Tirap controls Mycobacterium tuberculosis phagosomal acidification

Abstract

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.

Author summary

The efficiency of Mycobacterium tuberculosis in establishing its replicative niche relies on its capacity to manipulate host factors. The aim of our study was to identify the impact of a genetic deficiency in Tirap, a key factor of the innate immunity response, on the evolution of in vivo and ex vivo tuberculosis infections. Here, we show that mice heterozygous for a truncated Tirap protein were more resistant to the infection, displaying less bacterial burden in the lungs. At the cellular level, we identified a repression of Cish-mediated phagosomal acidification in Tirap-deficient macrophages resulting in an enhanced bactericidal activity. Our results provide new insights into how Mtb infection promotes Tirap expression to ensure its survival.