Article (Scientific journals)
Tirap controls Mycobacterium tuberculosis phagosomal acidification.
Belhaouane, Imène; Pochet, Amine; Chatagnon, Jonathan et al.
2023In PLoS Pathogens, 19 (3), p. 1011192
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Keywords :
Receptors, Interleukin-1; Adaptor Proteins, Signal Transducing; TIRAP protein, human; Membrane Glycoproteins; TIRAP protein, mouse; Humans; Mice; Animals; Receptors, Interleukin-1/genetics; Receptors, Interleukin-1/metabolism; Signal Transduction; Adaptor Proteins, Signal Transducing/metabolism; Hydrogen-Ion Concentration; Membrane Glycoproteins/metabolism; Mycobacterium tuberculosis; Tuberculosis; Virology; Genetics; Molecular Biology; Immunology; Microbiology; Parasitology
Abstract :
[en] Progression of tuberculosis is tightly linked to a disordered immune balance, resulting in inability of the host to restrict intracellular bacterial replication and its subsequent dissemination. The immune response is mainly characterized by an orchestrated recruitment of inflammatory cells secreting cytokines. This response results from the activation of innate immunity receptors that trigger downstream intracellular signaling pathways involving adaptor proteins such as the TIR-containing adaptor protein (Tirap). In humans, resistance to tuberculosis is associated with a loss-of-function in Tirap. Here, we explore how genetic deficiency in Tirap impacts resistance to Mycobacterium tuberculosis (Mtb) infection in a mouse model and ex vivo. Interestingly, compared to wild type littermates, Tirap heterozygous mice were more resistant to Mtb infection. Upon investigation at the cellular level, we observed that mycobacteria were not able to replicate in Tirap-deficient macrophages compared to wild type counterparts. We next showed that Mtb infection induced Tirap expression which prevented phagosomal acidification and rupture. We further demonstrate that the Tirap-mediated anti-tuberculosis effect occurs through a Cish-dependent signaling pathway. Our findings provide new molecular evidence about how Mtb manipulates innate immune signaling to enable intracellular replication and survival of the pathogen, thus paving the way for host-directed approaches to treat tuberculosis.
Disciplines :
Immunology & infectious disease
Author, co-author :
Belhaouane, Imène;  Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, Lille, France
Pochet, Amine;  Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, Lille, France
Chatagnon, Jonathan;  Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, Lille, France
Hoffmann, Eik;  Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, Lille, France
Queval, Christophe J;  High Throughput Screening Laboratory, The Francis Crick Institute, London, United Kingdom
Deboosère, Nathalie;  Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, Lille, France
Boidin-Wichlacz, Céline;  Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, Lille, France
Majlessi, Laleh;  Pasteur-TheraVectys Joint Lab, Institut Pasteur, Université Paris Cité, Paris, France
Sencio, Valentin;  Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, Lille, France
Heumel, Séverine;  Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, Lille, France
Vandeputte, Alexandre;  Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, Lille, France
Werkmeister, Elisabeth;  Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, Lille, France ; Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41-UMS 2014-PLBS, Lille, France
Fievez, Laurence ;  Université de Liège - ULiège > Département des sciences fonctionnelles (DSF) > Biochimie et biologie moléculaire ; Laboratory of Cellular and Molecular Immunology, GIGA-Research, Liège, Belgium
Bureau, Fabrice ;  Université de Liège - ULiège > GIGA > GIGA Inflammation, Infection & Immunity ; Laboratory of Cellular and Molecular Immunology, GIGA-Research, Liège, Belgium
Rouillé, Yves;  Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, Lille, France
Trottein, François ;  Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, Lille, France
Chamaillard, Mathias ;  Laboratory of Cell Physiology, INSERM U1003, University of Lille, Lille, France
Brodin, Priscille ;  Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, Lille, France
Machelart, Arnaud  ;  Univ. Lille, CNRS, INSERM, CHU Lille, Institut Pasteur de Lille, U1019-UMR 9017-CIIL-Center for Infection and Immunity of Lille, Lille, France
More authors (9 more) Less
 These authors have contributed equally to this work.
Language :
English
Title :
Tirap controls Mycobacterium tuberculosis phagosomal acidification.
Publication date :
March 2023
Journal title :
PLoS Pathogens
ISSN :
1553-7366
eISSN :
1553-7374
Publisher :
Public Library of Science (PLoS), United States
Volume :
19
Issue :
3
Pages :
e1011192
Peer reviewed :
Peer Reviewed verified by ORBi
Name of the research project :
EMBO Yong Investigator Program
Funders :
ANR - Agence Nationale de la Recherche [FR]
FEDER - Fonds Européen de Développement Régional [BE]
I-SITE ULNE Foundation [FR]
FRM - Fondation pour la Recherche Médicale [FR]
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