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Toll-like receptors (TLRs) are at the forefront of pathogen recognition ensuring host fitness and eliciting protective cellular and humoral responses. Signaling pathways downstream of TLRs are tightly regulated for preventing collateral damage and loss of tolerance toward commensals. To trigger effective intracellular signaling, these receptors require the involvement of adaptor proteins. Among these, Toll/Interleukin-1 receptor domain containing adaptor protein (Tirap or MAL) plays an important role in establishing immune responses. Loss of function of MAL was associated with either disease susceptibility or resistance. These opposite effects reveal paradoxical functions of MAL and their importance in containing infectious or non-infectious diseases. In this review, we summarize the current knowledge on the signaling pathways involving MAL in different pathologies and their impact on inducing protective or non-protective responses.

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.

Mycobacterium tuberculosis (Mtb), the pathogen causing human tuberculosis, has evolved multiple strategies to successfully prevent clearance by immune cells and to establish dissemination and long-term survival in the host. The modulation of host immunity to maximize pathogen elimination while minimizing inflammation-mediated tissue damage may provide another tool to fight drug-resistant Mtb strains. Metabolic reprogramming of phagocytes can dramatically influence the intracellular colonization by Mtb and the key players involved in this process remain a matter of debate. Here, we demonstrate that aconitate decarboxylase 1 (Acod1; also known as immune-responsive gene 1, IRG1), which converts cis-aconitate into the metabolite itaconate, is a major player in controlling the acute phase of Mtb infection. Exposure of IRG1-deficient mice to a virulent Mtb strain (H37Rv) was lethal, while M. bovis BCG and the H37Ra attenuated Mtb strain induced neither lethality nor severe lung immunopathology. Lungs of IRG1-deficient mice infected by Mtb H37Rv displayed large areas of necrotizing granulomatous inflammation and neutrophil infiltration, accompanied by reduced levels of B and T lymphocytes and increased levels of alveolar and interstitial macrophage populations, compared to their wild type counterparts. Next, we show that IRG1, beyond its recruitment to Mtb-containing vacuoles, restricts Mtb replication and lipid droplets accumulation in phagocytes, hallmarks of a tight interplay between the bacillus and the host. Altogether, IRG1 confines the host response to create a favourable phagocytic environment for Mtb controlled intracellular replication. Competing Interest Statement The authors have declared no competing interest. Footnotes * The revised version of our manuscript is an expansive extension of our previous manuscript with additional findings obtained in vivo and in vitro further supporting the role of IRG1 in controlling host responses to restrict Mycobacterium tuberculosis (Mtb) infection. The revised version includes 6 additional co-authors and demonstrates in new approaches the dependence of the susceptibility of IRG1 deficiency to the virulency of Mtb infection (Fig. 1B-C, 1G-H, 2C-D, S1A-B), the trained immunity aspects of our study in vaccination/challenge experiments to overcome susceptibility of IRG1-deficient mice (Fig. 2E-G) as well as further in vitro characterization of the infection. We now also show the immunometabolic adaptations of IRG1-deficient cells compared to WT conditions (Fig. 3) and a detailed characterization of the lipid droplet interactions by light microscopy (Fig. 4E, 5A) and electron microscopy (Fig. 5G-I). These novel findings further support the notion that IRG1 is an essential player in controlling the host response to virulent Mtb infections by restricting inflammatory responses and the availability of host nutrients stored in lipid droplet reservoirs.