulst, Tsung Po Lai, Athanase Benetos, Verhulst lab, Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Pôle Maladies du Vieillissement, Gérontologie et Soins Palliatif [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Rutgers New Jersey Medical School (NJMS), Rutgers University System (Rutgers), Groningen Institute for Evolutionary Life Sciences [Groningen] (GELIFES), University of Groningen [Groningen], Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Institut Pasteur [Paris] (IP), Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), National Institutes of Health [Bethesda] (NIH), Columbia Mailman School of Public Health, Columbia University [New York], New York State Psychiatric Institute, This study has been supported by the French National Research Agency (ANR), Translationnelle: N°ID RCB: 2014-A00298-39: 2014–2017 and partially supported by the French PIA project 'Lorraine Université d’Excellence ,' reference ANR-15-IDEX-04-LUE, and the Investments for the Future program under grant agreement no. ANR-15-RHU-0004. A.A.’s research is supported by National Institutes of Health grants R01HL134840 and U01AG066529 and Norwegian Institute of Public Health grants 262700 and 262043, ANR-15-IDEX-0004,LUE,Isite LUE(2015), ANR-15-RHUS-0004,FIGHT-HF,Combattre l'insuffisance cardiaque(2015), CHRU-Nancy, Pôle 'Maladies du Vieillissement, Gérontologie et Soins Palliatif, and Institut Pasteur [Paris]

Subjects
Senescence, COVID-19/physiopathology, Aging, Coronavirus disease 2019 (COVID-19), Lymphocyte, T-Lymphocytes, Peripheral blood mononuclear cell, Article, Restriction fragment, Andrology, 03 medical and health sciences, 0302 clinical medicine, Lymphopenia, 80 and over, Medicine, Humans, Viability assay, Lymphocytes, Lymphocyte Count, Telomere Shortening, Cellular Senescence, 030304 developmental biology, Southern blot, Aged, Aged, 80 and over, 0303 health sciences, Lymphopenia/etiology, biology, business.industry, SARS-CoV-2, [SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology, SARS-CoV-2/pathogenicity, COVID-19, T-Lymphocytes/immunology, 3. Good health, Telomere, Hospitalization, Ageing, medicine.anatomical_structure, Telomeres, 030220 oncology & carcinogenesis, Telomere Shortening/physiology, biology.protein, Geriatrics and Gerontology, business
Abstract

Background: Lymphopenia due to a plummeting T-cell count is a major feature of severe COVID-19. T-cell proliferation is telomere length (TL)-dependent and TL shortens with age. Older persons are disproportionally affected by severe COVID-19, and we hypothesized that those with short TL have less capacity to mount an adequate T-cell proliferative response to SARS-CoV-2. This hypothesis predicts that among older patients with COVID-19, shorter telomeres of peripheral blood mononuclear cells (PBMCs) will be associated with a lower lymphocyte count. Methods: Our sample comprised 17 COVID-19 and 21 non-COVID-19 patients, aged 87(8) (mean(SD)) and 87 (9) years, respectively. We measured TL by the Telomere Shortest Length Assay, a novel method that measures and tallies the short telomeres directly relevant to telomere-mediated biological processes. The primary analysis quantified TL as the proportion of telomeres shorter than 2 kilobases. For comparison, we also quantified TL by Southern blotting, which measures the mean length of telomeres. Results: Lymphocyte count (109/L) was 0.91 (0.42) in COVID-19 patients and 1.50(0.50) in non-COVID-19 patients (P < 0.001). In COVID-19 patients, but not in non-COVID-19 patients, lymphocyte count was inversely correlated with the proportion of telomeres shorter than 2 kilobases (P = 0.005) and positively correlated with the mean of telomeres measured by TeSLA (P = 0.03). Lymphocyte counts showed no statistically significant correlations with Southern blotting results in COVID-19 or non-COVID-19 patients. Conclusions: These results support the hypothesis that a compromised TL-dependent T-cell proliferative response contributes to lymphopenia and the resulting disproportionate severity of COVID-19 among old adults. We infer that infection with SARS-CoV-2 uncovers the limits of the TL reserves of older persons.

Published
2021

9. SARS-CoV-2 infection in schools in a northern French city: a retrospective serological cohort study in an area of high transmission, France, January to April 2020

Author

Ludivine Grzelak, Charlotte Renaudat, Yoann Madec, Lucie Kuhmel, Laurence Arowas, Caroline Demeret, Kuang-Yu Chen, Christèle Huon, Marie Noelle Ungeheuer, Marc Eloit, Olivier Schwartz, Thomas Bigot, Bernadette Crescenzo-Chaigne, Sandrine Fernandes Pellerin, Arnaud Fontanet, Isabelle Staropoli, Bruno Hoen, Nathalie Jolly, Camille Besombes, Sandie Munier, Isabelle Cailleau, Timothée Bruel, Pierre Charneau, Laura Tondeur, Sarah Temmam, Blanca Liliana Perlaza, Rebecca Grant, Epidémiologie des Maladies Emergentes - Emerging Diseases Epidemiology, Pasteur-Cnam Risques infectieux et émergents (PACRI), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Conservatoire National des Arts et Métiers [CNAM] (CNAM), Institut Pasteur [Paris]-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Découverte de pathogènes – Pathogen discovery, Institut Pasteur [Paris], Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Virus et Immunité - Virus and immunity, Université de Paris (UP), Direction de la recherche médicale de l'Institut Pasteur, Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Centre Médical de l'Institut Pasteur, Vaccine Research Institute (VRI), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Biologie des ARN et virus influenza - RNA Biology of Influenza Virus, Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Laboratoire commun Pasteur-TheraVectys, Institut Pasteur [Paris]-TheraVectys, Virologie Moléculaire et Vaccinologie / Molecular Virology and Vaccinology, École nationale vétérinaire d'Alfort (ENVA), The study was funded by Institut Pasteur, and several laboratories participating in the study receive funding from the Labex IBEID (ANR-10-LABX-62-IBEID), REACTing and the INCEPTION project (PIA/ANR-16-CONV-0005) for studies focusing on emerging viruses. OS lab is funded by Institut Pasteur, ANRS, Sidaction, the Vaccine Research Institute (ANR-10-LABX-77), 'TIMTAMDEN' ANR-14-CE14-0029, 'CHIKV-Viro- Immuno' ANR-14-CE14-0015-01 and the Gilead HIV cure program. LG is supported by the French Ministry of Higher Education, Research and Innovation. ME lab is funded by Institut Pasteur, Labex IBEID (ANR-10-LABX-62-IBEID), REACTing (Research & Action Emerging Infectious Diseases), EU Grant 101003589 RECoVER., 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-10-LABX-0077,VRI,Initiative for the creation of a Vaccine Research Institute(2010), ANR-14-CE14-0029,TIMTAMDEN,Rôle des récepteurs TIM et TAM dans l'infection des cellules cibles par le virus de la dengue(2014), ANR-14-CE14-0015,CHIKV-Viro-Immuno,Multiplication et Relation avec l'hôte du virus Chikungunya(2014), European Project: 101003589, H2020-SC1-PHE-CORONAVIRUS-2020,RECOVER(2020), 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)-Institut Pasteur [Paris]-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), HESAM Université - Communauté d'universités et d'établissements Hautes écoles Sorbonne Arts et métiers université (HESAM), Université Paris Cité (UPCité), Centre Médical de l'Institut Pasteur (CMIP), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), École nationale vétérinaire - Alfort (ENVA), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]-Université de Paris (UP), 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)-Institut Pasteur [Paris] (IP)-Conservatoire National des Arts et Métiers [CNAM] (CNAM), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Virus et Immunité - Virus and immunity (CNRS-UMR3569), Vaccine Research Institute [Créteil, France] (VRI), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Institut Pasteur [Paris] (IP)-TheraVectys

Subjects
0301 basic medicine, Emerging infectious diseases, medicine.medical_specialty, MESH: Schools, Epidemiology, [SDV]Life Sciences [q-bio], Context (language use), Asymptomatic, Serology, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Virology, MESH: Child, Humans, Medicine, MESH: COVID-19, MESH: SARS-CoV-2, 030212 general & internal medicine, Child, MESH: Cohort Studies, Retrospective Studies, Schools, MESH: Humans, Transmission (medicine), business.industry, SARS-CoV-2, Research, 4. Education, Public Health, Environmental and Occupational Health, COVID-19, Outbreak, Retrospective cohort study, MESH: Retrospective Studies, 3. Good health, Coronavirus disease 2019 (COVID-19), MESH: France, 030104 developmental biology, France, medicine.symptom, business, Demography, Cohort study
Abstract

Background Children’s role in SARS-CoV-2 epidemiology remains unclear. We investigated an initially unnoticed SARS-CoV-2 outbreak linked to schools in northern France, beginning as early as mid-January 2020. Aims This retrospective observational study documents the extent of SARS-CoV-2 transmission, linked to an affected high school (n = 664 participants) and primary schools (n = 1,340 study participants), in the context of unsuspected SARS-CoV-2 circulation and limited control measures. Methods Between 30 March and 30 April 2020, all school staff, as well as pupils and their parents and relatives were invited for SARS-CoV-2 antibody testing and to complete a questionnaire covering symptom history since 13 January 2020. Results In the high school, infection attack rates were 38.1% (91/239), 43.4% (23/53), and 59.3% (16/27), in pupils, teachers, and non-teaching staff respectively vs 10.1% (23/228) and 12.0% (14/117) in the pupils’ parents and relatives (p Conclusions Viral circulation can occur in high and primary schools so keeping them open requires consideration of appropriate control measures and enhanced surveillance.

Published
2021

10. Nasopharyngeal and serological anti SARS-CoV-2 IgG/IgA responses in COVID-19 patients

Author

Sylvie van der Werf, Caroline Demeret, Bernadette Crescenzo-Chaigne, Lila Bouadma, Jade Ghosn, Vincent Enouf, Sarah Tubiana, Stéphane Petres, Marie Noelle Ungeheuer, Sylvie Behillil, Nicolas Escriou, Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC), Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR), Institut Pasteur [Paris], Plateforme de Microbiologie Mutualisée (PIBnet) - Mutualized Platform for Microbiology (P2M), Laboratoire d’innovation : vaccins – Innovation lab : vaccines, Plateforme technologique Production et purification de protéines recombinantes – Production and Purification of Recombinant Proteins Technological Platform (PPR), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)-Université Sorbonne Paris Nord, Services de Maladies Infectieuses et Tropicales [CHU Bichat], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Investigations Cliniques [CHU Bichat] (CIC plurithématique), This work was supported by the « URGENCE COVID-19 » fundraising campaign of Institut Pasteur, by REACTING (Research & Action Emerging Infectious Diseases) and by the H2020 project 101003589 (RECOVER). The French Covid Cohort is funded through the Ministry of Health and Social Affairs (PHRC n°20-0424) and Ministry of Higher Education and Research dedicated COVID19 fund., List of the membership of the French COVID cohort study group : Mélanie RORIZ, Patrick RISPAL, Sarah REDL (CHG d'Agen), Laurent LEFEBVRE, Pascal GRANIER, Laurence MAULIN (CH du Pays d'Aix, Aix en Provence), Cédric JOSEPH, Julien MOYET, Sylvie LION-DAOLIO (CHU Amiens Nord), Rafael MAHIEU, Alexandra DU-CANCELLE, Vincent DUBEE (CHU d'Angers), Stéphane SALLA-BERRY, Aldric MANUEL, Gabriel MACHEDA, Mylène MAILLET, Bruno CHANZY (CH d'Annecy Genevois), Jean-Charles GAGNARD (Hôpital privé d'Antony), Guillermo GIORDANO, Clara MOUTON PERROT, Vincent PESTRE (CH Henri Duffaut, Avignon), Cécile FICKO, Marie GOMINET, Aurore BOUSQUET (Hôpital d'instruction des armées Begin), Charline VAUCHY, Kévin BOUILLER, Maïder PAGADOY, Solène MARTY-QUINTERNET, Quentin LEPILLER (CHU Jean Minjoz, Besançon), Cyril LE BRIS, Benoit THILL, Marie-Laure CASANOVA, Georges LE FALHER, Eric OZIOL (CH de Béziers), Hugues CORDEL, Nathalie DOURNON, Olivier BOUCHAUD, Ségolène BRICHLER (Hôpital Avicenne, Bobigny), Duc NGUYEN, Pantxika BELLECAVE, Camille CICCONE, Marie-Edith LAFON (CHU Pellegrin, Bordeaux), Ségolène GREFFE (CHU Ambroise Paré, Boulogne Billancourt), Camille BOUISSE, Nicholas SEDILLOT, Damien BOUHOUR (CH Fleyriat, Bourg en Bresse), Camille CHASSIN (CH Pierre Oudot, Bourgoin-Jallieu), Erwan L'HER, Séverine ANSART, Cécile TROMEUR, Dewi GUELLEC (CHRU de Brest), Antoine MERCKX (CH de Cahors), Felix DJOSSOU (CH Andrée Rosemon, Cayenne), Vincent PEIGNE, Carola PIEROBON, Marie-Christine CARRET, Florence JEGO, Margaux ISNARD (CHMS Chambéry NH), Johann AUCHABIE, Roxane COURTOIS (CH de Cholet), Olivier LESENS (CHU Gabriel Montpied, Clermont-Ferrand), Martin MARTINOT (Hôpital Pasteur, Colmar), Olivier PICONE (Hôpital Louis Mourier, Colombes), Marie LACOSTE (CH Alpes Leman Contamine sur Arve), Brigitte ELHAR-RAR, Valérie GARRAIT, Isabelle DELACROIX, Thomas MAITRE, Jean Baptiste ASSIE (Centre Hospitalier Intercommunal de Créteil), Elsa NYAMANKOLLY (CH de Dax), François Xavier CATHERINE, Ma-thieu BLOT, Sophie MAHY, Marielle BUISSON, Lionel PIROTH, Florence GUILLOTIN, Alexis DE ROUGEMONT (CHU de Dijon Bourgogne), Valentine CAMPANA, Jérémie PASQUIER, André CABIE (CHU de Martinique, Fort de France), Simon BESSIS (Hôpital Raymond Poincaré, Garches), Olivier EPAULARD, Nicolas TERZI, Jean-François PAYEN, Laurence BOUILLET, Rebecca HAMIDFAR, Marion Le MARECHAL (CHU de Grenoble), Moïse MACHADO, Audrey BARRELET, Alexandra BEDOSSA (Grand Hôpital de l'Est Francilien site Marne-la-Vallée, Jossigny), Gwenhaël COLIN, Romain DECOURS, Thomas GUIMARD (CHD Les Oudairies, La Roche Sur Yon), Cécile GOUJARD, Stéphane JAUREGUIBERRY, Antoine CHERET (Hôpital Universitaire Bicêtre, Le Kremlin-Bicêtre), Anne Sophie RESSEGUIER (CH Emile Roux, Le Puy en Velay), Julien POISSY, Daniel MATHIEU, Saad NSEIR, Ilka ENGELMANN, Martine REMY (CHRU de Lille, Hôpital Salengro), Fanny VUOTTO, Benoit GACHET, Karine FAURE, Marielle BOYER-BESSEYRE, Kazali Enagnon (CHRU de Lille, Hôpital Fourrier), Marc LAMBERT, Arnaud SCHERPEREEL, Dominique DEPLANQUE, Stéphanie FRY, Cécile YELNIK (CHRU de Lille, Hôpital Albert Calmette), Laurent BITKER, Mehdi MEZIDI, Hodane YONIS, Nicolas BENECH, Thomas PERPOINT, Anne CONRAD, Vinca ICARD, Martine VALETTE (Hôpital de la Croix Rousse, Lyon), Simon-Djamel THIBERVILLE (Hôpital Louis Raffalli, Manosque), Stanislas REBAUDET (Hôpital Européen de Marseille), Bertrand DUSSOL (Hôpital Conception, Marseille), Sylvain DIAMANTIS, Catherine CHAKVEATZE, Clara FLATEAU (Groupe Hospitalier Sud Ile De France, hôpital de Melun), Vincent DINOT, Rostane GACI, Nadia OUAMARA (Hôpital de Mercy, CHR Metz-Thionville, Ars laquenexy), Hajnal-Gabriela ILLES, Louis GER-BAUD MORLAES, Jérôme DIMET (CH de Mont Marsan), Vincent LE MOING, Nathalie PANSU, Clément LE BIHAN, Brigitte MONTES (CHU de Montpellier), Anne Sophie BOUREAU, Clotilde ALLAVENA, Sabelline BOUCHEZ, Romain GUERY, Paul LE TURNIER, Cécile MEAR-PASSARD, Virginie FERRE (CHU de Nantes), Christophe RAPP (Hôpital Américain de Paris, Neuilly sur Seine), Elisa DE-MONCHY, Céline MICHELANGELLI, Karine RISSO (CHU de Nice), Paul LOUBET, Jean-Phillippe LAVIGNE (CHU Caremeau, Nîmes), Etienne DE MONTMOLLIN, Juliette PATRIER, Paul Henri WICKY, Lucie LE FEVRE, Pierre JACQUET, Raphael BORIE, Antoine DOSSIER, Dominique LUTON, Valentina ISERNIA, Sylvie LE GAC (Hôpital Bichat, Paris), Cécile AZOULAY, Nicolas CARLIER, Liem LUONG, Marie LACHATRE, Odile LAUNAY (Hôpital Cochin, Paris), Younes KERROUMI, Vanina MEYSSONNIER (Groupe Hospitalier Diaconesses Croix Saint-Simon, Paris), Jean-Luc DIEHL, Jean-Sébastien HULOT, Bernard CHOLLEY, Jean-Benoît ARLET, Olivier SANCHEZ (Hôpital Européen Georges Pompidou, Paris), Victoria MANDA, Laurène AZEMAR, Guylaine CASTOR-ALEXANDRE (Hôpital Lariboisière, Paris), Karine LACOMBE, Thibault CHIARABINI, Bénédicte LEFEBVRE, Laurence MORAND-JOUBERT, Djeneba FOFANA, Aurélie SCHNURIGER (Hôpital Saint Antoine, Paris), Nathalie DE CASTRO, Constance DELAUGERRE, Marie-Laure CHAIX (Hôpital Saint Louis, Paris), Julie CHAS (Hôpital Tenon, Paris), Valérie GABORIEAU, Eve LE COUSTUMIER, Walter PICARD (CH de Pau), Jean-Benoît ZABBE, Florent PEELMAN, Edouard SOUM (CH de Périgueux), Hugues AUMAÎTRE (CH de Perpignan), Elodie CURLIER, Rachida OUISSA, Isabelle FABRE (CHU de Pointe à Pitre, Guadeloupe), Blandine RAMMAERT (CHU de Poitiers), Nadia SAIDANI (CH Quimper), Firouzé BANI-SADR, Maxime HENTZIEN, Yohan N 'GUYEN, Juliette ROMARU, Kévin DIDIER (CHU Reims), Isabelle ENDERLE, Vincent THIBAULT, Fabrice LAINE, Matthieu LESOU-HAITIER, Matthieu REVEST, Pierre TATTEVIN (CHU Rennes), Jean-Christophe PLANTIER, Manuel ETIENNE, Véronique LEMEE, Eglantine FERRAND DEVOUGE, Kévin ALEXANDRE, Elise ARTAUD-MACCARI (CHU Rouen), Nathalie ALLOU, Marie LAGRANGE, Julien JABOT (CH Saint Denis et Saint Pierre, La réunion), Benoît ROZE, Delphine BREGEAUD, Younes AIT TAMLIHAT (CH Saintes), Ali HACHEMI (CH Soisson), Hélène SALVATOR, Erwan FOURN, David ZUCMAN (Hôpital Foch, Suresnes), Eric DELAVEUVE, Coline JAUD-FISCHER, Paul DUNAND (Hôpital Bel Air, Thionville), François BISSUEL (CH Thonon les Bains), Karen DELAVIGNE, Marie PIEL-JULIAN, Pierre DELOBEL, Benjamine SARTON, Marie RAFIQ, Guillaume MARTIN-BLONDEL, Laurent GUILLEMINAULT, Marlène MURRIS, Agnès SOMMET (CHU de Toulouse), Eric SENNEVILLE, Olivier ROBINEAU, Agnès MEYBECK (CH Tourcoing), Denis GAROT, Laurent PLANTIER, Valérie GISSOT, Julien MARLET, Karl STEFIC, Catherine GAUDY-GRAFFIN, Francis BARIN, Adrien LEMAIGNEN (CHU Bretonneau, Tours), Grégory CORVAISIER, Delphine LARIVIERE, Marie LANGELOT-RICHARD (CH Vannes), Elisabeth BOTELHO-NEVERS , Amandine GAGNEUX-BRUNON, Tiffany TROUILLON, Thomas BOURLET, Thomas BOURLET, Sylvie PILLET, Bruno POZZETTO (CHU de St Etienne), Antoine KIMMOUM, Bruno LEVY, Mathieu MATTEI, François GOEHRINGER, Christian RABAUD, Sibylle BEVILACQUA, Benjamin LEFEVRE, Anne GUILLAUMOT, Véronique VENARD, Hélène JEULIN, Evelyne SCHVOERER, Cédric HARTARD (CHU de Nancy, Vandoeuvre les Nancy), Pauline CARAUX PAZ, Laurent RICHIER, Mohamed EL SANHARAWI (CH Villeneuve St Georges)., European Project: 101003589, H2020-SC1-PHE-CORONAVIRUS-2020,RECOVER(2020), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), 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), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord

Subjects
Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), [SDV]Life Sciences [q-bio], Severe disease, Infectious and parasitic diseases, RC109-216, Article, Serology, 03 medical and health sciences, 0302 clinical medicine, Medicine, Mucosal Immunity, 030304 developmental biology, 0303 health sciences, biology, 030306 microbiology, business.industry, Epithelium, 3. Good health, Nucleoprotein, medicine.anatomical_structure, Antibody response, SARS CoV, 030220 oncology & carcinogenesis, Immunology, biology.protein, Antibody, business
Abstract

BackgroundThe systemic antibody responses to SARS-CoV-2 in COVID-19 patients has been extensively studied. However, much less is known about the mucosal responses in the upper airways at the site of initial SARS-CoV-2 replication. Local antibody responses in the nasopharyngeal epithelium, that are likely to determine the course of infection, have not been analysed so far nor their correlation with antibody responses in serum.MethodsThe IgG and IgA antibody responses were analysed in the plasma as well as in nasopharyngeal swabs (NPS) from the first four COVID-19 patients confirmed by RT-qPCR in France. Two were pauci-symptomatic while two developed severe disease. Taking advantage of a comprehensive series of plasma and nasopharyngeal samples, we characterized their antibody profiles from the second week post symptoms onset, by using an in-house ELISA to detect anti-SARS-CoV-2 Nucleoprotein (N) IgG and IgA.ResultsAnti-N IgG and IgA antibodies were detected in the NPS of severe patients. Overall, the levels of IgA and IgG antibodies in plasma and NPS appeared specific to each patient.ConclusionsAnti-N IgG and IgA antibodies are detected in NPS, and their levels are related to antibody levels in plasma. The two patients with severe disease exhibited different antibody profiles that may reflect different disease outcome. For the pauci-symptomatic patients, one showed a low anti-N IgG and IgA response in the plasma only, while the other one did not exhibit overt serological response.

Published
2021

11. Age-associated gut microbiota impairs hippocampus-dependent memory in a vagus-dependent manner

Author

Pierre-Marie Lledo, Marie-Noelle Ungeheuer, Harry Sokol, Marianne Haddad, Damien Rei, Anna Haider Rubio, and Soham Saha

Subjects
Transplantation, medicine.medical_treatment, Neurogenesis, medicine, Memory impairment, Premovement neuronal activity, Hippocampus, Biology, Hippocampal formation, Neuroscience, Vagus nerve stimulation, Vagus nerve
Abstract

Aging is known to be associated with hippocampus-dependent memory decline, but the underlying causes of the age-related memory impairment remain yet highly debated. Here we showed that fecal microbiota transplantation (FMT) from aged, but not young, animal donors in young mice is sufficient to trigger profound hippocampal alterations including astrogliosis, decreased adult neurogenesis, decreased novelty-induced neuronal activation and impairment in hippocampus-dependent memory. Furthermore, similar alterations were reported when mice were subjected to an FMT from aged human donors. To decipher the mechanisms involved in mediating these microbiota-induced effects on brain function, we mapped the vagus nerve (VN)-related neuronal activity patterns and report that aged-mice FM transplanted animals showed a reduction in neuronal activity in the ascending VN output brain structure, both in basal condition and following VN stimulation. Targeted pharmacogenetic manipulation of VN-ascending neurons demonstrated that the decrease in vagal activity is detrimental to hippocampal functions. In contrast, increasing vagal ascending activity alleviated the adverse effects of aged mice FMT on hippocampal functions, and had a pro-mnesic effect in aged mice. Thus, pharmacogenetic VN stimulation is a potential therapeutic strategy to lessen microbiota-dependent age-associated impairments in hippocampal functions.Graphical abstract

Published
2021

12. Age-associated gut microbiota impair hippocampus-dependent memory in a vagus-dependent manner

Author

Damien Rei, Soham Saha, Marianne Haddad, Anna Haider Rubio, Blanca Liliana Perlaza, Marion Berard, Marie-Noelle Ungeheuer, Harry Sokol, Pierre-Marie Lledo, Perception et Mémoire / Perception and Memory, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Animalerie Centrale (plateforme) - Central Animal Facility (platform) (C2RA), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Paris Center for Microbiome Medicine (FHU PaCeMM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and BOUCHOT, Frédérique

Subjects
Adult, Aging, Behavior, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Neurogenesis, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Vagus Nerve, General Medicine, Fecal Microbiota Transplantation, Mouse models, Hippocampus, Gastrointestinal Microbiome, [SDV] Life Sciences [q-bio], Mice, Animals, Humans, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuroscience, Aged
Abstract

International audience; Aging is known to be associated with hippocampus-dependent memory decline, but the underlying causes of this age-related memory impairment remain highly debated. Here, we show that fecal microbiota transplantation (FMT) from aged, but not young, animal donors into young mice is sufficient to trigger profound hippocampal alterations, including astrogliosis, decreased adult neurogenesis, decreased novelty-induced neuronal activation, and impairment in hippocampus-dependent memory. Furthermore, similar alterations were reported when mice were subjected to an FMT from aged human donors. To decipher the mechanisms involved in mediating these microbiota-induced effects on brain function, we mapped the vagus nerve–related (VN-related) neuronal activity patterns and report that aged FMT animals showed a reduction in neuronal activity in the ascending-VN output brain structure, whether under basal condition or after VN stimulation. Targeted pharmacogenetic manipulation of VN-ascending neurons demonstrated that the decrease in vagal activity is detrimental to hippocampal functions. In contrast, increasing vagal ascending activity alleviated the adverse effects of aged mouse FMT on hippocampal functions and had a promnesic effect in aged mice. Thus, pharmacogenetic VN stimulation is a potential therapeutic strategy to lessen microbiota-dependent age-associated impairments in hippocampal functions.

Published
2021

13. In utero exposure to Azathioprine in autoimmune disease. Where do we stand?

Author

Rebecca Bromley, Laura Damian, Marianne Rivière, Hilde Kelchtermans, Katrien Devreese, Yehuda Shoenfeld, Daniel Henrion, Enrique Esteve-Valverde, Patrick Martin Mattera, Laurent Loufrani, Cristina Belizna, Alexandre Levy, Sebastián Udry, Anne-Laure Guihot, Angela Tincani, Jamilya Khizroeva, Taylor Pindi Sala, Rosario Lopez Pedrera, A. Djokovic, Milena Hasan, Nadia Bahi Buisson, Jaume Alijotas-Reig, Maria Orietta Borghi, Géraldine Gascoin, José Omar Latino, Jan Willem Cohen Tervaert, Pier Luigi Meroni, Hannah Cohen, Viktoria Bidsatze, Laurence Bernard, Cecilia Beatrice Chighizola, Johanna Gebhart, Francesca Pregnolato, N. Stanisavljevic, Marie Briet, Mathilde Saiet, Elisabeth Elefant-Amoura, Pascale Peretti, Laurence Lagarce, Ljudmila Stojanovich, Ingrid Pabinger, Jose Rakotonjanahary, Isabelle Pellier, Alexander Makatsariya, Céline Fassot, Marie Noelle Ungeheuer, Laura Andreoli, Christian Muchardt, Jan Voswinkel, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Clinical Immunology and Rheumatology Research Department Auxologico Institute, Milan, Italy., The Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Ghent University Hospital, Vall d'Hebron University Hospital [Barcelona], Althaia Healthcare Network of Manresa, Barcelona, University College London Hospitals (UCLH), Clinique de l'Anjou [Angers], Recherches en Psychopathologie, nouveaux symptômes et lien social (EA 4050), Université de Poitiers-Université de Brest (UBO)-Université Catholique de l'Ouest (UCO)-Université de Rennes 2 (UR2), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), University of Angers, Angers Hospital, French Lupus and Other Autoimmune Disease Patients Association, Institut Pasteur [Paris], Régulation épigénétique - Epigenetic regulation, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Laboratoire Recherches en psychopathologie et psychanalyse (RPPSY), Université Catholique de l'Ouest (UCO), Institut Pasteur [Paris] (IP), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Pediatrics, medicine.medical_specialty, Offspring, [SDV]Life Sciences [q-bio], Immunology, Population, Azathioprine, Autoimmune Diseases, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Genetic predisposition, Immunology and Allergy, Medicine, Humans, education, Prospective cohort study, Child, Female, Immunosuppressive Agents, Pregnancy Complications, Prenatal Exposure Delayed Effects, Retrospective Studies, 030203 arthritis & rheumatology, education.field_of_study, business.industry, Public health, Retrospective cohort study, medicine.disease, 3. Good health, 030211 gastroenterology & hepatology, business, medicine.drug
Abstract

International audience; Azathioprine (AZA), an oral immunosuppressant, is safe during pregnancy. Some reports suggested different impairments in the offspring of mothers with autoimmune diseases (AI) exposed in utero to AZA. These observations are available from retrospective studies or case reports. However, data with respect to the long-term safety in the antenatally exposed child are still lacking. The aim of this study is to summarize the current knowledge in this field and to focus on the need for a prospective study on this population. We performed a PubMed search using several search terms. The actual data show that although the risk of congenital anomalies in offspring, as well as the infertility risk, are similar to those found in general population, there is a higher incidence of prematurity, of lower weight at birth and an intra-uterine delay of development. There is also an increased risk of materno- fetal infections, especially cytomegalovirus infection. Some authors raise the interrogations about neurocognitive impairment. Even though the adverse outcomes might well be a consequence of maternal illness and disease activity, interest has been raised about a contribution of this drug. However, the interferences between the external agent (in utero exposure to AZA), with the host (child genetic susceptibility, immune system anomalies, emotional status), environment (public health, social context, availability of health care), economic, social, and behavioral conditions, cultural patterns, are complex and represent confounding factors. In conclusion, it is necessary to perform studies on the medium and long-term outcome of children born by mothers with autoimmune diseases, treated with AZA, in order to show the safety of AZA exposure. Only large-scale population studies with long-term follow-up will allow to formally conclude in this field

Published
2020

14. HIBISCUS: Hydroxychloroquine for the secondary prevention of thrombotic and obstetrical events in primary antiphospholipid syndrome

Author

Patrick Blanco, Maarten Limper, Jamilya Khizroeva, Pier Luigi Meroni, Olivier Lambotte, Nadine Magy-Bertrand, Loic Sentilhes, Raquel Ferrer-Oliveras, Pieter Van Paasen, Jan Willem Cohen Tervaert, Marie Noelle Ungeheuer, Enrique Esteve-Valverde, Katrien Devreese, Ricard Cervera, Laura Andreoli, A. Djokovic, Emmanuel Andrès, Antonia Caligaro, Jean Sibilia, Daniel Henrion, Angela Tincani, Guillaume Mahé, Jose Omar Latino, N. Stanisavljevic, Sebastián Udry, Patrick Saulnier, Ljudmila Stojanovich, Şule Apraş Bilgen, Bernard Imbert, Cédric Landron, Damien Sène, Karina de Leeuw, Céline Fassot, Fatma Said, Boris Bienvenu, Laura Damian, Florence Perrinet, Jaume Alijotas-Reig, Francesca Pregnolato, Alban Godon, Estibaliz Lazaro, Thierry Martin, Viktoria Bitsadze, Laurent Arnaud, Laurent Loufrani, Gilles Pernod, Alexander Makatsariya, Gilberto Pires da Rosa, Noémie Jourde-Chiche, Pierre Yves Jeandel, Elisabeta Candrea, Maria Orietta Borghi, Milena Hasan, Jean Marie Chretien, Crina Sinescu, Cristina Belizna, Mathilde Versini, Pascale Jeannin, Thomas Le Gallou, Fréderic Tollis, Marc Antoine Pistorius, Loukman Omarjee, Valentina Canti, Mohamed Hamidou, Achile Aouba, György Nagy, Ova Shovman, Sébastien Abad, Levent Kilic, Teresa Delross, Howard Amital, Lai-Shan Tam, Zahir Amoura, Christian Muchardt, Amelia Ruffatti, Laurent Chiche, Patrick Jego, Emmanuelle Dernis, Maria Favaro, Miri Blank, Romain Lubin, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Université Paris 13 (UP13), Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Vall d'Hebron University Hospital [Barcelona], Sackler Faculty of Medicine, Tel Aviv University (TAU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Brescia, CHU Strasbourg, Université de Caen Normandie (UNICAEN), Normandie Université (NU), Hacettepe University = Hacettepe Üniversitesi, Hôpital Saint-Joseph [Marseille], Department of Obstetrics and Gynecology, I.M. Sechenow First Moscow State Medical University, Moscow, Russia., Immunology from Concept and Experiments to Translation (ImmunoConcept), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Università degli Studi di Padova = University of Padua (Unipd), University of Medicine and Pharmacy, Luliu-Hatieganu, Hôpital Européen [Fondation Ambroise Paré - Marseille], Maastricht University [Maastricht], University of Alberta, Universitatea Babeş-Bolyai [Cluj-Napoca], Centre Hospitalier du Mans, Ghent University Hospital, University of Belgrade [Belgrade], Althaia Healthcare Network of Manresa, Barcelona, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Cardiovascular Functions In Vitro (CARFI), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), CHU Grenoble, Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Pontchaillou [Rennes], Vascular research center of Marseille (VRCM), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Obstetrics and Gynecology, I.M. Sechenow First Moscow State Medical University, Moscow, Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Hospital Carlos G. Durand, Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], University Medical Center Groningen [Groningen] (UMCG), University Medical Center [Utrecht], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellules Souches et Développement / Stem Cells and Development, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Semmelweis University [Budapest], Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-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 [2016-2019] (UGA [2016-2019]), Hospital de São João [Porto], Hôpital La Rabta [Tunis], Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service de rhumatologie [Strasbourg], CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Université de Médecine Carol Davila, The Chinese University of Hong Kong [Hong Kong], Diaverum Dialysis Center, Angers, Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Institut Arnault Tzanck, Barcelona Centre for International Health Research, Hospital Clinic (CRESIB), Universitat de Barcelona (UB), The HIBISCUS study is funded for its French part of the trial by the Ministery of Health, France in 2015 (PHRC N PAPIRUS)., The investigators are very grateful to Professor Y Shoenfeld for the scientific revision of the design and very valuable remarks. The investigators are also grateful to the patients, patients' association, collaborators and networks involved in the trial and to the research staff at all participating hospitals., Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Hôpital avicenne, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris 13 (UP13)-Hôpital Avicenne, Tel Aviv University [Tel Aviv], Service de médecine interne [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Universita degli Studi di Padova, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Centre de Recherche Translationnelle (CRT), Institut Pasteur [Paris], Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Centre recherche en CardioVasculaire et Nutrition (C2VN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Hôpital Jean Minjoz, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellules Souches et Développement, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Lariboisière-Fernand-Widal [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
ANTICOAGULANT, Pediatrics, Additional Therapy, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, RECOMMENDATIONS, COMPLEMENT, 0302 clinical medicine, Pregnancy, An international multicenter trial on Hydroxychloroquine for the secondary prevention of relapses in primary antiphospholipid syndrome is launched, Antiphospholipid syndrome, Immunology and Allergy, PREGNANT PATIENTS, SYSTEMIC-LUPUS-ERYTHEMATOSUS, Secondary prevention, Anticoagulant, Pregnancy Outcome, Take home messages, WOMEN, 3. Good health, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, medicine.drug, Hydroxychloroquine, Primary antiphospholipid syndrome, medicine.medical_specialty, medicine.drug_class, Immunology, Relapse rate, Relapse rate in antiphospholipid syndrome (APS) is high despite standard current therapies, 53 centers from 16 countries participate to this international trial, Orphan drug, 03 medical and health sciences, Survival rate in this population is 90.1% at 10 years and 65% at 15 years, There is a need for additional or alternative therapies in this disease, hydroxychloroquine, primary antiphospholipid syndrome, secondary prevention, medicine, MANAGEMENT, Humans, DRUGS, 030203 arthritis & rheumatology, business.industry, Thrombosis, Delivery, Obstetric, medicine.disease, ANTIBODIES, RISK-FACTORS, business
Abstract

International audience; The relapse rate in antiphospholipid syndrome (APS) remains high, i.e. around 20%–21% at 5 years in thrombotic APS and 20–28% in obstetrical APS [2, 3].Hydroxychloroquine (HCQ) appears as an additional therapy, as it possesses immunomodulatory and anti-thrombotic various effects [4–16].Our group recently obtained the orphan designation of HCQ in antiphospholipid syndrome by the European Medicine Agency.Furthermore, the leaders of the project made the proposal of an international project, HIBISCUS, about the use of Hydroxychloroquine in secondary prevention of obstetrical and thrombotic events in primary APS. This study has been launched in several countries and at now, 53 centers from 16 countries participate to this international trial.This trial consists in two parts: a retrospective and a prospective study.The French part of the trial in thrombosis has been granted by the French Minister of Health in December 2015 (the academic trial independent of the pharmaceutical industry PHRC N PAPIRUS) and is coordinated by one of the members of the leading consortium of HIBISCUS.

Published
2018

15. Low Prevalence of GSC Gene Mutations in a Large Cohort of Predominantly Caucasian Patients with Hidradenitis Suppurativa

Author

Andrea Altomare, Julien Vidil, Giovanni Damiani, Olivier Cogrel, Hessel H. van der Zee, Olivier Join-Lambert, Véronique Del Marmol, Marie Beylot-Barry, Sylvain Hanein, Sylvie Fraitag, Didier Bessis, Yi-Hua Liao, Marie Noelle Ungeheuer, Errol P. Prens, Patrick Nitschke, Snaigune Miskinyte, Farida Benhadou, Aude Nassif, Christos C. Zouboulis, Thi Lam, Georgios Nikolakis, Allard R. J. V. Vossen, Maïa Delage, Alain Hovnanian, Céline Girard, Mélanie Parisot, Sabine Duchatelet, and Dermatology

Subjects
Adult, Male, Oncology, medicine.medical_specialty, Adolescent, Biochimie, Dermatology, Gene mutation, Biochemistry, Cohort Studies, Young Adult, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Presenilin-1, medicine, Humans, Hidradenitis suppurativa, Young adult, Molecular Biology, Aged, 030304 developmental biology, Dermatologie, 0303 health sciences, Membrane Glycoproteins, business.industry, Membrane Proteins, Biologie moléculaire, Cell Biology, Middle Aged, medicine.disease, Hidradenitis Suppurativa, Large cohort, Gamma-secretase complex, Mutation, Mutation (genetic algorithm), Female, Biologie cellulaire, Amyloid Precursor Protein Secretases, business, Cohort study
Abstract

SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2020

16. Primary antiphospholipid syndrome and antiphospholipid syndrome associated to systemic lupus: Are they different entities?

Author

Pier Luigi Meroni, Laura Damian, Cristina Belizna, Daniel Henrion, Ljudmila Stojanovich, Laurent Loufrani, Patrick Saulnier, Guillaume Mahé, Pascal Reynier, Enrique Esteve-Valverde, Jan Willem Cohen-Tervaert, Milena Hasan, Jaume Alijotas-Reig, Ferdinando Nicoletti, Alban Godon, Laurent Arnaud, Katrien Devreese, Marie Noelle Ungeheuer, György Nagy, Loukman Omarjee, Céline Fassot, Marc Antoine Pistorius, Jean Marie Chretien, Christian Muchardt, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Belgrade [Belgrade], Maastricht University [Maastricht], Biologie Neurovasculaire Intégrée (BNVI), Semmelweis University [Budapest], Régulation épigénétique - Epigenetic regulation, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Institut Pasteur [Paris], Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), CHU Strasbourg, Universitat Autònoma de Barcelona (UAB), University of Catania [Italy], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Centre hospitalier universitaire de Nantes (CHU Nantes), Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Ghent University Hospital, MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), and Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Primary antiphospholipid syndrome, Some limitation, ERYTHEMATOSUS, Immunology, 030204 cardiovascular system & hematology, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Antiphospholipid syndrome, CARDIAC MANIFESTATIONS, Immunology and Allergy, Medicine, Humans, Lupus Erythematosus, Systemic, In patient, CLASSIFICATION CRITERIA, Secondary antiphospholipid syndrome, ANTIBODY TYPE, 030203 arthritis & rheumatology, Systemic lupus erythematosus, ANTICOAGULANT ACTIVITY, business.industry, Systemic lupus, SECONDARY, Genetic data, medicine.disease, 3. Good health, THROMBOGENIC MECHANISM, ANNEXIN A5, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, CARDIOVASCULAR-DISEASE, SYNDROME APS, Antibodies, Antiphospholipid, [SDV.IMM]Life Sciences [q-bio]/Immunology, Identification (biology), business
Abstract

International audience; Primary antiphospholipid syndrome (PAPS) and antiphospholipid syndrome associated to lupus (SAPS) have several overlapping characteristics. As systemic manifestations are also reported in patients with PAPS, and as a subgroup of PAPS patients could evaluate to a SAPS, the differentiation between the two types of APS could be performed based on the clinical experience of the medical teams and is related to a variety of clinical, biological, histological and genetic features. Several data are available in the literature with respect to the identification of distinctive features between these two entities. However, there are some limitation in the interpretation of results issued from studies performed prior to updated Sydney criteria. Based on recent data, a certain number of features more frequent in one type of APS as compared to the other could be distinguished. The major differentiation between these two entities is genetical. New genetic data allowing the identification of specific subgroups of APS are ongoing.

Published
2018

17. Standardized whole blood stimulation improves immunomonitoring of induced immune responses in multi-center study

Author

Alain Savenay, Matthew L. Albert, Delphine Louis, Manfred Schmolz, Nina Salabert-Le Guen, Olivier Lantz, Régis Josien, Darragh Duffy, Françoise Mascart, Antoine Toubert, Marie Noelle Ungeheuer, Vincent Rouilly, Raouf Djebali, Lydia Redjah, José J.G. Ruiz de Morales, Catherine Ottone, Véronique Corbière, Eva Martínez-Cáceres, Cécile Braudeau, Samuel S.T. LaBrie, Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle (CRT), Institut Pasteur [Paris], Laboratoire d’Immunologie, Centre d’Immunomonitorage Nantes Atlantique (CIMNA), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche en Transplantation et Immunologie (U1064 Inserm - CRTI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), laboratoire de vaccinologie et immunité mucosale, Université Libre de Bruxelles [Bruxelles] (ULB), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources (ICAReB), Myriad RBM, Immunité et cancer (U932), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospital Universitari Germans Trias I Pujol, Immunobiology Clinic, Hôpital Erasme, Complejo Asistencial Universitario de León, Alloimmunité-Autoimmunité-Transplantation (A2T), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), HOT Screen GmbH, Genentech, Inc. [San Francisco], TruCulture tubes, stimuli, and protein Luminex XMAP analysis were provided by Myriad RBM, Inc (Austin, USA) and TruCulture tubes were manufactured at HOT Screen (Reutlingen, Germany). Donor recruitment costs were covered by each participating FOCIS center of excellence. Author contributions: DD, VR, VC, SL, OL, EMC, RP, MS, AT & MLA designed the study. CB, RD, MNU, DL, FM, JGRM, CO, LR, AS performed experiments. DD, VR, & MLA performed analysis and wrote the paper. All authors reviewed the manuscript., Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris] (IP), Université libre de Bruxelles (ULB), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche Translationnelle ( CRT ), Centre Hospitalier Universitaire de Nantes, Centre de Recherche en Transplantation et Immunologie ( U1064 Inserm - CRTI - CHU Nantes ), Université de Nantes ( UN ) -Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Université Libre de Bruxelles [Bruxelles] ( ULB ), Investigation Clinique et d’Accès aux Ressources Biologiques (Plate-forme) - Clinical Investigation and Access to BioResources ( ICAReB ), Immunité et cancer ( U932 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Curie, Alloimmunité-Autoimmunité-Transplantation ( A2T ), and Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )

Subjects
0301 basic medicine, Lipopolysaccharides, Whole blood stimulation, CD3 Complex, medicine.medical_treatment, CD8 Antigens, Point-of-Care Systems, Immunology, Stimulation, Blood Donors, Immunologic Tests, Peripheral blood mononuclear cell, Antibodies, Functional immune responses, 03 medical and health sciences, Immune system, medicine, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Immunology and Allergy, Humans, Whole blood, biology, business.industry, Immunotherapy, Multi-center clinical studies, 3. Good health, Vaccination, Immunomonitoring, 030104 developmental biology, Gene Expression Regulation, PBMCs, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, Antibody, business, Biomarkers
Abstract

Functional immune responses are increasingly important for clinical studies, providing in depth biomarker information to assess immunotherapy or vaccination. Incorporating functional immune assays into routine clinical practice has remained limited due to challenges in standardizing sample preparation. We recently described the use of a whole blood syringe-based system, TruCulture (R), which permits point-of-care standardized immune stimulation. Here, we report on a multi-center clinical study in seven FOCIS Centers of Excellence to directly compare TruCulture to conventional PBMC methods. Whole blood and PBMC5 from healthy donors were exposed to LPS, anti-CD3 anti-CD28 antibodies, or media alone. 55 protein analytes were analyzed centrally by Luminex multi-analyte profiling in a CLIA-certified laboratory. TruCulture responses showed greater reproducibility and improved the statistical power for monitoring differential immune response activation. The use of TruCulture addresses a major unmet need through a robust and flexible method for immunomonitoring that can be reproducibly applied in multi-center clinical studies. One sentence summary: A multi-center study revealed greater reproducibility from whole blood stimulation systems as compared to PBMC stimulation for studying induced immune responses. (C) 2017 Published by Elsevier Inc.

Published
2017

18. Antibodies to tetanus, diphtheria and pertussis among healthy adults vaccinated according to the French vaccination recommendations

Author

Jean Beytout, Claire Bernède, Odile Launay, Sylvie Larnaudie, Christine Toneatti, Didier Guillemot, Annie Leblond, Damien Bouhour, Christian Raccurt, Elisabeth Njamkepo, C. Chidiac, Catherine Goujon, Marie-Noelle Ungeheuer, Nicole Guiso, Karine Petitprez, and Faiza Ajana

Subjects
Adult, Male, Pediatrics, medicine.medical_specialty, Adolescent, Whooping Cough, Immunology, Immunization, Secondary, complex mixtures, Serology, Young Adult, Seroepidemiologic Studies, medicine, Humans, General Pharmacology, Toxicology and Pharmaceutics, Young adult, Diphtheria-Tetanus-Pertussis Vaccine, Tetanus, business.industry, Diphtheria, Age Factors, Middle Aged, medicine.disease, Antibodies, Bacterial, Vaccination, Immunization, Humoral immunity, Population study, Female, France, business
Abstract

In this sero-epidemiological study, we investigated humoral immunity to three vaccine-preventable diseases--tetanus, diphtheria and pertussis--among 331 adults (aged 18-60 years) attending vaccination centres for travellers and who had been vaccinated according to national recommendations in France. Serological results showed that the percentage of subjects with antibodies to diphtheria and tetanus decreases with age. Results also confirmed surveillance data on vaccination in France, with 7.6% of the study population (13.4% of those aged 18-29 years) having recently acquired a pertussis infection. These results confirm the importance of following French recommendations for regular boosters for tetanus and diphtheria among adults. They also indicate the need for better implementation of the current recommendations for pertussis-vaccine boosters in adults.

Published
2009

19. Rapid diagnosis of diarrhea caused by Shigella sonnei using dipsticks; comparison of rectal swabs, direct stool and stool culture.

Author

Claudia Duran, Faridabano Nato, Sylvie Dartevelle, Lan Nguyen Thi Phuong, Neelam Taneja, Marie Noëlle Ungeheuer, Guillermo Soza, Leslie Anderson, Dona Benadof, Agustín Zamorano, Tai The Diep, Truong Quang Nguyen, Vu Hoang Nguyen, Catherine Ottone, Evelyne Bégaud, Sapna Pahil, Valeria Prado, Philippe Sansonetti, and Yves Germani

Subjects
Medicine, Science
Abstract

BACKGROUND: We evaluated a dipstick test for rapid detection of Shigella sonnei on bacterial colonies, directly on stools and from rectal swabs because in actual field situations, most pathologic specimens for diagnosis correspond to stool samples or rectal swabs. METHODOLOGY/PRINCIPAL FINDINGS: The test is based on the detection of S. sonnei lipopolysaccharide (LPS) O-side chains using phase I-specific monoclonal antibodies coupled to gold particles, and displayed on a one-step immunochromatographic dipstick. A concentration as low as 5 ng/ml of LPS was detected in distilled water and in reconstituted stools in 6 minutes. This is the optimal time for lecture to avoid errors of interpretation. In distilled water and in reconstituted stools, an unequivocal positive reaction was obtained with 4 x 10(6) CFU/ml of S. sonnei. The specificity was 100% when tested with a battery of Shigella and different unrelated strains. When tested on 342 rectal swabs in Chile, specificity (281/295) was 95.3% (95% CI: 92.9% - 97.7%) and sensitivity (47/47) was 100%. Stool cultures and the immunochromatographic test showed concordant results in 95.5 % of cases (328/342) in comparative studies. Positive and negative predictive values were 77% (95% CI: 65% - 86.5%) and 100% respectively. When tested on 219 stools in Chile, Vietnam, India and France, specificity (190/198) was 96% (95% CI 92%-98%) and sensitivity (21/21) was 100%. Stool cultures and the immunochromatographic test showed concordant results in 96.3 % of cases (211/219) in comparative studies. Positive and negative predictive values were 72.4% (95% CI 56.1%-88.6%) and 100 %, respectively. CONCLUSION: This one-step dipstick test performed well for diagnosis of S. sonnei both on stools and on rectal swabs. These data confirm a preliminary study done in Chile.

Published
2013
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20. Dipstick test for rapid diagnosis of Shigella dysenteriae 1 in bacterial cultures and its potential use on stool samples.

Author

Neelam Taneja, Faridabano Nato, Sylvie Dartevelle, Jean Marie Sire, Benoit Garin, Lan Nguyen Thi Phuong, Tai The Diep, Jean Christophe Shako, François Bimet, Ingrid Filliol, Jean-Jacques Muyembe, Marie Noëlle Ungeheuer, Catherine Ottone, Philippe Sansonetti, and Yves Germani

Subjects
Medicine, Science
Abstract

BACKGROUND: We describe a test for rapid detection of S. dysenteriae 1 in bacterial cultures and in stools, at the bedside of patients. METHODOLOGY/PRINCIPAL FINDINGS: The test is based on the detection of S. dysenteriae 1 lipopolysaccharide (LPS) using serotype 1-specific monoclonal antibodies coupled to gold particles and displayed on a one-step immunochromatographic dipstick. A concentration as low as 15 ng/ml of LPS was detected in distilled water and in reconstituted stools in 10 minutes. In distilled water and in reconstituted stools, an unequivocal positive reaction was obtained with 1.6×10⁶ CFU/ml and 4.9×10⁶ CFU/ml of S. dysenteriae 1, respectively. Optimal conditions to read the test have been determined to limit the risk of ambiguous results due to appearance of a faint yellow test band in some negative samples. The specificity was 100% when tested with a battery of Shigella and unrelated strains in culture. When tested on 328 clinical samples in India, Vietnam, Senegal and France by laboratory technicians and in Democratic Republic of Congo by a field technician, the specificity (312/316) was 98.7% (95% CI:96.6-99.6%) and the sensitivity (11/12) was 91.7% (95% CI:59.8-99.6%). Stool cultures and the immunochromatographic test showed concordant results in 98.4 % of cases (323/328) in comparative studies. Positive and negative predictive values were 73.3% (95% CI:44.8-91.1%) and 99.7% (95% CI:98-100%). CONCLUSION: The initial findings presented here for a simple dipstick-based test to diagnose S. dysenteriae 1 demonstrates its promising potential to become a powerful tool for case management and epidemiological surveys.

Published
2011
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21. Prevalence of SARS-CoV-2 antibodies in France: results from nationwide serological surveillance

Author

Stéphane Le Vu, Gabrielle Jones, François Anna, Thierry Rose, Jean-Baptiste Richard, Sibylle Bernard-Stoecklin, Sophie Goyard, Caroline Demeret, Olivier Helynck, Nicolas Escriou, Marion Gransagne, Stéphane Petres, Corinne Robin, Virgile Monnet, Louise Perrin de Facci, Marie-Noelle Ungeheuer, Lucie Léon, Yvonnick Guillois, Laurent Filleul, Pierre Charneau, Daniel Lévy-Bruhl, Sylvie van der Werf, and Harold Noel

Subjects
Science
Abstract

The percentage of national populations infected during the first stages of the COVID-19 pandemic are unclear owing to limited early testing. Here the authors provide a nation-wide prevalence study of SARS-CoV-2 antibodies in France from the first wave of COVID-19 in 2020, including stratification based on age, sex and region.

Published
2021
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22. Les enfants présentant un retard de croissance présentent une colonisation ectopique de l'intestin grêle par des bactéries buccales, qui provoquent une malabsorption des lipides dans des modèles expérimentaux

Author

Vonaesch, P., Araújo, J. R., Gody, J. C., Mbecko, J. R., Sanke, H., Andrianonimiadana, L., Naharimanananirina, T., Ningatoloum, S. N., Vondo, S. S., Gondje, P. B., Rodriguez-Pozo, A., Rakotondrainipiana, M., Kandou, K. J. E., Nestoret, A., Kapel, N., Djorie, S. G., Finlay, B. B., Wegener Parfrey, L., Collard, J. M., Randremanana, R. V., Sansonetti, P. J., Afribiota Investigators, Pathogénie microbienne moléculaire, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Swiss Tropical and Public Health Institute [Basel], Université de Lausanne = University of Lausanne (UNIL), University of Basel (Unibas), Centre pédiatrique de Bangui, Institut Pasteur de Bangui, Réseau International des Instituts Pasteur (RIIP), Unité de Bactériologie Expérimentale [Antananarivo, Madagascar] (IPM), Institut Pasteur de Madagascar, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre Hospitalier Universitaire Joseph Ravoahangy Andrianavalona (CHUJRA), Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of British Columbia (UBC), Collège de France (CdF (institution)), This project was funded by the Total Foundation, the Institut Pasteur, Bill and Melinda Gates Foundation Grant OPP1204689, the Fondation Petram, Nutricia Foundation Grant NRF 2016-10, and a donation from the Odyssey Re-Insurance Company. P.V. was supported by Swiss National Science Foundation Early Postdoctoral Fellowship P2EZP3_152159, Advanced Postdoctoral Fellowship P300PA_177876, and Return Grant P3P3PA_17877, a Roux-Cantarini fellowship (2016), a L’Oréal–UNESCO for Women in Science France fellowship (2017), and an Excellence Scholarship from the University of Basel (Forschungsfonds, 2019). Her group is funded through the NCCR Microbiomes, a National Centre of Competence in Research, funded by the Swiss National Science Foundation (grant number 180575). Work in the group of L.W.P. is funded by Human Frontier Science Program Grant RGY0078/2015. P.J.S. is a Howard Hughes Medical Institute Senior Foreign Scholar and CIFAR scholar in the human microbiome consortium., We thank all children and their families who participated in the Afribiota project. Further, we thank the Afribiota Consortium, the participating hospitals in Bangui and Antananarivo, the Institut Pasteur, the Institut Pasteur de Madagascar, the Institut Pasteur de Bangui, and members of the scientific advisory boards for their continuous support, and we thank the Centre de Recherche Translationelle and the Direction Internationale of the Institut Pasteur (especially Paméla Palvadeau, Jane Lynda Deuve, Cécile Artaud, Nathalie Jolly, Sophie Jarrijon, Mamy Ratsialonina, and Jean-François Damaras) for help in setting up and steering the Afribiota project. We also thank J.-M.C., Pierre-Alain Rubbo, Dieu-Merci Welekoi-Yapondo, L.A., Laurence Arowas, and Marie-Noelle Ungeheuer for managing the biobank, the members of the animal facility at the Institut Pasteur for taking care of the mice, the Centre d’Immunolgoie Humaine of the Institut Pasteur, especially Milena Hasan, Tarshana Stephen, and Esma Karkeni, for help with setting up the LUMINEX assays at their platform, Asmaa Tazi for identification of the bacteria by MALDI-TOF spectroscopy, Estelle Martineau at the Platform Spectrometries Capacités at the University of Nantes for quantification of the fermentation products, Kelsey Huus for critical reading of the manuscript, and Munir Winkel for streamlining of the R code., and Liste of Afribiota Inverstigators : Laurence Barbot-Trystram, Hôpital Pitié-Salpêtrière, Paris, France Robert Barouki, Hôpital Necker- Enfants maladies, Paris, France Alexandra Bastaraud, Institut Pasteur de Madagascar, Antananarivo, Madagascar Jean-Marc Collard, Institut Pasteur de Madagascar, Antananarivo, Madagascar Maria Doria, Institut Pasteur, Paris, France Darragh Duffy, Institut Pasteur, Paris, France B. Brett Finlay, University of British Columbia, Vancouver, Canada Serge Ghislain Djorie, Institut Pasteur de Bangui, Bangui, Central African Republic Tamara Giles-Vernick, Institut Pasteur, Paris, France Bolmbaye Privat Gondje, Complexe Pédiatrique de Bangui, Bangui, Central African Republic Jean-Chrysostome Gody, Complexe Pédiatrique de Bangui, Bangui, Central African Republic Milena Hasan, Institut Pasteur, France Francis Allen Hunald, Service de Chirurgie pédiatrique, Centre Hospitalier Universitaire Joseph Ravoahangy Andrianavalona (CHU-JRA), Antananarivo, Madagascar Nathalie Kapel, Hôpital Pitié-Salpêtrière, Paris, France Jean-Pierre Lombart, Institut Pasteur de Bangui, Bangui, Central African Republic Alexandre Manirakiza, Institut Pasteur de Bangui, Bangui, Central African Republic Synthia Nazita Nigatoloum, Complexe Pédiatrique de Bangui, Bangui, Central African Republic Laura Wegener Parfrey, University of British Columbia, Vancouver, Canada Lisette Raharimalala, Centre de Santé Materno-Infantile, Tsaralalana, Antananarivo, Madagascar Maheninasy Rakotondrainipiana, Institut Pasteur de Madagascar, Antananarivo, Madagascar Rindra Vatosoa Randremanana, Institut Pasteur de Madagascar, Antananarivo, Madagascar Harifetra Mamy Richard Randriamizao, Centre Hospitalier Universitaire Joseph Ravoahangy Andrianavalona (CHU-JRA), Antananarivo, Madagascar Frédérique Randrianirina, Institut Pasteur de Madagascar, Antananarivo, Madagascar Annick Robinson, Centre Hospitalier Universitaire Mère Enfant de Tsaralalana, Antananarivo, Madagascar Pierre-Alain Rubbo, Institut Pasteur de Bangui, Bangui, République Centrafricaine Philippe Sansonetti, Institut Pasteur, Paris, France Laura Schaeffer, Institut Pasteur, Paris, France Ionela Gouandjika-Vassilache, Institut Pasteur de Bangui, Bangui, République Centrafricaine Pascale Vonaesch, Institut Pasteur, Paris, France Sonia Sandrine Vondo, Complexe Pédiatrique de Bangui, Bangui, Central African Republic Inès Vigan-Womas, Institut Pasteur de Madagascar, Antananarivo, Madagasca

Subjects
Mouth, Multidisciplinary, Bacteria, lipid malabsorption, [SDV]Life Sciences [q-bio], [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Models, Theoretical, Lipid Metabolism, Lipids, Gastrointestinal Microbiome, Mice, Cross-Sectional Studies, Malabsorption Syndromes, stunted child growth, Child, Preschool, Intestine, Small, environmental enteric dysfunction, low-grade inflammation, Animals, Humans, Leukocyte L1 Antigen Complex, small intestine, Growth Disorders
Abstract

International audience; Environmental enteric dysfunction (EED) is an inflammatory syndrome postulated to contribute to stunted child growth and to be associated with intestinal dysbiosis and nutrient malabsorption. However, the small intestinal contributions to EED remain poorly understood. This study aimed to assess changes in the proximal and distal intestinal microbiota in the context of stunting and EED and to test for a causal role of these bacterial isolates in the underlying pathophysiology. We performed a cross-sectional study in two African countries recruiting roughly 1,000 children aged 2 to 5 years and assessed the microbiota in the stomach, duodenum, and feces. Upper gastrointestinal samples were obtained from stunted children and stratified according to stunting severity. Fecal samples were collected. We then investigated the role of clinical isolates in EED pathophysiology using tissue culture and animal models. We find that small intestinal bacterial overgrowth (SIBO) is extremely common (>80%) in stunted children. SIBO is frequently characterized by an overgrowth of oral bacteria, leading to increased permeability and inflammation and to replacement of classical small intestinal strains. These duodenal bacterial isolates decrease lipid absorption in both cultured enterocytes and mice, providing a mechanism by which they may exacerbate EED and stunting. Further, we find a specific fecal signature associated with the EED markers fecal calprotectin and alpha-antitrypsin. Our study shows a causal implication of ectopic colonization of oral bacterial isolated from the small intestine in nutrient malabsorption and gut leakiness in vitro. These findings have important therapeutic implications for modulating the microbiota through microbiota-targeted interventions.

Published
2022

23. Putative Biomarkers of Environmental Enteric Disease Fail to Correlate in a Cross-Sectional Study in Two Study Sites in Sub-Saharan Africa

Author

Vonaesch, P., Winkel, M., Kapel, N., Nestoret, A., Barbot-Trystram, L., Pontoizeau, C., Barouki, R., Rakotondrainipiana, M., Kandou, K., Andriamanantena, Z., Andrianonimiadana, L., Habib, A., Rodriguez-Pozo, A., Hasan, M., Vigan-Womas, I., Collard, J. M., Gody, J. C., Djorie, S., Sansonetti, P. J., Randremanana, R. V., On Behalf Of The Afribiota Investigators, Pathogénie microbienne moléculaire, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lausanne = University of Lausanne (UNIL), Swiss Tropical and Public Health Institute [Basel], University of Basel (Unibas), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Pasteur de Madagascar, Réseau International des Instituts Pasteur (RIIP), Institut Pasteur de Bangui, Cytometrie et Biomarqueurs – Cytometry and Biomarkers (UTechS CB), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Centre National Hospitalier Universitaire [Bangui] (CNHUB), This project was funded by the Total Foundation, Institut Pasteur, the Bill and Melinda Gates Foundation (OPP1204689), the Fondation Petram and a donation by the Odyssey Re-Insurance company. PV was supported by an Early Postdoctoral Fellowship (P2EZP3_152159), an Advanced Postdoctoral Fellowship (P300PA_177876) as well as a Return Grant (P3P3PA_17877) from the Swiss National Science Foundation, a Roux-Cantarini Fellowship (award year: 2016), a L’Oréal-UNESCO for Women in Science France Fellowship (award year: 2017) and an Excellence Scholarship from the University of Basel (Forschungsfonds, award year: 2019)., and We wish to thank all implicated children and their families, the AFRIBIOTA Consortium, the participating hospitals in Bangui and Antananarivo, Institut Pasteur, Institut Pasteur de Madagascar and Institut Pasteur de Bangui and members of the scientific advisory board for their continuous support. Furthermore, we wish to thank the Centre de Recherche Translationelle and the Direction Internationale of the Institut Pasteur, and especially Paméla Palvadeau, Jane Lynda Deuve, Cécile Artaud, Nathalie Jolly, Sophie Jarrijon, Mamy Ratsialonina, and Jean-François Damaras for precious help in setting-up and steering the AFRIBIOTA project. We would also like to thank Jean-Marc Collard, Pierre-Alain Rubbo, Dieu-Merci Welekoi-Yapondo, Lova Andrianonimiadana, Laurence Arowas and Marie-Noelle Ungeheuer for managing the AFRIBIOTA biobank. Furthermore, we would like to thank the Centre d’Immunologie Humaine of the Institut Pasteur, especially Tarshana Stephen and Esma Karkeni for help with setting-up the LUMINEX assays at their platform.

Subjects
alpha-1-antitrypsin, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, calprotectin, Environmental Illness, insulin-like growth factor, stunted child growth, Intestine, Small, Humans, Africa South of the Sahara, Growth Disorders, Nutrition and Dietetics, Sub-Saharan Africa, environmental enteric dysfunction, anemia, biomarker, citrulline, lactulose-mannitol test, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Intestinal Diseases, C-Reactive Protein, Cross-Sectional Studies, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Child, Preschool, [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Leukocyte L1 Antigen Complex, Biomarkers, Food Science
Abstract

International audience; Environmental enteric dysfunction (EED) is an elusive, inflammatory syndrome of the small intestine thought to be associated with enterocyte loss and gut leakiness and lead to stunted child growth. To date, the gold standard for diagnosis is small intestine biopsy followed by histology. Several putative biomarkers for EED have been proposed and are widely used in the field. Here, we assessed in a cross-sectional study of children aged 2–5 years for a large set of biomarkers including markers of protein exudation (duodenal and fecal alpha-1-antitrypsin (AAT)), inflammation (duodenal and fecal calprotectin, duodenal, fecal and blood immunoglobulins, blood cytokines, C-reactive protein (CRP)), gut permeability (endocab, lactulose-mannitol ratio), enterocyte mass (citrulline) and general nutritional status (branched-chain amino acids (BCAA), insulin-like growth factor) in a group of 804 children in two Sub-Saharan countries. We correlated these markers with each other and with anemia in stunted and non-stunted children. AAT and calprotectin, CRP and citrulline and citrulline and BCAA correlated with each other. Furthermore, BCAA, citrulline, ferritin, fecal calprotectin and CRP levels were correlated with hemoglobin levels. Our results show that while several of the biomarkers are associated with anemia, there is little correlation between the different biomarkers. Better biomarkers and a better definition of EED are thus urgently needed.

Published
2022
Full Text
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24. Stunted children display ectopic small intestinal colonization by oral bacteria, which cause lipid malabsorption in experimental models

Author

Vonaesch, Pascale, Araújo, João, Gody, Jean-Chrysostome, Mbecko, Jean-Robert, Sanke, Hugues, Andrianonimiadana, Lova, Naharimanananirina, Tanteliniaina, Ningatoloum, Synthia Nazita, Vondo, Sonia Sandrine, Gondje, Privat Bolmbaye, Rodriguez-Pozo, Andre, Rakotondrainipiana, Maheninasy, Kandou, Kaleb Jephté Estimé, Nestoret, Alison, Kapel, Nathalie, Djorie, Serge Ghislain, Finlay, B. Brett, Wegener Parfrey, Laura, Collard, Jean-Marc, Randremanana, Rindra Vatosoa, Sansonetti, Philippe, Collard, Jean-Marc, Pathogénie microbienne moléculaire, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Swiss Tropical and Public Health Institute [Basel], Université de Lausanne = University of Lausanne (UNIL), University of Basel (Unibas), Centre pédiatrique de Bangui, Institut Pasteur de Bangui, Réseau International des Instituts Pasteur (RIIP), Unité de Bactériologie Expérimentale [Antananarivo, Madagascar] (IPM), Institut Pasteur de Madagascar, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre Hospitalier Universitaire Joseph Ravoahangy Andrianavalona (CHUJRA), Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of British Columbia (UBC), Collège de France (CdF (institution)), This project was funded by the Total Foundation, the Institut Pasteur, Bill and Melinda Gates Foundation Grant OPP1204689, the Fondation Petram, Nutricia Foundation Grant NRF 2016-10, and a donation from the Odyssey Re-Insurance Company. P.V. was supported by Swiss National Science Foundation Early Postdoctoral Fellowship P2EZP3_152159, Advanced Postdoctoral Fellowship P300PA_177876, and Return Grant P3P3PA_17877, a Roux-Cantarini fellowship (2016), a L’Oréal–UNESCO for Women in Science France fellowship (2017), and an Excellence Scholarship from the University of Basel (Forschungsfonds, 2019). Her group is funded through the NCCR Microbiomes, a National Centre of Competence in Research, funded by the Swiss National Science Foundation (grant number 180575). Work in the group of L.W.P. is funded by Human Frontier Science Program Grant RGY0078/2015. P.J.S. is a Howard Hughes Medical Institute Senior Foreign Scholar and CIFAR scholar in the human microbiome consortium., We thank all children and their families who participated in the Afribiota project. Further, we thank the Afribiota Consortium, the participating hospitals in Bangui and Antananarivo, the Institut Pasteur, the Institut Pasteur de Madagascar, the Institut Pasteur de Bangui, and members of the scientific advisory boards for their continuous support, and we thank the Centre de Recherche Translationelle and the Direction Internationale of the Institut Pasteur (especially Paméla Palvadeau, Jane Lynda Deuve, Cécile Artaud, Nathalie Jolly, Sophie Jarrijon, Mamy Ratsialonina, and Jean-François Damaras) for help in setting up and steering the Afribiota project. We also thank J.-M.C., Pierre-Alain Rubbo, Dieu-Merci Welekoi-Yapondo, L.A., Laurence Arowas, and Marie-Noelle Ungeheuer for managing the biobank, the members of the animal facility at the Institut Pasteur for taking care of the mice, the Centre d’Immunolgoie Humaine of the Institut Pasteur, especially Milena Hasan, Tarshana Stephen, and Esma Karkeni, for help with setting up the LUMINEX assays at their platform, Asmaa Tazi for identification of the bacteria by MALDI-TOF spectroscopy, Estelle Martineau at the Platform Spectrometries Capacités at the University of Nantes for quantification of the fermentation products, Kelsey Huus for critical reading of the manuscript, and Munir Winkel for streamlining of the R code., and Liste of Afribiota Inverstigators : Laurence Barbot-Trystram, Hôpital Pitié-Salpêtrière, Paris, France Robert Barouki, Hôpital Necker- Enfants maladies, Paris, France Alexandra Bastaraud, Institut Pasteur de Madagascar, Antananarivo, Madagascar Jean-Marc Collard, Institut Pasteur de Madagascar, Antananarivo, Madagascar Maria Doria, Institut Pasteur, Paris, France Darragh Duffy, Institut Pasteur, Paris, France B. Brett Finlay, University of British Columbia, Vancouver, Canada Serge Ghislain Djorie, Institut Pasteur de Bangui, Bangui, Central African Republic Tamara Giles-Vernick, Institut Pasteur, Paris, France Bolmbaye Privat Gondje, Complexe Pédiatrique de Bangui, Bangui, Central African Republic Jean-Chrysostome Gody, Complexe Pédiatrique de Bangui, Bangui, Central African Republic Milena Hasan, Institut Pasteur, France Francis Allen Hunald, Service de Chirurgie pédiatrique, Centre Hospitalier Universitaire Joseph Ravoahangy Andrianavalona (CHU-JRA), Antananarivo, Madagascar Nathalie Kapel, Hôpital Pitié-Salpêtrière, Paris, France Jean-Pierre Lombart, Institut Pasteur de Bangui, Bangui, Central African Republic Alexandre Manirakiza, Institut Pasteur de Bangui, Bangui, Central African Republic Synthia Nazita Nigatoloum, Complexe Pédiatrique de Bangui, Bangui, Central African Republic Laura Wegener Parfrey, University of British Columbia, Vancouver, Canada Lisette Raharimalala, Centre de Santé Materno-Infantile, Tsaralalana, Antananarivo, Madagascar Maheninasy Rakotondrainipiana, Institut Pasteur de Madagascar, Antananarivo, Madagascar Rindra Vatosoa Randremanana, Institut Pasteur de Madagascar, Antananarivo, Madagascar Harifetra Mamy Richard Randriamizao, Centre Hospitalier Universitaire Joseph Ravoahangy Andrianavalona (CHU-JRA), Antananarivo, Madagascar Frédérique Randrianirina, Institut Pasteur de Madagascar, Antananarivo, Madagascar Annick Robinson, Centre Hospitalier Universitaire Mère Enfant de Tsaralalana, Antananarivo, Madagascar Pierre-Alain Rubbo, Institut Pasteur de Bangui, Bangui, République Centrafricaine Philippe Sansonetti, Institut Pasteur, Paris, France Laura Schaeffer, Institut Pasteur, Paris, France Ionela Gouandjika-Vassilache, Institut Pasteur de Bangui, Bangui, République Centrafricaine Pascale Vonaesch, Institut Pasteur, Paris, France Sonia Sandrine Vondo, Complexe Pédiatrique de Bangui, Bangui, Central African Republic Inès Vigan-Womas, Institut Pasteur de Madagascar, Antananarivo, Madagasca

Subjects
[SDV] Life Sciences [q-bio], stunted child growth, lipid malabsorption, [SDV]Life Sciences [q-bio], environmental enteric dysfunction, low-grade inflammation, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, small intestine, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology
Abstract

International audience; Environmental enteric dysfunction (EED) is an inflammatory syndrome postulated to contribute to stunted child growth and to be associated with intestinal dysbiosis and nutrient malabsorption. However, the small intestinal contributions to EED remain poorly understood. This study aimed to assess changes in the proximal and distal intestinal microbiota in the context of stunting and EED and to test for a causal role of these bacterial isolates in the underlying pathophysiology. We performed a cross-sectional study in two African countries recruiting roughly 1,000 children aged 2 to 5 years and assessed the microbiota in the stomach, duodenum, and feces. Upper gastrointestinal samples were obtained from stunted children and stratified according to stunting severity. Fecal samples were collected. We then investigated the role of clinical isolates in EED pathophysiology using tissue culture and animal models. We find that small intestinal bacterial overgrowth (SIBO) is extremely common (>80%) in stunted children. SIBO is frequently characterized by an overgrowth of oral bacteria, leading to increased permeability and inflammation and to replacement of classical small intestinal strains. These duodenal bacterial isolates decrease lipid absorption in both cultured enterocytes and mice, providing a mechanism by which they may exacerbate EED and stunting. Further, we find a specific fecal signature associated with the EED markers fecal calprotectin and alpha-antitrypsin. Our study shows a causal implication of ectopic colonization of oral bacterial isolated from the small intestine in nutrient malabsorption and gut leakiness in vitro. These findings have important therapeutic implications for modulating the microbiota through microbiota-targeted interventions.

Published
2022

25. High prevalence of small intestine bacteria overgrowth and asymptomatic carriage of enteric pathogens in stunted children in Antananarivo, Madagascar

Author

Collard, Jean-Marc, Andrianonimiadana, Lova, Habib, Azimdine, Rakotondrainipiana, Maheninasy, Andriantsalama, Prisca, Randriamparany, Ravaka, Rabenandrasana, M., Weill, François-Xavier, Sauvonnet, Nathalie, Randremanana, Rindra Vatosoa, Guillemot, Vincent, Vonaesch, Pascale, Sansonetti, Philippe, Bidault, Floran, Unité de Bactériologie Expérimentale [Antananarivo, Madagascar] (IPM), Institut Pasteur de Madagascar, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Unité d’Épidémiologie et de Recherche clinique [Antananarivo, Madagascar], Bactéries pathogènes entériques (BPE), Institut Pasteur [Paris] (IP), Pathogénie microbienne moléculaire, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics, This project was funded by the Total and Petram Foundations and by Institut Pasteur. LA, PA and RR wages were supported by the Total Foundation and MR wage by the Petram Foundation. PV was supported by an Early Postdoctoral Fellowship (P2EZP3_152159), an Advanced Postdoctoral Fellowship (P300PA_177876) as well as a Return Grant (P3P3PA_17877) from the Swiss National Science Foundation, a Roux-Cantarini Fellowship (2016), a L'Oréal-UNESCO for Women in Science France Fellowship (2017) and an Excellence Scholarship from the University of Basel (Forschungsfonds, 2019)., We wish to thank all participating families, the AFRIBIOTA Consortium, the participating hospitals in Antananarivo, as well as the Institut Pasteur, the Institut Pasteur de Madagascar, and members of the scientific advisory board for their continuous support, Prof. Jean-Louis Demarquez for training sessions to teach the local health professionals the methods used for duodenal aspirations, Aurélie Etienne for precious help with the clinical procedures and first aspirations performed, the field workers Tseheno Harisoa and Rado Andrianantenaina, as well as all implicated community health workers, for countless hours spent in the field, and the Centre de Recherche Translationelle and the Direction Internationale of the Institut Pasteur, and especially Paméla Palvadeau, Jane Lynda Deuve, Marc Rovatiana Ranarijesy, Kanto Liantsoa Razanakolona, Cécile Artaud, Nathalie Jolly, Sophie Jarrijon, Mamy Ratsialonina, Jean-François Damaras, Marie-Noelle Ungeheuer, and Laurence Arowas for precious help in setting up and steering the AFRIBIOTA project and managing the funds and the biobank. We would like to thank the staff of the 'Plateforme de Microbiologie Mutualisée (P2M)' at Institut Pasteur Paris where the whole genome sequencing was performed, Sophie Lefevre from the Centre National de Référence des Escherichia coli, Shigella et Salmonella in Paris, France for Shigella serotyping, and Claude Parsot and Alexandre Grassart for the interesting discussions on Shigella.

Subjects
Adult, Diarrhea, MESH: Intestine, Small, MESH: Bacterial Infections, MESH: Shigella, MESH: Madagascar, Feces, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Child, Intestine, Small, Escherichia coli, Madagascar, Prevalence, Humans, Child, MESH: Prevalence, MESH: Humans, Bacteria, MESH: Escherichia coli, digestive, oral, and skin physiology, Public Health, Environmental and Occupational Health, MESH: Feces, MESH: Adult, Bacterial Infections, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH: Bacteria, MESH: Diarrhea, Infectious Diseases, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Shigella, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Abstract

Environmental Enteric Dysfunction (EED) refers to an incompletely defined syndrome of inflammation, reduced absorptive capacity, and reduced barrier function in the small intestine. It is widespread among children and adults in low- and middle-income countries and is also associated with poor sanitation and certain gut infections possibly resulting in an abnormal gut microbiota, small intestinal bacterial overgrowth (SIBO) and stunting. We investigated bacterial pathogen exposure in stunted and non-stunted children in Antananarivo, Madagascar by collecting fecal samples from 464 children (96 severely stunted, 104 moderately stunted and 264 non-stunted) and the prevalence of SIBO in 109 duodenal aspirates from stunted children (61 from severely stunted and 48 from moderately stunted children). SIBO assessed by both aerobic and anaerobic plating techniques was very high: 85.3% when selecting a threshold of ≥105 CFU/ml of bacteria in the upper intestinal aspirates. Moreover, 58.7% of the children showed more than 106 bacteria/ml in these aspirates. The most prevalent cultivated genera recovered were Streptococcus, Neisseria, Staphylococcus, Rothia, Haemophilus, Pantoea and Branhamella. Feces screening by qPCR showed a high prevalence of bacterial enteropathogens, especially those categorized as being enteroinvasive or causing mucosal disruption, such as Shigella spp., enterotoxigenic Escherichia coli, enteropathogenic E. coli and enteroaggregative E. coli. These pathogens were detected at a similar rate in stunted children and controls, all showing no sign of severe diarrhea the day of inclusion but both living in a highly contaminated environment (slum-dwelling). Interestingly Shigella spp. was the most prevalent enteropathogen found in this study (83.3%) without overrepresentation in stunted children.

Published
2022

26. Stunted childhood growth is associated with decompartmentalization of the gastrointestinal tract and overgrowth of oropharyngeal taxa

Author

Jean-Marc Collard, Tanteliniaina Naharimanananirina, Jepthé Estimé Kaleb Kandou, Laura Wegener Parfrey, Maheninasy Rakotondrainipiana, Philippe J. Sansonetti, Kelsey E. Huus, Synthia Nazita Nigatoloum, Rindra Randremanana, Florent Mazel, Serge Ghislain Djorie, Pierre-Alain Rubbo, Jean-Robert Mbecko, Jean-Chrysostome Gody, Evan Morien, Sonia Sandrine Vondo, Pascale Vonaesch, Bolmbaye Privat Gondje, Lova Andrianonimiadana, B. Brett Finlay, Hugues Sanke, Pathogénie microbienne moléculaire, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of British Columbia (UBC), Unité de Bactériologie Expérimentale [Antananarivo, Madagascar] (IPM), Institut Pasteur de Madagascar, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Institut Pasteur de Bangui, Réseau International des Instituts Pasteur (RIIP), Centre Hospitalier Universitaire Joseph Ravoahangy Andrianavalona (CHUJRA), Centre pédiatrique de Bangui, Unité d'Epidémiologie [Antananarivo, Madagascar] (IPM), Collège de France - Chaire Microbiologie et Maladies infectieuses, Collège de France (CdF (institution)), This project was funded by the Total Foundation, Institut Pasteur, Pasteur Foundation Switzerland, as well as the Nutricia Research Foundation. P.V. was supported by an Early and Advanced postdoctoral fellowship from the Swiss National Science Foundation, a Roux-Cantarini fellowship, and a L’Oréal–United Nations Educational, Scientific, and Cultural Organization for Women in Science France fellowship. P.J.S. is a HHMI Senior Foreign Scholar and a Canadian Institute for Advanced Research scholar in the human microbiome consortium. K.E.H. is recipient of a Vanier Canada Graduate Scholarship. B.B.F. is a member of the Canadian Institute for Advanced Research human microbiome consortium. Work in his group is funded by the Canadian Institute for Health Research. Work in L.W.P.’s group is funded by the Human Frontier Science Program RGY0078/2015. F.M. is recipient of a Banting Postdoctoral fellowship., We thank all participating families, the AFRIBIOTA Consortium, the participating hospitals in Bangui and Antananarivo, as well as the Institut Pasteur, the Institut Pasteur de Madagascar and de Bangui, and members of the scientific advisory board for their continuous support, Prof. Jean-Louis Demarquez for training sessions to teach the local health professionals the methods used for duodenal aspirations, Aurélie Etienne for precious help with the clinical procedures and first aspirations performed, the field workers Jélide Dépot, Monique Gbacko, Noella Kemba, Carine Domolomo-Angaze, Olivier Deholo, Dieu-Merci Welekoi, Florent Mbombo, Gildas Gonetomy, Prisca Andriatsalama, Ravaka Randriamparany, Tsheno Harisoa, and Rado Andrianantenaina, as well as all implicated community health workers, for countless hours spent in the field, the Centre de Recherche Translationelle and the Direction Internationale of the Institut Pasteur, and especially Paméla Palvadeau, Jane Lynda Deuve, Cécile Artaud, Nathalie Jolly, Sophie Jarijon, Mamy Ratsialonina, Jean-François Damaras, Marie-Noelle Ungeheuer, and Laurence Arowas for precious help in setting up and steering the AFRIBIOTA project and managing the biobank, Amine Ghozlane and Emna Achouri for discussion and critical reading of the manuscript, and Tracy Wang and Rachelle Loo for transcribing the tracking documents., RANDRIAMANANTSOA, Volatiana Manohisoa, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Chaire Microbiologie et Maladies infectieuses, and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Male, sub-Saharan Africa, MESH: Intestine, Small, Physiology, MESH: Shigella, Child Development, Small intestinal bacterial overgrowth, Intestine, Small, Growth Disorders, Gastrointestinal tract, Multidisciplinary, biology, MESH: Escherichia coli, Stomach, digestive, oral, and skin physiology, stunting, MESH: Growth Disorders, oropharyngeal taxa, 3. Good health, medicine.anatomical_structure, PNAS Plus, Child, Preschool, Female, Digestion, 030106 microbiology, MESH: Gastrointestinal Microbiome, Clostridia, 03 medical and health sciences, medicine, Escherichia coli, microbiota, Humans, Microbiome, decompartmentalization, Feces, Clostridium, MESH: Child Development, MESH: Humans, MESH: Clostridium, MESH: Child, Preschool, Campylobacter, medicine.disease, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Small intestine, MESH: Male, Gastrointestinal Microbiome, Shigella, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH: Campylobacter, MESH: Female
Abstract

International audience; Linear growth delay (stunting) affects roughly 155 million children under the age of 5 years worldwide. Treatment has been limited by a lack of understanding of the underlying pathophysiological mechanisms. Stunting is most likely associated with changes in the microbial community of the small intestine, a compartment vital for digestion and nutrient absorption. Efforts to better understand the pathophysiology have been hampered by difficulty of access to small intestinal fluids. Here, we describe the microbial community found in the upper gastrointestinal tract of stunted children aged 2-5 y living in sub-Saharan Africa. We studied 46 duodenal and 57 gastric samples from stunted children, as well as 404 fecal samples from stunted and nonstunted children living in Bangui, Central African Republic, and in Antananarivo, Madagascar, using 16S Illumina Amplicon sequencing and semiquantitative culture methods. The vast majority of the stunted children showed small intestinal bacterial overgrowth dominated by bacteria that normally reside in the oropharyngeal cavity. There was an overrepresentation of oral bacteria in fecal samples of stunted children, opening the way for developing noninvasive diagnostic markers. In addition, Escherichia coli/Shigella sp. and Campylobacter sp. were found to be more prevalent in stunted children, while Clostridia, well-known butyrate producers , were reduced. Our data suggest that stunting is associated with a microbiome "decompartmentalization" of the gastrointestinal tract characterized by an increased presence of oropharyngeal bacteria from the stomach to the colon, hence challenging the current view of stunting arising solely as a consequence of small intestine overstimulation through recurrent infections by enteric pathogens.

Published
2018

27. Durability of immunogenicity and strain coverage of MenBvac, a meningococcal vaccine based on outer membrane vesicles: Lessons of the Normandy campaign

Author

Ludovic Lemée, Eva Hong, Julien Sevestre, Valérie Delbos, Ala-Eddine Deghmane, François Caron, Eric Mallet, Muhamed-Kheir Taha, Aude Terrade, CHU Rouen, Normandie Université (NU), Université de Rouen Normandie (UNIROUEN), Institut Pasteur [Paris], Department of Statistics [Oxford], University of Oxford [Oxford], This work was supported the Institut Pasteur and Rouen University Hospital. JS receives a fellowship from the Conseil Régional de Haute Normandie. We thank Marie-Noelle Ungeheuer (Institut Pasteur-ICAReB) for supply of human serum samples for complement sources., Institut Pasteur [Paris] (IP), and University of Oxford

Subjects
0301 basic medicine, Male, persistence of vaccine response, MESH: Secretory Vesicles, Neisseria meningitidis, Serogroup B, medicine.disease_cause, MESH: Meningococcal Infections, MESH: Meningococcal Vaccines, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, 030212 general & internal medicine, Strain (chemistry), Immunogenicity, Neisseria meningitidis, MESH: Blood Bactericidal Activity, MESH: Infant, 3. Good health, Vaccination, Titer, Infectious Diseases, Child, Preschool, Molecular Medicine, Female, France, Bacterial outer membrane, Blood Bactericidal Activity, Meningococcal Vaccines, Meningococcal vaccine, Biology, Microbiology, PorA, serum bactericidal activity, 03 medical and health sciences, MESH: Neisseria meningitidis, Serogroup B, medicine, Humans, MESH: Humans, General Veterinary, General Immunology and Microbiology, outbreak, Secretory Vesicles, invasive meningococcal disease, MESH: Child, Preschool, Public Health, Environmental and Occupational Health, Outbreak, Infant, vaccination, Virology, MESH: Male, Meningococcal Infections, MESH: France, 030104 developmental biology, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, Neisseria meningitidis serogroup B, MESH: Female
Abstract

International audience; OBJECTIVES:MenBvac® is an outer membrane vesicle (OMV)-based meningococcal vaccine. From 2006 to 2012, it was used to control a clonal B outbreak in Normandy (France). We aimed to analyse the durability of the response against the epidemic strain and coverage beyond the vaccine strain. These data should help to optimize the use of OMV-containing vaccines, such as the new 4CMenB/Bexsero® recombinant vaccine.METHODS:Serum bactericidal activity (SBA) was measured in two cohorts of children who received their first dose of MenBvac® at 1-5years of age and accepted to provide a blood sample either one or four years after a 2+1+1 schedule. All sera were tested against the outbreak strain. Sera from responder subjects were also tested against 12 additional B or C strains which were chosen to entirely, partially, or not at all match the two variable regions (VR1 and VR2) of the PorA vaccine strain.RESULTS:Only 47.9% and 31.3% of subjects showed an SBA titre consistent with protection one and four years, respectively, after the last boost. Protective SBA titres were observed in all sera against B or C strains that entirely matched P1.7,16, and was high (75-100%) for all but one strain that partially matched VR1 or VR2. Extrapolating our data to the OMV component of 4CMenB/Bexsero® suggests that 14.5% of the current B strains would be covered based on PorA matching to the OMV component of 4CMenB/Bexsero® (regardless of the coverage of the three other vaccine components).CONCLUSIONS:Our data confirm that OMV-based vaccines elicit short-lasting SBA titres and may require repeated booster injections. However, strain coverage may be greater than expected.

Published
2017

28. Molecular diagnostic and genetic characterization of highly pathogenic viruses: application during Crimean–Congo haemorrhagic fever virus outbreaks in Eastern Europe and the Middle East

Author

Noël Tordo, S. Chinikar, Antoine Gessain, T. Avsic-Zupanc, Claudia Filippone, Séverine Murri, N. Mollard, Philippe Marianneau, Nicolas Berthet, Valérie Caro, Philippe Desprès, Epidémiologie et Physiopathologie des Virus Oncogènes, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Lyon [ANSES], Université de Lyon-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Biologie des Infections Virales Émergentes - Biology of Emerging Viral Infections (UBIVE), Institut Pasteur [Paris] (IP), Centre national de Référence Fièvres hémorragiques virales - Biologie des infections virales émergentes (UBIVE) (CNR FHV - UBIVE), Institute of Microbiology and Immunology - Inštitut za mikrobiologijo in imunologijo [Ljubljana, Slovenia], Department of Arboviruses and Viral Hemorrhagic Fevers [Tehran], Institut Pasteur d'Iran, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Interactions Moléculaires Flavivirus-Hôtes, Génotypage des Pathogènes et Santé Publique (Plate-forme) (PF8), Stratégies Antivirales, This research was financially supported by PTR no 426-DEVA, by Grant no. UC1 AI062613 (Kennedy) from the US National Institute of Allergy and Infectious Diseases, National Institutes of Health, by Total-Institut Pasteur Foundation and by three European programmes including CCHFV studies: (i) the FP7 Coordination and Support Action ‘ARBO–ZOONET’ no. 211757, an International Network for Capacity Building for the Control of Emerging Vector-Borne Zoonotic Diseases, particularly CCHF, Rift Valley Haemorrhagic Fever and West-Nile Fever (Coordination: Michèle Bouloy), (ii) the FP7 Large-Scale Integrating Research Project ‘EMPERIE’ no. 223498, an European Management Platform for Emerging and Re-emerging Infectious Disease Entities (Coordination: Albertus Osterhaus), (iii) the FP7 Large-Scale Integrating Research Project ‘EDENEXT’ no. 261504 on Biology and control of vector-borne infections in Europe (Coordination: Renaud Lancelot). Claudia Filippone is financially supported by a postdoctoral grant from Ile de France (DIM) and by the FP7 ‘EMPERIE’. The platform ‘Genotyping of Pathogens and Public Health’ is supported in part by the Institut de Veille Sanitaire (Saint-Maurice, France)., We thank all members of the ‘Programme Transversal de Recherche’ PTR no. 426-DEVA at the Institut Pasteur, Paris: Félix Rey, Jean-Claude Manuguerra, Hervé Bourhy and Michèle Bouloy. We acknowledge the Foundation Mérieux, Lyon, for the availability of the Affymetrix station. We thank the ICAReB (Marie-Noelle Ungeheuer, Sylvie Gerbaud) and the PIRC at Institut Pasteur for assistance in complying with ethics guidelines. Animal experiments were conducted in the BioSafety Level 4 facilities (‘Jean Mérieux’ Laboratory, Lyon, France)., European Project: 211757,EC:FP7:KBBE,FP7-KBBE-2007-1,ARBO-ZOONET(2008), European Project: 223498,EC:FP7:HEALTH,FP7-HEALTH-2007-B,EMPERIE(2009), and European Project: 261504,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,EDENEXT(2011)

Subjects
Microbiology (medical), Hemorrhagic Fevers, Viral, Paramyxoviridae, Arenaviridae, [SDV]Life Sciences [q-bio], Loop-mediated isothermal amplification, Filoviridae, MESH: Molecular Diagnostic Techniques, Sensitivity and Specificity, Virus, Disease Outbreaks, 03 medical and health sciences, Flaviviridae, Middle East, Virology, differential diagnosis, Humans, Europe, Eastern, MESH: Disease Outbreaks, 030304 developmental biology, Oligonucleotide Array Sequence Analysis, 0303 health sciences, MESH: Europe, Eastern, MESH: Humans, biology, viral zoonoses, 030306 microbiology, Crimean–Congo haemorrhagic fever virus, Outbreak, MESH: Hemorrhagic Fevers, Viral, General Medicine, biology.organism_classification, MESH: Sensitivity and Specificity, 3. Good health, Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Molecular Diagnostic Techniques, MESH: Middle East, MESH: Oligonucleotide Array Sequence Analysis, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Bunyaviridae, viral haemorrhagic fevers, microarray, MESH: Virology
Abstract

International audience; Several haemorrhagic fevers are caused by highly pathogenic viruses that must be handled in Biosafety level 4 (BSL-4) containment. These zoonotic infections have an important impact on public health and the development of a rapid and differential diagnosis in case of outbreak in risk areas represents a critical priority. We have demonstrated the potential of a DNA resequencing microarray (PathogenID v2.0) for this purpose. The microarray was first validated in vitro using supernatants of cells infected with prototype strains from five different families of BSL-4 viruses (e.g. families Arenaviridae, Bunyaviridae, Filoviridae, Flaviviridae and Paramyxoviridae). RNA was amplified based on isothermal amplification by Phi29 polymerase before hybridization. We were able to detect and characterize Nipah virus and Crimean-Congo haemorrhagic fever virus (CCHFV) in the brains of experimentally infected animals. CCHFV was finally used as a paradigm for epidemics because of recent outbreaks in Turkey, Kosovo and Iran. Viral variants present in human sera were characterized by BLASTN analysis. Sensitivity was estimated to be 10(5) -10(6) PFU/mL of hybridized cDNA. Detection specificity was limited to viral sequences having ~13-14% of global divergence with the tiled sequence, or stretches of ~20 identical nucleotides. These results highlight the benefits of using the PathogenID v2.0 resequencing microarray to characterize geographical variants in the follow-up of haemorrhagic fever epidemics; to manage patients and protect communities; and in cases of bioterrorism.

Published
2013

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