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1. A widespread family of polymorphic toxins encoded by temperate phages

Author

Jamet, Anne, Touchon, Marie, Ribeiro-Gonçalves, Bruno, Carriço, João André, Charbit, Alain, Nassif, Xavier, Ramirez, Mario, Rocha, Eduardo P. C., BMC, BMC, Pathogénie des infections systémiques (Inserm U1002), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC), Instituto de Medicina Molecular (iMM), Faculdade de Medicina [Lisboa], Universidade de Lisboa = University of Lisbon (ULISBOA)-Universidade de Lisboa = University of Lisbon (ULISBOA), Instituto de Microbiologia [Lisboa, Portugal], Génomique évolutive des Microbes / Microbial Evolutionary Genomics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), The laboratory of Xavier Nassif is supported by La Fondation pour la Recherche Médicale, l’Institut National de la Santé et de la Recherche Médicale, le Centre National de la Recherche Scientifique, and l’Université Paris Descartes. The laboratory of Eduardo Rocha is supported by the Centre National de la Recherche Scientifique and the Institut Pasteur., Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universidade de Lisboa (ULISBOA)-Universidade de Lisboa (ULISBOA), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Pathogénie des infections systémiques ( Inserm U1002 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Sorbonne Paris Cité ( USPC ), Instituto de Medicina Molecular, Universidade de Lisboa ( ULISBOA ) -Universidade de Lisboa ( ULISBOA ), Génomique évolutive des Microbes, and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS )

Subjects
[ SDV ] Life Sciences [q-bio], Bacteria, Bacterial toxins, Prophages, [SDV]Life Sciences [q-bio], Exotoxins, Gastrointestinal Microbiome, [SDV] Life Sciences [q-bio], lcsh:Biology (General), Phages, Humans, Bacteriophages, lcsh:QH301-705.5, Genome, Bacterial, Bacterial genomics, Research Article
Abstract

Background Polymorphic toxins (PTs) are multi-domain bacterial exotoxins belonging to distinct families that share common features in terms of domain organization. PTs are found in all major bacterial clades, including many toxic effectors of type V and type VI secretion systems. PTs modulate the dynamics of microbial communities by killing or inhibiting the growth of bacterial competitors lacking protective immunity proteins. Results In this work, we identified a novel widespread family of PTs, named MuF toxins, which were exclusively encoded within temperate phages and their prophages. By analyzing the predicted proteomes of 1845 bacteriophages and 2464 bacterial genomes, we found that MuF-containing proteins were frequently part of the DNA packaging module of tailed phages. Interestingly, MuF toxins were abundant in the human gut microbiome. Conclusions Our results uncovered the presence of the MuF toxin family in the temperate phages of Firmicutes. The MuF toxin family is likely to play an important role in the ecology of the human microbiota where pathogens and commensal species belonging to the Firmicutes are abundant. We propose that MuF toxins could be delivered by phages into host bacteria and either influence the lysogeny decision or serve as bacterial weapons by inhibiting the growth of competing bacteria. Electronic supplementary material The online version of this article (doi:10.1186/s12915-017-0415-1) contains supplementary material, which is available to authorized users.

Published
2016
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2. Gluconeogenesis, an essential metabolic pathway for pathogenic Francisella

Author

Brissac, Terry, Ziveri, Jason, Ramond, Elodie, Tros, Fabiola, Kock, Stephanie, Dupuis, Marion, Brillet, Magali, Barel, Monique, Peyriga, Lindsay, Cahoreau, Edern, Charbit, Alain, Pathogénie des infections systémiques (Inserm U1002), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés (LISBP), Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Recherche Agronomique (INRA), INSERM, CNRS, Universite Paris Descartes Paris Cite Sorbonne, Region Ile de France, Delegation Generale a l'Armement ANR-12-ASTR-0018, Institut National de la Recherche Agronomique (INRA)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), ANR-12-ASTR-0018,TulareDrug,Identification de nouvelles molécules ciblant les effecteurs sécrétés de Francisella tularensis(2012), Pathogénie des infections systémiques ( Inserm U1002 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Sorbonne Paris Cité ( USPC ), Institut Necker Enfants-Malades (INEM) ( INEM - UM 111 (UMR 8253 / U1151) ), Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés ( LISBP ), Institut National de la Recherche Agronomique ( INRA ) -Institut National des Sciences Appliquées - Toulouse ( INSA Toulouse ), Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), MetaToul FluxoMet (TBI-MetaToul), MetaboHUB-MetaToul, MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), and Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
TRANSCRIPTIONAL ADAPTATION, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology, TRANSPOSON MUTAGENESIS, VIRULENCE DETERMINANTS, TULARENSIS SCHU S4, ENTERICA SEROVAR TYPHIMURIUM, AMINO-ACIDS, MYCOBACTERIUM-TUBERCULOSIS, INTRACELLULAR REPLICATION, ALLELIC REPLACEMENT, BACTERIAL PATHOGENS
Abstract

Intracellular multiplication and dissemination of the infectious bacterial pathogen Francisella tularensis implies the utilization of multiple host-derived nutrients. Here, we demonstrate that gluconeogenesis constitutes an essential metabolic pathway in Francisella pathogenesis. Indeed, inactivation of gene glpX, encoding the unique fructose 1,6-bisphosphatase of Francisella, severely impaired bacterial intracellular multiplication when cells were supplemented by gluconeogenic substrates such as glycerol or pyruvate. The glpX mutant also showed a severe virulence defect in the mouse model, confirming the importance of this pathway during the in vivo life cycle of the pathogen. Isotopic profiling revealed the major role of the Embden-Meyerhof (glycolysis) pathway in glucose catabolism in Francisella and confirmed the importance of glpX in gluconeogenesis. Altogether, the data presented suggest that gluconeogenesis allows Francisella to cope with the limiting glucose availability it encounters during its infectious cycle by relying on host amino acids. Hence, targeting the gluconeogenic pathway might constitute an interesting therapeutic approach against this pathogen.

Published
2015
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3. Validation of the post-delivery perceived stress inventory

Author

Catherine Sellenet, Chantal Razurel, Marc Dupuis, Jean-Philippe Antonietti, Barbara Kaiser, Manuela Epiney, Centre de recherche en éducation de Nantes ( CREN ), Université de Nantes - UFR Lettres et Langages ( UFRLL ), Université de Nantes ( UN ) -Université de Nantes ( UN ), lgp, Laboratoire de géographie physique ( LGP ), Université Panthéon-Sorbonne ( UP1 ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Panthéon-Sorbonne ( UP1 ) -Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Centre National de la Recherche Scientifique ( CNRS ), Pathogénie des infections systémiques ( Inserm U1002 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Sorbonne Paris Cité ( USPC ), Centre de recherche en éducation de Nantes (CREN), Le Mans Université (UM)-Université de Nantes - UFR Lettres et Langages (UFRLL), Université de Nantes (UN)-Université de Nantes (UN), Laboratoire de géographie physique : Environnements Quaternaires et Actuels (LGP), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Centre National de la Recherche Scientifique (CNRS), Pathogénie des infections systémiques (Inserm U1002), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Université Panthéon-Sorbonne (UP1)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Université Panthéon-Sorbonne (UP1), Université de Nantes - UFR Lettres et Langages (UFRLL), Université de Nantes (UN)-Université de Nantes (UN)-Le Mans Université (UM), and Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Predictive validity, post-delivery perceived stress, Psychometrics, [SHS.EDU]Humanities and Social Sciences/Education, Psychological intervention, Breastfeeding, Mothers, Perceived Stress Scale, Anxiety, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Surveys and Questionnaires, medicine, Humans, Childbirth, 030212 general & internal medicine, Applied Psychology, Analysis of Variance, 030219 obstetrics & reproductive medicine, ddc:618, Depression, Postpartum Period, Parturition, Discriminant Analysis, [ SHS.EDU ] Humanities and Social Sciences/Education, Delivery, Obstetric, Confirmatory factor analysis, Parity, Psychiatry and Mental health, Clinical Psychology, Breast Feeding, Linear Models, Female, France, medicine.symptom, Factor Analysis, Statistical, Psychology, Stress, Psychological, Postpartum period, Clinical psychology
Abstract

International audience; This article presents the post-delivery perceived stress inventory (PDPSI) and its psychometric properties. This inventory is unique in that it links the measurement of perceived stress to events experienced during and after delivery. A total of 235 French-speaking, primiparous mothers completed the PDPSI two days after their delivery. To evaluate the predictive validity of the PDPSI on anxiety and depression, participants also completed the EPDS and the STAI two days and six weeks postpartum. The exploratory analysis revealed a 16-item structure divided into five factors: F1: relationship with the child; F2: delivery; F3: fatigue after delivery; F4: breastfeeding; and F5: relationship with the caregivers. The PDPSI demonstrated good internal consistency. Moreover, confirmatory factor analysis produced excellent indices, indicating that the complexity of the PDPSI was taken into account and its fit to the sample. The discriminant analysis showed that the PDPSI was not sensitive to specific changes in the sample making the inventory generalizable to other populations. Predictive validity showed that the scale significantly predicted depression and anxiety in the early postpartum period as well as anxiety six weeks postpartum. Overall, the PDPSI showed excellent psychometric qualities, making it a useful tool for future research-evaluating interventions related to perceived stress during the postpartum period.

Published
2013
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4. Posttranslational modification of pili upon cell contact triggers N. meningitidis dissemination

Author

Luc Camoin, Mikael Trellet, Guillain Mikaty, Michael Nilges, Xavier Nassif, Christian Malosse, Audrey Dumont, Guilhem Clary, Patricia Martin, Julia Chamot-Rooke, Philippe Chafey, Guillaume Duménil, Anne-Flore Imhaus, Joseph Gault, Magali Soyer, Laboratoire des mécanismes réactionnels (DCMR), École polytechnique (X)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Pathogénie des infections systémiques (Inserm U1002), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bioinformatique Structurale, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire des mécanismes réactionnels ( DCMR ), École polytechnique ( X ) -Centre National de la Recherche Scientifique ( CNRS ), Pathogénie des infections systémiques ( Inserm U1002 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), École polytechnique (X)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Glycerol, Models, Molecular, Transcription, Genetic, Population, Neisseria meningitidis, Biology, medicine.disease_cause, Bacterial Adhesion, Pilus, Microbiology, 03 medical and health sciences, Cell Line, Tumor, Organelle, medicine, Humans, Colonization, Phosphorylation, education, Gene, 030304 developmental biology, 0303 health sciences, education.field_of_study, Multidisciplinary, 030306 microbiology, Phosphotransferases, Epithelial Cells, Gene Expression Regulation, Bacterial, biology.organism_classification, Epithelium, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, medicine.anatomical_structure, Fimbriae, Bacterial, [ CHIM.THEO ] Chemical Sciences/Theoretical and/or physical chemistry, Fimbriae Proteins, Protein Processing, Post-Translational, Bacteria
Abstract

International audience; The Gram-negative bacterium Neisseria meningitidis asymptomatically colonizes the throat of 10 to 30% of the human population, but throat colonization can also act as the port of entry to the blood (septicemia) and then the brain (meningitis). Colonization is mediated by filamentous organelles referred to as type IV pili, which allow the formation of bacterial aggregates associated with host cells. We found that proliferation of N. meningitidis in contact with host cells increased the transcription of a bacterial gene encoding a transferase that adds phosphoglycerol onto type IV pili. This unusual posttranslational modification specifically released type IV pili-dependent contacts between bacteria. In turn, this regulated detachment process allowed propagation of the bacterium to new colonization sites and also migration across the epithelium, a prerequisite for dissemination and invasive disease.

Published
2011
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5. La déficience de USF1 favorise la dégradation de p53 au cours de l'infection par Helicobacter pylori et accélère la cancérogenèse gastrique

Author

Nicolas Mouchet, Margarita Camorlinga, Hilde De Reuse, Valérie Michel, Javier Torres, Julien Fernandes, Marie-Dominique Galibert, Lionel Costa, David Da Silva Barreira, Mario Milco D'Elios, Krysten Le Luel, Eliette Touati, Laurence Fiette, Sébastien Corre, Anne Danckaert, Grégory Jouvion, Jason Ziveri, Pathogenèse de Helicobacter - Helicobacter Pathogenesis, Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre de Ressources et de Recherche Technologique - Center for Technological Resources and Research (C2RT), Institut Pasteur [Paris], Pathogénie des infections systémiques (Inserm U1002), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuropathologie expérimentale - Experimental neuropathology, Institut Pasteur [Paris]-Université Paris Descartes - Paris 5 (UPD5), AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Instituto Mexicano del Seguro Social [Mexico City, Mexico] (IMSS), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Institut Mutualiste de Montsouris (IMM), CHU Pontchaillou [Rennes], Université Paris Diderot, Ligue Contre le Cancer, Odyssey Reinsurance Company, FIS/IMSS/PROT/PRIO/13/027), Fondo de Investigacion en salud, IMSS, Mexico, West committee Ligue Nationale Contre le Cancer, UMS Biosit, We thank Sophie Vaulont (Institut Cochin, Paris, France) for Usf1-/- mice, Timothy C Wang (Columbia University, NY, USA) for providing us couples of INS-GAS mice and Joana Gomes and Celso Reis (I3S-IPATIMUP, Porto, Portugal) for MKN45 cells. We also thank Laurence Bernard-Touami and the Animal Housing ARCHE (UMS Biosit, https://biosit.univ-rennes1.fr, University of Rennes, France), and David Hardy and Magalie Tichit (Unit of Experimental Neuropathology, Institut Pasteur, Paris, France) for her technical help on the histology part and the UtechS Photonic BioImaging (Imagopole), C2RT, Institut Pasteur, supported by the French National Research Agency (France BioImaging, ANR-10–INSB–04, Investments for the Future), both as a part of the FranceBioImaging infrastructure., and ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010)

Subjects
0301 basic medicine, Proteasome Endopeptidase Complex, Carcinogenesis, oncogenes, DNA damage, [SDV]Life Sciences [q-bio], Cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, Context (language use), medicine.disease_cause, Genomic Instability, Helicobacter Infections, Cell Line, gastric cancer, genetic instability, helicobacter pylori infection, Animals, DNA Damage, Humans, Mice, Tumor Suppressor Protein p53, Ubiquitination, Upstream Stimulatory Factors, Gastric Mucosa, Helicobacter pylori, Stomach Neoplasms, 03 medical and health sciences, 0302 clinical medicine, In vivo, medicine, Chemistry, Stomach, Gastroenterology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, In vitro, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Cytoplasm, 030220 oncology & carcinogenesis, Cancer research, Camptothecin, medicine.drug
Abstract

ObjectiveHelicobacter pylori (Hp) is a major risk factor for gastric cancer (GC). Hp promotes DNA damage and proteasomal degradation of p53, the guardian of genome stability. Hp reduces the expression of the transcription factor USF1 shown to stabilise p53 in response to genotoxic stress. We investigated whether Hp-mediated USF1 deregulation impacts p53-response and consequently genetic instability. We also explored in vivo the role of USF1 in gastric carcinogenesis.DesignHuman gastric epithelial cell lines were infected with Hp7.13, exposed or not to a DNA-damaging agent camptothecin (CPT), to mimic a genetic instability context. We quantified the expression of USF1, p53 and their target genes, we determined their subcellular localisation by immunofluorescence and examined USF1/p53 interaction. Usf1-/- and INS-GAS mice were used to strengthen the findings in vivo and patient data examined for clinical relevance.ResultsIn vivo we revealed the dominant role of USF1 in protecting gastric cells against Hp-induced carcinogenesis and its impact on p53 levels. In vitro, Hp delocalises USF1 into foci close to cell membranes. Hp prevents USF1/p53 nuclear built up and relocates these complexes in the cytoplasm, thereby impairing their transcriptional function. Hp also inhibits CPT-induced USF1/p53 nuclear complexes, exacerbating CPT-dependent DNA damaging effects.ConclusionOur data reveal that the depletion of USF1 and its de-localisation in the vicinity of cell membranes are essential events associated to the genotoxic activity of Hp infection, thus promoting gastric carcinogenesis. These findings are also of clinical relevance, supporting USF1 expression as a potential marker of GC susceptibility.

Published
2019
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6. Transketolase of Staphylococcus aureus in the Control of Master Regulators of Stress Response During Infection

Author

Elodie Ramond, Xin Tan, Fabiola Tros, Jean-Philippe Barnier, Daniel Euphrasie, Jason Ziveri, Ivan Nemazanyy, Xavier Nassif, Anne Jamet, Baptiste Decaux-Tramoni, Alain Charbit, Marion Dupuis, Mathieu Coureuil, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Pathogénie des infections systémiques (Inserm U1002), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), SOGIP, SOGIP (ERC 249236)/Laboratoire d'Anthropologie des Institutions et des Organisations Sociales (IIAC-LAIOS), Institut interdisciplinaire d'anthropologie du contemporain (IIAC), École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS)-École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS)-Institut interdisciplinaire d'anthropologie du contemporain (IIAC), École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS)-École des hautes études en sciences sociales (EHESS)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), U1002, Pathogénie des infections systémiques (UMR_S 570), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), and Charbit, Alain

Subjects
0301 basic medicine, Staphylococcus aureus, RNAIII, 030106 microbiology, Mutant, pentose phosphate pathway, Transketolase, Biology, Pentose phosphate pathway, Kidney, medicine.disease_cause, Microbiology, Mice, 03 medical and health sciences, Stress, Physiological, sigma B, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Transcription (biology), RpiRc, medicine, Animals, Humans, Metabolomics, Immunology and Allergy, Gene Silencing, Gene, ComputingMilieux_MISCELLANEOUS, Gene Expression Profiling, metabolic adaptation, Gene Expression Regulation, Bacterial, Staphylococcal Infections, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Carbon, 3. Good health, Disease Models, Animal, Phenotype, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, 030104 developmental biology, Infectious Diseases, Genes, Bacterial, Mutation, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, transketolase, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Intracellular, Signal Transduction
Abstract

Staphylococcus aureus is a leading cause of both acute and chronic infections in humans. The importance of the pentose phosphate pathway (PPP) during S. aureus infection is currently largely unexplored. In the current study, we focused on one key PPP enzyme, transketolase (TKT). We showed that inactivation of the unique gene encoding TKT activity in S. aureus USA300 (∆tkt) led to drastic metabolomic changes. Using time-lapse video imaging and mice infection, we observed a major defect of the ∆tkt strain compared with wild-type strain in early intracellular proliferation and in the ability to colonize kidneys. Transcriptional activity of the 2 master regulators sigma B and RpiRc was drastically reduced in the ∆tkt mutant during host cells invasion. The concomitant increased RNAIII transcription suggests that TKT—or a functional PPP—strongly influences the ability of S. aureus to proliferate within host cells by modulating key transcriptional regulators.

Published
2019
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7. USF1 defect drives p53 degradation during Helicobacter pylori infection and accelerates gastric carcinogenesis

Author

Costa, Lionel, Corre, Sébastien, Michel, Valérie, Le Luel, Krysten, Fernandes, Julien, Ziveri, Jason, Jouvion, Grégory, Danckaert, Anne, Mouchet, Nicolas, da Silva Barreira, David, Torres, Javier, Camorlinga, Margarita, d'Elios, Mario Milco, Fiette, Laurence, de Reuse, Hilde, Galibert, Marie-Dominique, Touati, Eliette, Pathogenèse de Helicobacter - Helicobacter Pathogenesis, Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Ressources et de Recherche Technologique - Center for Technological Resources and Research (C2RT), Institut Pasteur [Paris] (IP), Pathogénie des infections systémiques (Inserm U1002), Neuropathologie expérimentale - Experimental neuropathology, Institut Pasteur [Paris] (IP)-Université Paris Descartes - Paris 5 (UPD5), AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Instituto Mexicano del Seguro Social [Mexico City, Mexico] (IMSS), Università degli Studi di Firenze = University of Florence (UniFI), Institut Mutualiste de Montsouris (IMM), CHU Pontchaillou [Rennes], Université Paris Diderot, Ligue Contre le Cancer, Odyssey Reinsurance Company, FIS/IMSS/PROT/PRIO/13/027), Fondo de Investigacion en salud, IMSS, Mexico, West committee Ligue Nationale Contre le Cancer, UMS Biosit, We thank Sophie Vaulont (Institut Cochin, Paris, France) for Usf1-/- mice, Timothy C Wang (Columbia University, NY, USA) for providing us couples of INS-GAS mice and Joana Gomes and Celso Reis (I3S-IPATIMUP, Porto, Portugal) for MKN45 cells. We also thank Laurence Bernard-Touami and the Animal Housing ARCHE (UMS Biosit, https://biosit.univ-rennes1.fr, University of Rennes, France), and David Hardy and Magalie Tichit (Unit of Experimental Neuropathology, Institut Pasteur, Paris, France) for her technical help on the histology part and the UtechS Photonic BioImaging (Imagopole), C2RT, Institut Pasteur, supported by the French National Research Agency (France BioImaging, ANR-10–INSB–04, Investments for the Future), both as a part of the FranceBioImaging infrastructure., ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut Pasteur [Paris], Institut Pasteur [Paris]-Université Paris Descartes - Paris 5 (UPD5), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Touati, Eliette, and Développment d'une infrastructure française distribuée coordonnée - - France-BioImaging2010 - ANR-10-INBS-0004 - INBS - VALID

Subjects
[SDV] Life Sciences [q-bio], [SDV.CAN] Life Sciences [q-bio]/Cancer, oncogenes, gastric cancer, [SDV]Life Sciences [q-bio], DNA damage, genetic instability, [SDV.CAN]Life Sciences [q-bio]/Cancer, helicobacter pylori infection, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Abstract

International audience; Objective - Design - Human gastric epithelial cell lines were infected with 7.13, exposed or not to a DNA-damaging agent camptothecin (CPT), to mimic a genetic instability context. We quantified the expression of , and their target genes, we determined their subcellular localisation by immunofluorescence and examined USF1/p53 interaction. and INS-GAS mice were used to strengthen the findings in vivo and patient data examined for clinical relevance. Results - In vivo we revealed the dominant role of USF1 in protecting gastric cells against -induced carcinogenesis and its impact on p53 levels. In vitro, delocalises USF1 into foci close to cell membranes. prevents USF1/p53 nuclear built up and relocates these complexes in the cytoplasm, thereby impairing their transcriptional function. also inhibits CPT-induced USF1/p53 nuclear complexes, exacerbating CPT-dependent DNA damaging effects. Conclusion - Our data reveal that the depletion of USF1 and its de-localisation in the vicinity of cell membranes are essential events associated to the genotoxic activity of infection, thus promoting gastric carcinogenesis. These findings are also of clinical relevance, supporting USF1 expression as a potential marker of GC susceptibility.

Published
2020
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8. Critical Role of a Sheath Phosphorylation Site On the Assembly and Function of an Atypical Type VI Secretion System

Author

Mathieu Coureuil, Ida Chiara Guerrera, Guénolé Prigent, Claire Lays, Monique Barel, Fabiola Tros, Nicholas H. Keep, Jason Ziveri, Alain Charbit, Anne Jamet, Cerina Chhuon, Héloïse Rytter, Thomas Henry, Pathogénie des infections systémiques (Inserm U1002), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plateforme Protéomique Necker [SFR Necker] (PPN - 3P5), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CHU Necker - Enfants Malades [AP-HP], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Pathogénie des infections systémiques (UMR_S 570), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Pathogénie des Staphylocoques – Staphylococcal Pathogenesis, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Inflammasome, Infections bactériennes et autoinflammation, Inflammasome, Bacterial Infections and Autoinflammation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Inflammasome, Bacterial Infections and Autoinflammation (I2BA), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), University of London [London], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Pathogénie des Staphylocoques – Staphylococcal Pathogenesis (StaPath), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), U1002, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunité infection vaccination (I2V), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Charbit, Alain

Subjects
Proteomics, Stimulation, Biochemistry, Gas Chromatography-Mass Spectrometry, Analytical Chemistry, Cell Line, Potassium Chloride, 03 medical and health sciences, chemistry.chemical_compound, Bacterial Proteins, Tandem Mass Spectrometry, Humans, Secretion, Phosphorylation, Francisella tularensis, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Type VI secretion system, Alanine, 0303 health sciences, Electronic Data Processing, Phosphomimetics, biology, Molecular Structure, Research, Macrophages, 030302 biochemistry & molecular biology, Type VI Secretion Systems, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Cell biology, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, chemistry, Mutagenesis, Site-Directed, Francisella, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Protein Processing, Post-Translational, Biogenesis
Abstract

The bacterial pathogen Francisella tularensis possesses a noncanonical type VI secretion system (T6SS) that is required for phagosomal escape in infected macrophages. KCl stimulation has been previously used to trigger assembly and secretion of the T6SS in culture. By differential proteomics, we found here that the amounts of the T6SS proteins remained unchanged upon KCl stimulation, suggesting involvement of post-translational modifications in T6SS assembly. A phosphoproteomic analysis indeed identified a unique phosphorylation site on IglB, a key component of the T6SS sheath. Substitutions of Y139 with alanine or phosphomimetics prevented T6SS formation and abolished phagosomal escape whereas substitution with phenylalanine delayed but did not abolish phagosomal escape in J774-1 macrophages. Altogether our data demonstrated that the Y139 site of IglB plays a critical role in T6SS biogenesis, suggesting that sheath phosphorylation could participate to T6SS dynamics. Data are available via ProteomeXchange with identifier PXD013619; and on MS-Viewer, key lkaqkllxwx.

Published
2019
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9. Manipulation of host membranes by the bacterial pathogens Listeria, Francisella, Shigella and Yersinia

Author

Frank Lafont, Jost Enninga, Alain Charbit, Pascale Cossart, Javier Pizarro-Cerdá, vicente, marie-therese, Identification des nouvelles molécules cellulaires cibles pour combattre les infections bactériennes - - StopBugEntry2015 - ANR-15-CE15-0017 - AAPG2015 - VALID, Bacterial, cellular and epigenetic factors that control enteropathogenicity - BacCellEpi - - H20202015-10-01 - 2018-09-30 - 670823 - VALID, Interactions Bactéries-Cellules (UIBC), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Sorbonne Paris Cité (USPC), Pathogénie des infections systémiques (Inserm U1002), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Dynamique des Interactions Hôte-Pathogène - Dynamics of Host-Pathogen Interactions, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), This work was supported by the Institut Pasteur (PTR 460 and PTR 521 to JPC), l’Agence Nationale de la Recherche (ANR) (ANR-15-CE15-0017 StopBugEn-try to JPC, AC, JE And FL), Institut National de la Santé et de la Recherche Médicale (PC: INSERM Unité 604), Institut National de la Recherche Agronomique (PC: INRA Unité Sous Contrat 2020), Centre National de la Recherche Scientifique AC: CNRS Unité Mixte de Recherche 8253, FL: CNRS Unité Mixte De Recherche 8204 (ERC) Advanced Grant (670823 BacCellEpi to PC) And ERC Start-Ing Grant (26116 RuptEffects to JE). PC is an International Senior Research Scholar Of the Howard Hughes Medical Institute., ANR-15-CE15-0017,StopBugEntry,Identification des nouvelles molécules cellulaires cibles pour combattre les infections bactériennes(2015), European Project: 670823,H2020,ERC-2014-ADG,BacCellEpi(2015), Institut National de la Recherche Agronomique (INRA)-Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris]-Institut National de la Recherche Agronomique (INRA), Dynamique des Interactions Hôte-Pathogène, Institut Pasteur [Paris], and ANR-15-CE15-0017,StopBugEntry,Novel common host targets during bacterial invasion of humans(2015)

Subjects
0301 basic medicine, Listeria, [SDV]Life Sciences [q-bio], Membrane trafficking, Yersinia, medicine.disease_cause, Article, Shigella flexneri, Microbiology, 03 medical and health sciences, Phagocytosis, Listeria monocytogenes, medicine, Animals, Humans, Yersinia pseudotuberculosis, Francisella, Francisella tularensis, 030102 biochemistry & molecular biology, biology, Intracellular parasite, Cell Membrane, Cell Biology, bacterial infections and mycoses, biology.organism_classification, Virology, [SDV] Life Sciences [q-bio], 030104 developmental biology, Host-Pathogen Interactions, Bacterial Model, Shigella, Developmental Biology
Abstract

International audience; Bacterial pathogens display an impressive arsenal of molecular mechanisms that allow survival in diverse host niches. Subversion of plasma membrane and cytoskeletal functions are common themes associated to infection by both extracellular and intracellular pathogens. Moreover, intracellular pathogens modify the structure/stability of their membrane-bound compartments and escape degradation from phagocytic or autophagic pathways. Here, we review the manipulation of host membranes by Listeria monocytogenes, Francisella tularensis, Shigella flexneri and Yersinia spp. These four bacterial model pathogens exemplify generalized strategies as well as specific features observed during bacterial infection processes.

Published
2016
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10. Francisella tularensis IglG Belongs to a Novel Family of PAAR-Like T6SS Proteins and Harbors a Unique N-terminal Extension Required for Virulence

Author

Mélanie Rigard, Claire Lays, Olivier Walker, Laurent Terradot, Amandine Martin, Anders Sjöstedt, Lena Lindgren, Wayne Conlan, Maggy Hologne, Philippe Telouk, Claire Punginelli, Thomas Henry, Amandine Mosnier, Jeanette E. Bröms, Alain Charbit, Inflammasome, Infections bactériennes et autoinflammation, Inflammasome, Bacterial Infections and Autoinflammation (I2BA), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Medical Biochemistry and Biophysics and Laboratory for Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå, Immunologie de l'allergie cutanée et vaccination – Immunology of skin allergy and vaccination, Biophysics of complex systems, Institut des Sciences Analytiques (ISA), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Géologie de Lyon - Terre, Planètes, Environnement [Lyon] (LGL-TPE), Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École normale supérieure - Lyon (ENS Lyon), National Research Council of Canada (NRC), Microbiologie moléculaire et biochimie structurale / Molecular Microbiology and Structural Biochemistry (MMSB), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), This work is supported by a FINOVI grant to TH, an ANR grant to TH and AC (ANR-12-ASTR-0018), Direction Generale de l'Armemen (DGA) and Fondation pour la recherche medicale (FRM) (#FDT20150532668) fellowships to MR and a collaborative grant from the Swedish Research Agency K2013-4581 and K2013-8621. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., ANR-12-ASTR-0018,TulareDrug,Identification de nouvelles molécules ciblant les effecteurs sécrétés de Francisella tularensis(2012), Centre International de Recherche en Infectiologie ( CIRI ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-École normale supérieure - Lyon ( ENS Lyon ), Umeå University, Institut des Sciences Analytiques ( ISA ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ) -École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Pathogénie des infections systémiques ( Inserm U1002 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Sorbonne Paris Cité ( USPC ), Laboratoire de Géologie de Lyon - Terre, Planètes, Environnement [Lyon] ( LGL-TPE ), Université de Lyon-Université de Lyon-Institut national des sciences de l'Univers ( INSU - CNRS ) -Centre National de la Recherche Scientifique ( CNRS ), National Research Council Canada - Human Hlth Therapeut Portfolio, Molecular Microbiology and Structural Biochemistry, Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon, ANR-12-ASTR-0018,TulareDrug,Identification de nouvelles molécules ciblant les effecteurs sécrétés de Francisella tularensis ( 2012 ), Centre International de Recherche en Infectiologie (CIRI), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Géologie de Lyon - Terre, Planètes, Environnement (LGL-TPE), Université de Lyon-Université de Lyon-Institut national des sciences de l'Univers (INSU - CNRS)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS), Bussy, Agnès, Accompagnement spécifique des travaux de recherches et d’innovation Défense - Identification de nouvelles molécules ciblant les effecteurs sécrétés de Francisella tularensis - - TulareDrug2012 - ANR-12-ASTR-0018 - ASTRID - VALID, and Université de Lyon-Université de Lyon-Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Applied Microbiology, type VI secretion system, Pathology and Laboratory Medicine, Biochemistry, Animal Cells, Microbial Physiology, Genomic island, Bacterial Physiology, Amino Acids, Francisella tularensis, lcsh:QH301-705.5, Tularemia, Organic Compounds, Effector, Type VI Secretion Systems, Bacterial Pathogens, Zinc, T6SS, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Medical Microbiology, Physical Sciences, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Cellular Types, Chemical Elements, [SDV.IMM] Life Sciences [q-bio]/Immunology, Virulence Factors, Immune Cells, 030106 microbiology, Immunology, Virulence, Sequence alignment, Microbiology, 03 medical and health sciences, Bacterial Proteins, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, Genetics, Sulfur Containing Amino Acids, Amino Acid Sequence, DUF4280, Microbial Pathogens, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Molecular Biology, Secretion, Type VI secretion system, Blood Cells, Bacteria, Macrophages, Organisms, Chemical Compounds, Biology and Life Sciences, Proteins, Protein Secretion, Pathogenicity island, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Parasitology, [ CHIM.ANAL ] Chemical Sciences/Analytical chemistry, Physiological Processes, lcsh:RC581-607, Biokemi och molekylärbiologi, 0301 basic medicine, Models, Molecular, Physiology, Secretion Systems, White Blood Cells, PF14107, [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology, Medicine and Health Sciences, phage, Francisella, Sequence Deletion, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, biology, Biochemistry and Molecular Biology, Chemistry, Protein Transport, Cell Processes, [SDV.IMM]Life Sciences [q-bio]/Immunology, Pathogens, Research Article, lcsh:Immunologic diseases. Allergy, [CHIM.ANAL] Chemical Sciences/Analytical chemistry, Genomic Islands, Virology, Animals, Cysteine, PAAR, Organic Chemistry, Bacteriology, Cell Biology, Gene Expression Regulation, Bacterial, biology.organism_classification, lcsh:Biology (General), [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Sequence Alignment
Abstract

The virulence of Francisella tularensis, the etiological agent of tularemia, relies on an atypical type VI secretion system (T6SS) encoded by a genomic island termed the Francisella Pathogenicity Island (FPI). While the importance of the FPI in F. tularensis virulence is clearly established, the precise role of most of the FPI-encoded proteins remains to be deciphered. In this study, using highly virulent F. tularensis strains and the closely related species F. novicida, IglG was characterized as a protein featuring a unique α-helical N-terminal extension and a domain of unknown function (DUF4280), present in more than 250 bacterial species. Three dimensional modeling of IglG and of the DUF4280 consensus protein sequence indicates that these proteins adopt a PAAR-like fold, suggesting they could cap the T6SS in a similar way as the recently described PAAR proteins. The newly identified PAAR-like motif is characterized by four conserved cysteine residues, also present in IglG, which may bind a metal atom. We demonstrate that IglG binds metal ions and that each individual cysteine is required for T6SS-dependent secretion of IglG and of the Hcp homologue, IglC and for the F. novicida intracellular life cycle. In contrast, the Francisella-specific N-terminal α-helical extension is not required for IglG secretion, but is critical for F. novicida virulence and for the interaction of IglG with another FPI-encoded protein, IglF. Altogether, our data suggest that IglG is a PAAR-like protein acting as a bi-modal protein that may connect the tip of the Francisella T6SS with a putative T6SS effector, IglF., Author Summary Francisella tularensis is a highly pathogenic bacterium causing tularemia. Its ability to cause disease is linked to its ability to replicate in the macrophage cytosol. The intracellular life cycle of Francisella is controlled by a type VI secretion system (T6SS), which is thought to inject effectors into the host cell to allow bacterial escape into the host cytosol. The molecular mechanisms behind this process are still largely unclear. In this work, we identify IglG as a protein with two important domains, one conserved in proteins from more than 250 bacterial species (DUF4280, renamed here as PAAR-like domain) and one specific for the Francisella genus. Using protein sequence analysis and three-dimensional structure predictions, comparative modeling and biochemistry approaches, our data demonstrate that IglG is a metal-binding protein that based on its PAAR-like domain might cap the VgrG spike of the T6SS and act as a membrane-puncturing protein. Furthermore, we identified that the Francisella-specific domain is directly involved in forming a protein complex with another virulence protein, IglF. This work, in addition to enhancing the molecular understanding of the Francisella T6SS, defines the features of the conserved DUF4280, a novel PAAR-like domain involved in type VI secretion (T6S) of many bacterial species.

Published
2016
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11. Chronic Meningococcemia Cutaneous Lesions Involve Meningococcal Perivascular Invasion Through the Remodeling of Endothelial Barriers

Author

Marie-Cécile Vacher-Lavenu, Mathieu Coureuil, Hervé Lécuyer, Johan Chanal, Claire Poyart, Xavier Nassif, Muhamed-Kheir Taha, Philippe Morand, Nicolas Dupin, Agnès Carlotti, Alain Schmitt, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), CHU Necker - Enfants Malades [AP-HP], Pathogénie des infections systémiques (Inserm U1002), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Infections Bactériennes Invasives, Institut Pasteur [Paris] (IP), This work was supported by Université Paris Descartes, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Institut Pasteur, and Institut Cochin. The laboratory of X. N. is supported by INSERM, Université Paris Descartes, Agence Nationale de la Recherche, and Fondation pour la Recherche Médicale. The laboratory of M. K. T. is supported by Institut Pasteur and the Department of Health., Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris], and CHU Cochin [AP-HP]

Subjects
Microbiology (medical), Pathology, medicine.medical_specialty, MESH: Skin Diseases, Bacterial, Endothelium, endothelium, skin lesion, Bacteremia, MESH: Endothelium, medicine.disease_cause, Meningococcal disease, MESH: Meningococcal Infections, Sepsis, sepsis, 03 medical and health sciences, neisseria meningitidis, In vivo, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Medicine, Compartment (pharmacokinetics), MESH: Bacteremia, 030304 developmental biology, drug administration routes, 0303 health sciences, 030306 microbiology, business.industry, Neisseria meningitidis, MESH: Chronic Disease, Skin Diseases, Bacterial, medicine.disease, Chronic meningococcemia, 3. Good health, Peripheral, Meningococcal Infections, chronic, Infectious Diseases, medicine.anatomical_structure, Chronic Disease, Immunology, meningococcemia, blood capillaries, business, dislocations
Abstract

International audience; Chronic meningococcemia is a form of sepsis with frequent polymorphous skin lesions. Both in vivo and in vitro data suggest that, in these lesions, meningococci gain access from the capillary lumen to the peripheral extravascular compartment, in the absence of vascular dislocation, through a paraendothelial route.

Published
2012
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12. Overexpression of proinflammatory TLR-2-signalling lipoproteins in hypervirulent mycobacterial variants

Author

Roux, Anne-Laure, Ray, Aurélie, Pawlik, Alexandre, Medjahed, Halima, Etienne, Gilles, Rottman, Martin, Catherinot, Emilie, Coppée, Jean-Yves, Chaoui, Karima, Monsarrat, Bernard, Toubert, Antoine, Daffé, Mamadou, Puzo, Germain, Gaillard, Jean-Louis, Brosch, Roland, Dulphy, Nicolas, Nigou, Jérôme, Herrmann, Jean-Louis, Epidémiologie et Physiopathologie des Infections Microbiennes (EPIM), Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Microbiologie [Garches], Hôpital Raymond Poincaré [AP-HP], Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT), Pathogénomique mycobactérienne intégrée, Institut Pasteur [Paris] (IP), Pathogénie des infections systémiques (Inserm U1002), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Transcriptome et Epigénome (PF2), Service d'Immunologie et d'Histocompatibilité, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), This work received support from the ‘Vaincre La Mucoviscidose’ Association., We greatly acknowledge Dr Ben Marshall (Southampton University Hospitals Trust, UK) for careful review of the manuscript., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées, Institut Pasteur [Paris], Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)

Subjects
Lipoproteins, Fluorescent Antibody Technique, MESH: Virulence, MESH: Phenotype, Polymerase Chain Reaction, Mycobacterium, Mice, MESH: Cell Membrane / immunology, MESH: Mycobacterium Infections / microbiology, MESH: Glycopeptides / metabolism, MESH: Mycobacterium Infections / immunology, Animals, Humans, MESH: Animals, MESH: Cytokines / immunology, MESH: Lipoproteins / metabolism, MESH: Fluorescent Antibody Technique, MESH: Mice, MESH: Mycobacterium / immunology, Inflammation, MESH: Inflammation / immunology, Mycobacterium Infections, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, MESH: Humans, Virulence, Macrophages, Cell Membrane, MESH: Cytokines / metabolism, Glycopeptides, MESH: Macrophages, MESH: Polymerase Chain Reaction, MESH: Toll-Like Receptor 2 / metabolism, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Toll-Like Receptor 2, MESH: Signal Transduction, MESH: Mycobacterium / pathogenicity, MESH: Toll-Like Receptor 2 / agonists, HEK293 Cells, Phenotype, MESH: HEK293 Cells, MESH: Cytokines / biosynthesis, Cytokines, Electrophoresis, Polyacrylamide Gel, MESH: Mycobacterium / metabolism, MESH: Lipoproteins / immunology, MESH: Glycopeptides / immunology, Signal Transduction, MESH: Electrophoresis, Polyacrylamide Gel
Abstract

International audience; Changes in the cell envelope composition of mycobacteria cause major changes in cytokine profiles of infected antigen presenting cells. We describe here the modulation of inflammatory responses by Mycobacterium abscessus, an emerging pathogen in cystic fibrosis. M. abscessus is able to switch from a smooth (S) to a rough (R) morphotype by the loss of a surface glycopeptidolipid. R variants are associated with severe clinical forms and a 'hyper-proinflammatory' response in ex vivo and in vivo models. Using partitioning of cell surface components we found that a complex fraction, more abundant in R variants than in S variants, made a major contribution to the TLR-2-dependent hyper-proinflammatory response induced by R variants. Lipoproteins were the main TLR-2 agonists in this fraction, consistent with the larger amounts of 16 lipoproteins in cell surface extracts from R variants; 15 out of 16 being more strongly induced in R variant than in S variant. Genetic interruption of glycopeptidolipid pathway in wild-type S variant resulted in R phenotype with similar induction of lipoprotein genes. In conclusion, R morphotype in M. abscessus is associated with increased synthesis/exposure at the cell surface of lipoproteins, these changes profoundly modifying the innate immune response through TLR-2-dependent mechanisms.

Published
2011
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13. Efficacy of Rifampin-Moxifloxacin-Metronidazole Combination Therapy in Hidradenitis Suppurativa

Author

Olivier Lortholary, Aude Nassif, Sylvain Poirée, Paul Henri Consigny, Jacques Thèze, Anne-Sophie Le Guern, Patrick Berche, Sylvie Behillil, Anne Leflèche, Sylvie Fraitag, H. Coignard, Olivier Join-Lambert, Xavier Nassif, Florence Ribadeau-Dumas, Hélène Guet-Revillet, Jean-Philippe Jais, Vincent Jullien, Pathogénie des infections systémiques (Inserm U1002), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Service des Maladies infectieuses et tropicales [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'informatique médicale et biostatistiques [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris]-CHU Necker - Enfants Malades [AP-HP], Service d'Anatomie et de Cytologie Pathologiques, Hôpital Saint-Vincent de Paul, Centre Médical de l'Institut Pasteur (CMIP), Institut Pasteur [Paris], Cellule d'Intervention Biologique d'Urgence - Laboratory for Urgent Response to Biological Threats (CIBU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut Pasteur [Paris], Centre Médical de l'Institut Pasteur, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], and Institut Pasteur [Paris] (IP)

Subjects
Male, MESH: Remission Induction, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Moxifloxacin, MESH: Logistic Models, Kaplan-Meier Estimate, Gastroenterology, MESH: Hidradenitis Suppurativa, 030207 dermatology & venereal diseases, 0302 clinical medicine, Anti-Infective Agents, Recurrence, Hidradenitis suppurativa, MESH: Metronidazole, MESH: Antibiotics, Antitubercular, Antibacterial agent, MESH: Treatment Outcome, MESH: Middle Aged, Remission Induction, Middle Aged, Prognosis, 3. Good health, Hidradenitis Suppurativa, Treatment Outcome, MESH: Young Adult, 030220 oncology & carcinogenesis, Quinolines, Drug Therapy, Combination, Female, Rifampin, MESH: Quinolines, medicine.drug, Fluoroquinolones, Adult, medicine.medical_specialty, Combination therapy, MESH: Anti-Infective Agents, Dermatology, MESH: Prognosis, 03 medical and health sciences, Young Adult, Pharmacotherapy, Internal medicine, Metronidazole, medicine, Humans, Adverse effect, Antibiotics, Antitubercular, MESH: Kaplan-Meier Estimate, Retrospective Studies, Chemotherapy, Aza Compounds, MESH: Humans, business.industry, MESH: Adult, MESH: Retrospective Studies, MESH: Fluoroquinolones, medicine.disease, MESH: Moxifloxacin, MESH: Rifampin, MESH: Male, Surgery, MESH: Recurrence, MESH: Drug Therapy, Combination, Logistic Models, MESH: Aza Compounds, business, MESH: Female
Abstract

Background: Antibiotics have been shown to improve hidradenitis suppurativa (HS) patients but complete remission is rare using these treatments. Objective: To assess the efficacy and safety of a combination of oral rifampin, moxifloxacin and metronidazole in long-lasting refractory HS. Methods: We retrospectively studied 28 consecutive HS patients including 6, 10 and 12 Hurley stage 1, 2 and 3 patients, respectively. Complete remission, defined as a clearance of all inflammatory lesions including hypertrophic scars, was the main outcome criterion of the study. Results: Complete remission was obtained in 16 patients, including 6/6, 8/10 and 2/12 patients with Hurley stage 1, 2 and 3, respectively (p = 0.0004). The median duration of treatment to obtain complete remission was 2.4 (range 0.9–6.5) and 3.8 months (range 1.6–7.4) in stage 1 and 2 patients, respectively, and 6.2 and 12 months in the 2 stage 3 patients. Main adverse events of the treatments were gastrointestinal disorders (64% of patients) and vaginal candidiasis (35% of females). Reversible tendinopathy and hepatitis occurred in 4 and 1 patient, respectively. Conclusions: Complete remission of refractory HS can be obtained using broad-spectrum antibiotics and Hurley staging is a prognostic factor of response to the treatment.

Published
2011
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14. Genotypic and Phenotypic Modifications of Neisseria meningitidis after an Accidental Human Passage

Author

Colin Tinsley, Xavier Nassif, Stephen D. Bentley, Keith A. Jolley, Martin C. J. Maiden, Eric Frapy, Emmanuelle Bille, Hélène Omer, Graham Rose, Jean-Ralph Zahar, U1002, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), The Wellcome Trust Sanger Institute [Cambridge], Dept Zool, University of Oxford [Oxford], AP HP, Microbiol Lab, CHU Necker - Enfants Malades [AP-HP], MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Fondation pour la Recherche Medicale, Pathogénie des infections systémiques (Inserm U1002), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Zoology [Oxford], University of Oxford, AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Tinsley, Colin, Institut National de la Santé et de la Recherche Médicale, Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), Wellcome Trust Sanger Institute, MICrobiologie de l'ALImentation au Service de la Santé humaine ( MICALIS ), Institut National de la Recherche Agronomique ( INRA ) -AgroParisTech, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and ProdInra, Archive Ouverte

Subjects
Bacterial Diseases, [SDV]Life Sciences [q-bio], lcsh:Medicine, Meningococcal Disease, Neisseria meningitidis, medicine.disease_cause, ANTIGENIC VARIATION, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Genotype, Medical Laboratory Personnel, Genome Sequencing, lcsh:Science, Genetics, 0303 health sciences, Cross Infection, CAPSULE NULL LOCUS, Multidisciplinary, biology, Microbial Mutation, Genomics, STRAIN MC58, 3. Good health, Bacterial Pathogens, Host-Pathogen Interaction, [SDV] Life Sciences [q-bio], Infectious Diseases, Phenotype, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Medicine, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, Research Article, Adult, OUTER-MEMBRANE PROTEIN, HUMAN IMMUNITY, Single-nucleotide polymorphism, Microbiology, ACQUIRED MENINGOCOCCAL DISEASE, PHASE-VARIABLE GENES, PATHOGENIC NEISSERIA, SERUM RESISTANCE, VIRULENCE GENES, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetic variation, medicine, Antigenic variation, Accidents, Occupational, Humans, Allele, Gene, Biology, Microbial Pathogens, 030304 developmental biology, [ SDV ] Life Sciences [q-bio], 030306 microbiology, lcsh:R, Genetic Variation, Comparative Genomics, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Meningococcal Infections, Pilin, biology.protein, lcsh:Q, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Abstract

International audience; A scientist in our laboratory was accidentally infected while working with Z5463, a Neisseria meningitidis serogroup A strain. She developed severe symptoms (fever, meningism, purpuric lesions) that fortunately evolved with antibiotic treatment to complete recovery. Pulse-field gel electrophoresis confirmed that the isolate obtained from the blood culture (Z5463BC) was identical to Z5463, more precisely to a fourth subculture of this strain used the week before the contamination (Z5463PI). In order to get some insights into genomic modifications that can occur in vivo, we sequenced these three isolates. All the strains contained a mutated mutS allele and therefore displayed an hypermutator phenotype, consistent with the high number of mutations (SNP, Single Nucleotide Polymorphism) detected in the three strains. By comparing the number of SNP in all three isolates and knowing the number of passages between Z5463 and Z5463PI, we concluded that around 25 bacterial divisions occurred in the human body. As expected, the in vivo passage is responsible for several modifications of phase variable genes. This genomic study has been completed by transcriptomic and phenotypic studies, showing that the blood strain used a different haemoglobin-linked iron receptor (HpuA/B) than the parental strains (HmbR). Different pilin variants were found after the in vivo passage, which expressed different properties of adhesion. Furthermore the deletion of one gene involved in LOS biosynthesis (lgtB) results in Z5463BC expressing a different LOS than the L9 immunotype of Z2491. The in vivo passage, despite the small numbers of divisions, permits the selection of numerous genomic modifications that may account for the high capacity of the strain to disseminate.

Published
2011
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