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1. Host phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports Pseudomonas aeruginosa-driven pathology.

Author

Salimata Bagayoko, Stephen Adonai Leon-Icaza, Miriam Pinilla, Audrey Hessel, Karin Santoni, David Péricat, Pierre-Jean Bordignon, Flavie Moreau, Elif Eren, Aurélien Boyancé, Emmanuelle Naser, Lise Lefèvre, Céline Berrone, Nino Iakobachvili, Arnaud Metais, Yoann Rombouts, Geanncarlo Lugo-Villarino, Agnès Coste, Ina Attrée, Dara W Frank, Hans Clevers, Peter J Peters, Céline Cougoule, Rémi Planès, and Etienne Meunier

Subjects
Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract

Regulated cell necrosis supports immune and anti-infectious strategies of the body; however, dysregulation of these processes drives pathological organ damage. Pseudomonas aeruginosa expresses a phospholipase, ExoU that triggers pathological host cell necrosis through a poorly characterized pathway. Here, we investigated the molecular and cellular mechanisms of ExoU-mediated necrosis. We show that cellular peroxidised phospholipids enhance ExoU phospholipase activity, which drives necrosis of immune and non-immune cells. Conversely, both the endogenous lipid peroxidation regulator GPX4 and the pharmacological inhibition of lipid peroxidation delay ExoU-dependent cell necrosis and improve bacterial elimination in vitro and in vivo. Our findings also pertain to the ExoU-related phospholipase from the bacterial pathogen Burkholderia thailandensis, suggesting that exploitation of peroxidised phospholipids might be a conserved virulence mechanism among various microbial phospholipases. Overall, our results identify an original lipid peroxidation-based virulence mechanism as a strong contributor of microbial phospholipase-driven pathology.

Published
2021
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2. Protein O-mannosylation deficiency increases LprG-associated lipoarabinomannan release by Mycobacterium tuberculosis and enhances the TLR2-associated inflammatory response

Author

Henar Alonso, Julien Parra, Wladimir Malaga, Delphine Payros, Chia-Fang Liu, Céline Berrone, Camille Robert, Etienne Meunier, Odile Burlet-Schiltz, Michel Rivière, and Christophe Guilhot

Subjects
Medicine, Science
Abstract

Abstract Protein O-mannosylation is crucial for the biology of Mycobacterium tuberculosis but the key mannosylated protein(s) involved and its(their) underlying function(s) remain unknown. Here, we demonstrated that the M. tuberculosis mutant (Δpmt) deficient for protein O-mannosylation exhibits enhanced release of lipoarabinomannan (LAM) in a complex with LprG, a lipoprotein required for LAM translocation to the cell surface. We determined that LprG is O-mannosylated at a unique threonine position by mass spectrometry analyses of the purified protein. However, although replacement of this amino acid by an alanine residue completely abolished LprG O-mannosylation, the increased release of the LAM/LprG complex was preserved. We found that the increased secretion of this complex is due to enhanced LAM production in the Δpmt M. tuberculosis and M. smegmatis mutants relative to their wild-type counterparts. This abnormal release of LAM/LprG has functional consequences on the induction of inflammatory responses and provides a possible explanation for the reduced virulence of the M. tuberculosis Δpmt mutant.

Published
2017
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3. Phospholipid peroxidation fuels ExoU phospholipase-dependent cell necrosis and supportsPseudomonas aeruginosa-driven pathology

Author

Aurélien Boyance, Karin Santoni, Stephen Adonai Leon-Icaza, Hans Clevers, Yoann Rombouts, Arnaud Métais, Etienne Meunier, Agnès Coste, Emmanuelle Naser, Ina Attrée, Peter J. Peters, Rémi Planès, Audrey Hessel, Elif Eren, Salimata Bagayoko, Céline Berrone, Céline Cougoule, N. Iacobachvili, Pierre-Jean Bordignon, Miriam Pinilla, Flavie Moreau, Lise Lefèvre, and Dara W. Frank

Subjects
Pathology, medicine.medical_specialty, Necrosis, Chemistry, Pseudomonas aeruginosa, Phospholipid, Virulence, Phospholipase, GPX4, medicine.disease_cause, Lipid peroxidation, chemistry.chemical_compound, Immune system, medicine, medicine.symptom
Abstract

SummaryRegulated cell necrosis supports immune and anti-infectious strategies of the body; however, dysregulation of these processes drives pathological organ damage.Pseudomonas aeruginosaexpresses a phospholipase, ExoU that triggers pathological host cell necrosis through a poorly characterized pathway. Here, we investigated the molecular and cellular mechanisms of ExoU-mediated necrosis. We show that cellular peroxidised phospholipids enhance ExoU phospholipase activity, which drives necrosis of immune and non-immune cells. Conversely, both the endogenous lipid peroxidation regulator GPX4 and the pharmacological inhibition of lipid peroxidation delay ExoU-dependent cell necrosis and improve bacterial eliminationin vitroandin vivo. Our findings also pertain to the ExoU-related phospholipase from the bacterial pathogenBurkholderia thailandensis, suggesting that exploitation of peroxidised phospholipids might be a conserved virulence mechanism among various microbial phospholipases. Overall, our results identify an original lipid peroxidation-based virulence mechanism as a strong contributor of microbial phospholipase-driven pathology.

Published
2021

4. Host phospholipid peroxidation fuels ExoU-dependent cell necrosis and supports $Pseudomonas\ aeruginosa$-driven pathology

Author

Flavie Moreau, Geanncarlo Lugo-Villarino, Aurélien Boyance, Arnaud Métais, Peter J. Peters, Karin Santoni, Céline Cougoule, Stephen Adonai Leon-Icaza, Hans Clevers, Lise Lefèvre, Etienne Meunier, Yoann Rombouts, Agnès Coste, Pierre-Jean Bordignon, Miriam Pinilla, Emmanuelle Naser, Audrey Hessel, David Péricat, Ina Attrée, Rémi Planès, Nino Iakobachvili, Dara W. Frank, Elif Eren, Salimata Bagayoko, Céline Berrone, 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), Geroscience and rejuvenation research center (RESTORE), Université de Toulouse (UT)-Université de Toulouse (UT)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Maastricht University [Maastricht], Groupe Pathogenèse Bactérienne et Réponses Cellulaires / Bacterial Pathogenesis and Cellular Responses Group (IBS-PBRC), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Medical College of Wisconsin [Milwaukee] (MCW), Hubrecht Institute [Utrecht, Netherlands], University Medical Center [Utrecht]-Royal Netherlands Academy of Arts and Sciences (KNAW), ANR-18-CE14-0007,ENDIABAC,LE SYSTEME NERVEUX ENTERIQUE COMME CIBLE POUR TRAITER LE DIABETE DE TYPE 2 : ROLES DES LIPIDES BIOACTIFS BACTERIENS(2018), ANR-17-CE11-0006,MacGlycoTB,Rôle de ST8SIA4 et de la polysialylation des protéines des macrophages dans la réponse immunitaire contre une infection par Mycobacterium tuberculosis(2017), European Project: 804249,INFLAME, Hubrecht Institute for Developmental Biology and Stem Cell Research, ATTREE, Ina, APPEL À PROJETS GÉNÉRIQUE 2018 - LE SYSTEME NERVEUX ENTERIQUE COMME CIBLE POUR TRAITER LE DIABETE DE TYPE 2 : ROLES DES LIPIDES BIOACTIFS BACTERIENS - - ENDIABAC2018 - ANR-18-CE14-0007 - AAPG2018 - VALID, Rôle de ST8SIA4 et de la polysialylation des protéines des macrophages dans la réponse immunitaire contre une infection par Mycobacterium tuberculosis - - MacGlycoTB2017 - ANR-17-CE11-0006 - AAPG2017 - VALID, Deciphering the host and microbial grounds that license inflammasome-mediated execution - INFLAME - 804249 - INCOMING, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, RS: M4I - Nanoscopy, and Institute of Nanoscopy (IoN)

Subjects
Pathology, Hydrolases, Necrosis/metabolism, GPX4, Pathology and Laboratory Medicine, Biochemistry, Lipid peroxidation, Mice, 0302 clinical medicine, Animal Cells, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Biology (General), 0303 health sciences, Bacterial Proteins/metabolism, Esterases, Lipids, 3. Good health, Bacterial Pathogens, Pseudomonas aeruginosa/metabolism, Organoids, Medical Microbiology, Biological Cultures, Cellular Types, medicine.medical_specialty, QH301-705.5, Virulence/physiology, Knockout, Immune Cells, Immunology, Virulence, PATATIN-LIKE PHOSPHOLIPASES, Transfection, Microbiology, 03 medical and health sciences, IMMUNE RECOGNITION, Necrosis, Signs and Symptoms, Bacterial Proteins, Pseudomonas, Genetics, A(2) ENZYMES, Humans, Pseudomonas Infections, CYTOTOXIN EXOU, Molecular Biology Techniques, Microbial Pathogens, Molecular Biology, Lipid Peroxidation/physiology, Blood Cells, Bacteria, Macrophages, Organisms, Biology and Life Sciences, Proteins, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Parasitology, Lipid Peroxidation, Immunologic diseases. Allergy, Clinical Medicine, 030217 neurology & neurosurgery, Phospholipase, medicine.disease_cause, chemistry.chemical_compound, White Blood Cells, Medicine and Health Sciences, OXIDATIVE STRESS, Organ Cultures, Phospholipids, Mice, Knockout, Chemistry, DEATH, Pseudomonas Aeruginosa, LIPID-PEROXIDATION, Enzymes, Host-Pathogen Interactions/physiology, Phospholipases, SECRETION SYSTEM, Host-Pathogen Interactions, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, medicine.symptom, Pathogens, Research Article, Phospholipid, Research and Analysis Methods, Immune system, Virology, medicine, Animals, 030304 developmental biology, Pseudomonas aeruginosa, Pseudomonas Infections/metabolism, Cell Biology, RC581-607, FERROPTOSIS, Enzymology, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Abstract

Regulated cell necrosis supports immune and anti-infectious strategies of the body; however, dysregulation of these processes drives pathological organ damage. Pseudomonas aeruginosa expresses a phospholipase, ExoU that triggers pathological host cell necrosis through a poorly characterized pathway. Here, we investigated the molecular and cellular mechanisms of ExoU-mediated necrosis. We show that cellular peroxidised phospholipids enhance ExoU phospholipase activity, which drives necrosis of immune and non-immune cells. Conversely, both the endogenous lipid peroxidation regulator GPX4 and the pharmacological inhibition of lipid peroxidation delay ExoU-dependent cell necrosis and improve bacterial elimination in vitro and in vivo. Our findings also pertain to the ExoU-related phospholipase from the bacterial pathogen Burkholderia thailandensis, suggesting that exploitation of peroxidised phospholipids might be a conserved virulence mechanism among various microbial phospholipases. Overall, our results identify an original lipid peroxidation-based virulence mechanism as a strong contributor of microbial phospholipase-driven pathology., Author summary Although a proper activation of various regulated cell necrosis confer a significant advantage against various infectious agents, their dysregulation drives host tissue damages that can end up with fatal sepsis. Specifically, 30% of the bacterial strains of Pseudomonas aeruginosa (P. aeruginosa) express the phospholipase A2-like toxin ExoU that is injected into host target cells through the Type-3 Secretion System. This toxin induces, through a yet unknown mechanism, a strong and fast necrotic cell death that supports fatal respiratory infections. Therefore, in this study, we sought to determine the cellular mechanisms by which ExoU triggers host cell necrosis. In this context, we found that ExoU exploits basal cellular phospholipid peroxidation to promote cell necrosis. Mechanistically, host cell lipid peroxidation stimulates ExoU phospholipase activity, which then triggers a pathological cell necrosis both in vitro and in vivo. Altogether, our results unveil that targeting host cell lipid peroxidation constitutes a virulence mechanism developed by microbial phospholipases, a process that contributes to P. aeruginosa-mediated pathology.

Published
2021

5. From environmental bacteria to obligate pathogen: the study of adaptations enhancing the persistence of tuberculosis bacilli

Author

Christophe Guilhot, Roland Brosch, Catherine Astarie-Dequeker, Aideen C. Allen, Ali Hassan, Philip Supply, Wladimir Malaga, Céline Berrone, and Flavie Moreau

Subjects
Genetics, Experimental evolution, Tuberculosis, Obligate, biology, business.industry, Virulence, Human pathogen, biology.organism_classification, medicine.disease, Mycobacterium tuberculosis, Medicine, business, Pathogen, Mycobacterium
Abstract

The highly contagious human pathogen Mycobacterium tuberculosis is responsible for an estimated 1.5 million deaths each year. A major feature of M. tuberculosis is its unique capacity to survive within the host for decades. In contrast, the evolutionary early-branching rare tubercle bacilli Mycobacterium canettii, which is thought to have originated from the same pool of ancestors as M. tuberculosis, rarely causes tuberculosis (TB) in humans and has a reduced capacity to persist and cause disease in the mouse model. Our objectives are to identify the genetic adaptations which allow persistence of TB bacilli within the host, and to characterise their functional consequences. Using an experimental evolution strategy, we have shown that recurrent in vivo passaging of a M. canettii strain (for more than 2 years) allows clones to emerge as “persistent mutants” that have a greater ability to survive in the host, and gain the characteristics of classical M. tuberculosis strains. Several “persistent mutants” were selected and the persistence phenotype was confirmed in several mouse genetic backgrounds. Next, these mutants were subjected to extensive phenotypic characterisation and were found to have enhanced resistance to stress encountered during infection, and increased virulence in human monocyte-derived macrophages. Currently, the mutations responsible for these phenotypes are being characterised. Comparing the genetic differences between the parental M. canettii strain, the “persistent” M. canettii clones and M. tuberculosis will help identify the molecular mechanisms driving evolution from putative generalist mycobacteria, towards professional human pathogen.

Published
2019

6. From environmental bacteria to obligate human pathogen: adaptations associated with the emergence of tuberculosis bacilli

Author

Delphine Payros, Wladimir Malaga, Alexandre Pawlik, Serge Mazères, Céline Berrone, Flavie Moreau, Catherine Astarie-Dequeker, Roland Brosch, Christophe Guilhot, ToxAlim (ToxAlim), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Pathogénomique mycobactérienne intégrée, Institut Pasteur [Paris], Pathogénomique mycobactérienne intégrée - Integrated Mycobacterial Pathogenomics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

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

International audience; The current hypothesis is that tuberculosis (TB) bacilli, Mycobacterium tuberculosis, have emerged from an environmental ancestor by adaptation of existing functions and acquisition of specific genes. The closest relations to this ancestor are the Mycobacterium canettii strains, which rarely cause TB and are unable to transmit in humans. Here, we aim to depict the molecular events that contributed to the emergence of a highly efficient human pathogen. Genomic sequence comparison of M. canettii and M. tuberculosis strains reveals polymorphisms in the genes phoPR, which encode a two component regulatory system required for virulence. RNA-Seq analyses showed that most genes controlled by the PhoPR regulon are underexpressed in M. canettii when compared with M. tuberculosis. Consistently, most M. canettii strains display reduced capacity to produce and secrete several major virulence factors controlled by PhoPR. Genetic transfer of the phoPR allele from M. tuberculosis to a M. canettii strain deficient for phoPR resulted in a higher capacity to infect human macrophages and mice, and to induce inflammatory responses. These results shed light on the transition from opportunistic to obligatory human pathogen, and indicate that this transition selected a highly active phoPR allele that confers an advantage for colonization of mammalian hosts.

Published
2019

7. Parallel in vivo experimental evolution reveals that increased stress resistance was key for the emergence of persistent tuberculosis bacilli

Author

Alexandre Pawlik, Roland Brosch, Christophe Guilhot, Flavie Moreau, Philip Supply, Rudy Antoine, Ali Hassan, Catherine Astarie-Dequeker, Antonio Peixoto, Aideen C. Allen, Wladimir Malaga, Céline Berrone, Arnaud Volle, Cyril Gaudin, Wafa Frigui, 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), Genoscreen [Lille], Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Pathogénomique mycobactérienne intégrée - Integrated Mycobacterial Pathogenomics, Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This project received funding from the European Respiratory Society and the European Union’s H2020 research and innovation programme under the Marie Sklodowska–Curie grant agreement no. 713406 awarded to A.C.A. This work was also supported by grants from the French National Research Agency (TBemerg contract no. ANR-16-CE35-0009 awarded to R.B., P.S. and C. Guilhot, Equipex ANINFIMIP ANR-11-EQUIPEX-0003 to C. Guilhot, Labex ANR-10-LABX-62-IBEID awarded to R.B.), the European Union (PathoNgenTrace contract no. FP7-278864 awarded to P.S.), and the Fondation pour la Recherche Médicale (Equipe FRM 2016 DEQ20160334879), the Fondation Bettencourt Schueller and the Fondation MSDAvenir (Fight-TB project) to C. Guilhot., ANR-16-CE35-0009,TBemerg,Naissance d'un tueur: facteurs génétiques et adaptations métaboliques impliquées dans l'émergence des bacilles tuberculeux épidémiques(2016), ANR-11-EQPX-0003,ANINFIMIP,Equipements plateforme animalerie infectieuse de haute-sécurité de Midi Pyrénées(2011), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), European Project: 713406,H2020,H2020-MSCA-COFUND-2015,RESPIRE 3(2016), European Project: 278864,EC:FP7:HEALTH,FP7-HEALTH-2011-two-stage,PATHONGEN-TRACE(2012), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), GUILHOT, Christophe, Naissance d'un tueur: facteurs génétiques et adaptations métaboliques impliquées dans l'émergence des bacilles tuberculeux épidémiques - - TBemerg2016 - ANR-16-CE35-0009 - AAPG2016 - VALID, Equipements plateforme animalerie infectieuse de haute-sécurité de Midi Pyrénées - - ANINFIMIP2011 - ANR-11-EQPX-0003 - EQPX - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, REspiratory Science Promoted by International Research Exchanges 3 - RESPIRE 3 - - H20202016-09-01 - 2021-08-31 - 713406 - VALID, and Next Generation Genome Based High Resolution Tracing of Pathogens - PATHONGEN-TRACE - - EC:FP7:HEALTH2012-01-01 - 2016-06-30 - 278864 - VALID

Subjects
Microbiology (medical), Tuberculosis, Immunology, Mutant, Human pathogen, [SDV.GEN] Life Sciences [q-bio]/Genetics, Applied Microbiology and Biotechnology, Microbiology, Mycobacterium, Mycobacterium tuberculosis, 03 medical and health sciences, Mice, Stress, Physiological, Genetics, medicine, Animals, Humans, 030304 developmental biology, 0303 health sciences, Experimental evolution, [SDV.GEN]Life Sciences [q-bio]/Genetics, Mice, Inbred BALB C, Mice, Inbred C3H, Obligate, biology, 030306 microbiology, Cell Biology, biology.organism_classification, medicine.disease, Phenotype, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Biological Evolution, 3. Good health, Mutation, Female, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Abstract

International audience; Pathogenomic evidence suggests that Mycobacterium tuberculosis evolved from an environmental ancestor similar to Mycobacterium canettii, a rare human pathogen. However, the adaptations responsible for the transition from an environmental mycobacterium to an obligate human pathogen are poorly characterised. The ability to persist in the human host appears to be one important trait. Here we set out to identify the adaptations that contribute to the evolution of persistence in M. tuberculosis. By using experimental evolution of 8 M. canettii populations in mice, we selected mutants with enhanced persistence in vivo when compared to parental strains, which were thus phenotypically closer to M. tuberculosis. Genome sequencing of 140 M. canettii mutants and complementation analysis revealed that mutations in two loci were responsible for the enhanced persistence phenotypes. Most of the tested mutants were more resistant than their parental strains to nitric oxide, which is an important effector of immunity against M. tuberculosis infection. This resistance was common to modern M. tuberculosis strains but not to M. canettii strains. Our findings demonstrate phenotypic convergence during the experimental evolution of M. canettii, which mirrors natural evolution of M. tuberculosis. Furthermore, they indicate that the ability to withstand hostinduced stresses, such as nitric oxide, was key for the emergence of persistent M. tuberculosis.

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