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1. Identification of genes required for Mycobacterium abscessus growth in vivo with a prominent role of the ESX-4 locus.

Author

Laencina, Laura, Dubois, Violaine, Le Moigne, Vincent, Viljoen, Albertus, Majlessi, Laleh, Pritchard, Justin, Bernut, Audrey, Piel, Laura, Roux, Anne-Laure, Gaillard, Jean-Louis, Lombard, Bérengère, Loew, Damarys, Rubin, Eric J., Brosch, Roland, Kremer, Laurent, Herrmann, Jean-Louis, and Girard-Misguich, Fabienne

Subjects
*MICROBIAL virulence, *PATHOGENIC microorganisms, *PATHOGENIC bacteria, *FRANCISELLA tularensis, *MYCOBACTERIUM tuberculosis
Abstract

Mycobacterium abscessus, a rapidly growing mycobacterium (RGM) and an opportunistic human pathogen, is responsible for a wide spectrum of clinical manifestations ranging from pulmonary to skin and soft tissue infections. This intracellular organism can resist the bactericidal defense mechanisms of amoebae and macrophages, an ability that has not been observed in other RGM. M. abscessus can up-regulate several virulence factors during transient infection of amoebae, thereby becoming more virulent in subsequent respiratory infections in mice. Here, we sought to identify the M. abscessus genes required for replication within amoebae. To this end, we constructed and screened a transposon (Tn) insertion library of an M. abscessus subspecies massiliense clinical isolate for attenuated clones. This approach identified five genes within the ESX-4 locus, which in M. abscessus encodes an ESX-4 type VII secretion system that exceptionally also includes the ESX conserved EccE component. To confirm the screening results and to get further insight into the contribution of ESX-4 to M. abscessus growth and survival in amoebae and macrophages, we generated a deletion mutant of eccB4 that encodes a core structural element of ESX-4. This mutant was less efficient at blocking phagosomal acidification than its parental strain. Importantly, and in contrast to the wild-type strain, it also failed to damage phagosomes and showed reduced signs of phagosome-to-cytosol contact, as demonstrated by a combination of cellular and immunological assays. This study attributes an unexpected and genuine biological role to the underexplored mycobacterial ESX-4 system and its substrates. [ABSTRACT FROM AUTHOR]

Published
2018
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2. Identification of genes required for Mycobacterium abscessus growth in vivo with a prominent role of the ESX-4 locus

Author

Vincent Le Moigne, Jean Louis Gaillard, Anne Laure Roux, Bérengère Lombard, Albertus Viljoen, Jean-Louis Herrmann, Eric J. Rubin, Damarys Loew, Audrey Bernut, Laurent Kremer, Laura Piel, Fabienne Girard-Misguich, Justin R. Pritchard, Laleh Majlessi, Roland Brosch, Laura Laencina, Violaine Dubois, Infection et inflammation (2I), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut de Recherche en Infectiologie de Montpellier (IRIM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Pathogénomique mycobactérienne intégrée - Integrated Mycobacterial Pathogenomics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Harvard T.H. Chan School of Public Health, Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut Curie [Paris], This work was supported by the French Cystic Fibrosis Patients Association Vaincre la Mucoviscidose Grant RF20150501377, French Research National Agency Program DIMIVYR Grant ANR-13-BSV3-0007-01(to J.-L.H. and L.K.), and Fondation pour la Recherche Médicale Grant DEQ20150331719 (to L.K.). The Région Ile-de-France (Domaine d’Intérêt Majeur Maladies Infectieuses et Emergentes) funded postdoctoral fellowships (to V.L.M.) and for mass spectrometry analysis (to D.L.). L.L. is a doctoral fellow of the Ministère de l’Enseignement Supérieur et de la Recherche., ANR-13-BSV3-0007,DIMYVIR,Identification et Visualisation des Mécanismes Permettant l'Acquisition d'un Phénotype Invasif chez les Mycobactéries Pathogènes à Croissance Rapide(2013), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Transposable element, Multidisciplinary, biology, TVIISS-ESX4, Mutant, Virulence, Human pathogen, Locus (genetics), Mycobacterium abscessus, biology.organism_classification, survival, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, 3. Good health, Microbiology, 03 medical and health sciences, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, M. abscessus, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Gene, Mycobacterium
Abstract

International audience; Mycobacterium abscessus, a rapidly growing mycobacterium (RGM) and an opportunistic human pathogen, is responsible for a wide spectrum of clinical manifestations ranging from pulmonary to skin and soft tissue infections. This intracellular organism can resist the bactericidal defense mechanisms of amoebae and macrophages, an ability that has not been observed in other RGM. M. abscessus can up-regulate several virulence factors during transient infection of amoebae, thereby becoming more virulent in subsequent respiratory infections in mice. Here, we sought to identify the M. abscessus genes required for replication within amoebae. To this end, we constructed and screened a transposon (Tn) insertion library of an M. abscessus subspecies massiliense clinical isolate for attenuated clones. This approach identified five genes within the ESX-4 locus, which in M. abscessus encodes an ESX-4 type VII secretion system that exceptionally also includes the ESX conserved EccE component. To confirm the screening results and to get further insight into the contribution of ESX-4 to M. abscessus growth and survival in amoebae and macrophages, we generated a deletion mutant of eccB4 that encodes a core structural element of ESX-4. This mutant was less efficient at blocking phagosomal acidification than its parental strain. Importantly, and in contrast to the wild-type strain, it also failed to damage phagosomes and showed reduced signs of phagosome-to-cytosol contact, as demonstrated by a combination of cellular and immunological assays. This study attributes an unexpected and genuine biological role to the underexplored mycobacterial ESX-4 system and its substrates.

Published
2018
Full Text
View/download PDF

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