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The VII secretion system is the main channel for Mycobacterium tuberculosis ( MTB ) to secrete virulence proteins. The ESAT-like proteins EsxA/B and EsxW/V in the RD region of its genome have been used as targets for vaccine antigens. However, the function of EsxO/P has not been explored, although it was predicted to potentially induce Th1 cell responses as a vaccine development target. In this study, the VII secretion system effector molecule Rv2347c was heterologously expressed in Mycobacterium smegmatis and found to inhibit the expression of the early marker RAB5 of phagosomes, thus preventing the maturation process of phagosomes toward lysosomes, and activated the host cytoplasmic sensing pathway. It inhibited autophagy and activated IFNβ transcription through the STING/TBK1 pathway promoting the host's survival. Therefore, Rv2347c plays an important role in the pathogenesis of MTB with the potential to be utilized as a new target for tuberculosis vaccine development., Importance: We found that the ESAT-like protein Rv2347c (EsxP) can inhibit the maturation of phagosomes, leading to mycobacterium escape from phagosomes into the cytoplasm, which triggers the host's cytoplasmic sensing pathway STING/TBK1, inhibiting autophagy and upregulating IFNβ transcription, which contributes to the survival of mycobacterium in the host cell. We also found that Rv2347c was able to activate host immunity by activating NF-κB via STING and promoting the transcription of downstream pro-inflammatory factors. Meanwhile, the host also produces IL-1β to repair phagosome maturation arrest via the STING-mediated non-NF-κB pathway., Competing Interests: The authors declare no conflict of interest.

The causative agent of human tuberculosis, Mycobacterium tuberculosis , has a complex lipid-rich diderm envelope, which acts as a major barrier protecting the bacterium against the hostile environment inside the host cells. For the transfer of diverse molecules across this complex cell envelope, M. tuberculosis has a series of general and specialized protein secretion systems, characterized by the SecA general secretion pathway, the twin-arginine translocation pathway, and five specific ESX type VII secretion systems. In this review, we focus on the latter systems, known as ESX-1 to ESX-5, which were first discovered almost 20 years ago during the in silico analysis of the genome sequence of M. tuberculosis H37Rv. Since then, these systems have been the subject of highly dynamic research due to their involvement in several key biological processes and host-pathogen interactions of the tubercle bacilli.

Type VII secretion (T7S) systems of mycobacteria secrete substrates over the unusual diderm cell envelope. Furthermore, T7S gene clusters are present throughout the phylum Actinobacteria, and functional T7S-like systems have been identified in Firmicutes. Most of the T7S substrates can be divided into two families: the Esx proteins, which are found in both Firmicutes and Actinobacteria, and the PE and PPE proteins, which are more mycobacterium-specific. Members of both families have been shown to be secreted as folded heterodimers, suggesting that this is a conserved feature of T7S substrates. Most knowledge of the mechanism of T7S and the roles of T7S systems in virulence comes from studies of pathogenic mycobacteria. These bacteria can contain up to five T7S systems, called ESX-1 to ESX-5, each having its own role in bacterial physiology and virulence. In this article, we discuss the general composition of T7S systems and the role of the individual components in secretion. These conserved components include two membrane proteins with (predicted) enzymatic activities: a predicted ATPase (EccC), likely to be required for energy provision of T7S, and a subtilisin-like protease (MycP) involved in processing of specific substrates. Additionally, we describe the role of a conserved intracellular chaperone in T7S substrate recognition, based on recently published crystal structures and molecular analysis. Finally, we discuss system-specific features of the different T7S systems in mycobacteria and their role in pathogenesis and provide an overview of the role of T7S in virulence of other pathogenic bacteria.