Mechanisms of immune evasion by Mycobacterium tuberculosis: the impact of T7SS and cell wall lipids on host defenses.

Mycobacterium tuberculosis (M. tb) is one of the most successful human pathogens, causing a severe and widespread infectious disease. The frequent emergence of multidrug-resistant (MDR) strains has exacerbated this public health crisis, particularly in underdeveloped regions. M. tb employs a sophisticated array of virulence factors to subvert host immune responses, both innate and adaptive. It utilizes the early secretory antigenic target (ESAT6) secretion system 1 (ESX-1) type VII secretion system (T7SS) and cell wall lipids to disrupt phagosomal integrity, inhibiting phagosome maturation, and fusion with lysosomes. Although host cells activate mechanisms such as ubiquitin (Ub), Ub-ligase, and cyclic GMP-AMP synthase-stimulator of interferon genes 1 (CGAS-STING1)-mediated autophagy to inhibit M. tb survival within macrophages, the pathogen counteracts these defenses with its own virulence factors, thereby inhibiting autophagy and dampening host-directed responses. T7SSs are critical for transporting proteins across the complex mycobacterial cell envelope, performing essential functions, including metabolite uptake, immune evasion, and conjugation. T7SS substrates fall into two main families: ESAT-6 system proteins, which are found in both Firmicutes and Actinobacteria, and proline-glutamic acid (PE) and proline-proline-glutamic acid (PPE) proteins, which are unique to mycobacteria. Recent studies have highlighted the significance of T7SSs in mycobacterial growth, virulence, and pathogenesis. Understanding the mechanisms governing T7SSs could pave the way for novel therapeutic strategies to combat mycobacterial diseases, including tuberculosis (TB). T7SS of M. tb plays a critical role in the bacterium's virulence, pathogenesis, and survival within host cells. T7SS mediates the secretion of PE-PPE proteins and ESX substrates, which are pivotal in various cellular processes. These include damaging the phagosome, inducing ubiquitination, autophagy, and promoting the release dsDNA. Furthermore, T7SS activates key immune responses such as inflammasome formation, CGAS-STING1 signaling, and type I IFN production, while stimulating the secretion of proinflammatory cytokines. It also contributes to inflammation, necroptosis, pyroptosis, and facilitates the dissemination of M. tb to neighboring cells. In addition to promoting immune responses, T7SS is involved in nutrient acquisition and inhibits host cell defense mechanisms. It prevents phagosome-lysosome fusion, impairs phagosome repair mechanisms, and inhibits phagosome maturation, enabling M. tb to survive within macrophages. Targeting multiple stages of the T7SS pathway offers potential therapeutic strategies to inhibit its function, thereby reducing M. tb replication, virulence, and pathogenicity, as highlighted in the accompanying figure through cross-marks. These insights provide promising avenues for the development of interventions aimed at disrupting the T7SS and mitigating M. tb infection. AR = autophagy receptors (SQSTM1/p62, NBR1, CALCOCO2, TAX1BP1, OPTN, TRIM16, and TRIM32). HIGHLIGHTS: Emergence of MDR strains exacerbates the TB health crisis. M. tb uses T7SS to disrupt host immune responses. Pathogen counters autophagy, dampening host defense mechanisms. T7SSs critical for protein transport and immune evasion. Understanding T7SSs may lead to new TB therapies. [ABSTRACT FROM AUTHOR]