Rv2741 Promotes Mycobacterium Survival by Modulating Macrophage Function via the IL-1α-MAPK Axis

One of the primary healthcare problems in the world today is tuberculosis (TB), a chronic infectious illness brought on by <i>Mycobacterium tuberculosis</i> (<i>M. tuberculosis</i>). A distinct family of PE_PGRS proteins, encoded by the <i>M. tuberculosis</i> genome, has attracted more attention because of their involvement in immune evasion and bacterial pathogenicity. Nevertheless, the specific functions and mechanisms of action for the majority of PE_PGRS proteins remain largely unexplored. This study focuses on the Rv2741 (PE_PGRS47) gene, which is exclusively present in pathogenic mycobacteria. To examine the function of Rv2741 in host-pathogen interactions, we created recombinant strains of <i>Mycobacterium smegmatis</i> (<i>M. smegmatis</i>) that expressed the <i>M. tuberculosis</i> Rv2741 gene. IL-1α was found to be a key mediator of host response modulation by Rv2741. Rv2741 downregulates the secretion of IL-1α and inhibits the MAPK signaling pathway, particularly the p38 and ERK1/2 pathways, thereby cooperatively inhibiting macrophage autophagy and apoptosis. Meanwhile, the decrease in IL-1α secretion directly leads to changes in the cytokine secretion pattern and a reduction in nitric oxide (NO) production. This multifaceted regulatory mechanism ultimately favors the survival of <i>M. smegmatis</i> in macrophages. This research significantly expands our understanding of Rv2741 function, revealing its crucial role as a multifunctional virulence factor in the immune evasion of <i>M. tuberculosis</i>.