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Tirap controls Mycobacterium tuberculosis phagosomal acidification
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 secretin...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9994722/ https://www.ncbi.nlm.nih.gov/pubmed/36888688 http://dx.doi.org/10.1371/journal.ppat.1011192 |
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author | Belhaouane, Imène Pochet, Amine Chatagnon, Jonathan Hoffmann, Eik Queval, Christophe J. Deboosère, Nathalie Boidin-Wichlacz, Céline Majlessi, Laleh Sencio, Valentin Heumel, Séverine Vandeputte, Alexandre Werkmeister, Elisabeth Fievez, Laurence Bureau, Fabrice Rouillé, Yves Trottein, François Chamaillard, Mathias Brodin, Priscille Machelart, Arnaud |
author_facet | Belhaouane, Imène Pochet, Amine Chatagnon, Jonathan Hoffmann, Eik Queval, Christophe J. Deboosère, Nathalie Boidin-Wichlacz, Céline Majlessi, Laleh Sencio, Valentin Heumel, Séverine Vandeputte, Alexandre Werkmeister, Elisabeth Fievez, Laurence Bureau, Fabrice Rouillé, Yves Trottein, François Chamaillard, Mathias Brodin, Priscille Machelart, Arnaud |
author_sort | Belhaouane, Imène |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9994722 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-99947222023-03-09 Tirap controls Mycobacterium tuberculosis phagosomal acidification Belhaouane, Imène Pochet, Amine Chatagnon, Jonathan Hoffmann, Eik Queval, Christophe J. Deboosère, Nathalie Boidin-Wichlacz, Céline Majlessi, Laleh Sencio, Valentin Heumel, Séverine Vandeputte, Alexandre Werkmeister, Elisabeth Fievez, Laurence Bureau, Fabrice Rouillé, Yves Trottein, François Chamaillard, Mathias Brodin, Priscille Machelart, Arnaud PLoS Pathog Research Article 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. Public Library of Science 2023-03-08 /pmc/articles/PMC9994722/ /pubmed/36888688 http://dx.doi.org/10.1371/journal.ppat.1011192 Text en © 2023 Belhaouane et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Belhaouane, Imène Pochet, Amine Chatagnon, Jonathan Hoffmann, Eik Queval, Christophe J. Deboosère, Nathalie Boidin-Wichlacz, Céline Majlessi, Laleh Sencio, Valentin Heumel, Séverine Vandeputte, Alexandre Werkmeister, Elisabeth Fievez, Laurence Bureau, Fabrice Rouillé, Yves Trottein, François Chamaillard, Mathias Brodin, Priscille Machelart, Arnaud Tirap controls Mycobacterium tuberculosis phagosomal acidification |
title | Tirap controls Mycobacterium tuberculosis phagosomal acidification |
title_full | Tirap controls Mycobacterium tuberculosis phagosomal acidification |
title_fullStr | Tirap controls Mycobacterium tuberculosis phagosomal acidification |
title_full_unstemmed | Tirap controls Mycobacterium tuberculosis phagosomal acidification |
title_short | Tirap controls Mycobacterium tuberculosis phagosomal acidification |
title_sort | tirap controls mycobacterium tuberculosis phagosomal acidification |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9994722/ https://www.ncbi.nlm.nih.gov/pubmed/36888688 http://dx.doi.org/10.1371/journal.ppat.1011192 |
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