Journal Article

Tirap controls Mycobacterium tuberculosis phagosomal acidification

Fievez, Laurence, Bureau, Fabrice, Queval, Christophe J., Deboosère, Nathalie, Vandeputte, Alexandre, Sencio, Valentin, Chamaillard, Mathias, Heumel, Séverine, Hoffmann, Eik, Pochet, Amine, Rouillé, Yves, Machelart, Arnaud, Belhaouane, Imène, Majlessi, Laleh, Boidin-Wichlacz, Céline, Brodin, Priscille, Trottein, François, Werkmeister, Elisabeth, Chatagnon, Jonathan

2023

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acidification / Adapters / Adaptor proteins / Adaptor Proteins, Signal Transducing / Adaptor Proteins, Signal Transducing - metabolism / Analysis / Animals / B cells / Biology and Life Sciences / Care and treatment / Cytokines / Development and progression / Diagnosis / Disease / Drug resistance in microorganisms / Flow cytometry / Genes / Genetic engineering / Genetics / Health aspects / Human health sciences / Humans / Hydrogen-Ion Concentration / Immune response / Immune system / Immunologie & maladie infectieuse / Immunology / Immunology & infectious disease / Infections / Inflammation / Innate immunity / Intracellular / Intracellular signalling / Life Sciences / Lungs / Macrophages / Medicine and Health Sciences / Membrane Glycoproteins / Membrane Glycoproteins - metabolism / Mice / Microbiology / Molecular Biology / Mycobacterium tuberculosis / Parasitology / Polymorphism / Prevention / Proteins / Receptors, Interleukin-1 / Receptors, Interleukin-1 - genetics / Receptors, Interleukin-1 - metabolism / Replication / Research and Analysis Methods / Risk factors / Sciences de la santé humaine / Signal Transduction / Signaling / TIRAP protein, human / TIRAP protein, mouse / Tuberculosis / Tumor necrosis factor-TNF / Virology