Tirap controls Mycobacterium tuberculosis phagosomal acidification.

Autor: Imène Belhaouane, Amine Pochet, Jonathan Chatagnon, Eik Hoffmann, Christophe J Queval, Nathalie Deboosère, Céline Boidin-Wichlacz, Laleh Majlessi, Valentin Sencio, Séverine Heumel, Alexandre Vandeputte, Elisabeth Werkmeister, Laurence Fievez, Fabrice Bureau, Yves Rouillé, François Trottein, Mathias Chamaillard, Priscille Brodin, Arnaud Machelart
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: PLoS Pathogens, Vol 19, Iss 3, p e1011192 (2023)
Druh dokumentu: article
ISSN: 1553-7366
1553-7374
DOI: 10.1371/journal.ppat.1011192
Popis: 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.
Databáze: Directory of Open Access Journals
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