The virulence regulator Rv3425 mediates stress adaptation and promotes intracellular survival of Mycobacterium tuberculosis avirulent strain

Mycobacterium tuberculosis (M. tuberculosis), the etiological agent responsible for tuberculosis, possesses a gene family encoding proteins characterized by Pro-Glu/Pro-Pro-Glu motifs, collectively referred to as the PE/PPE family. Despite being a member of this family, the biological function of Rv3425, which encodes PPE57, remains poorly understood. In the current study, we investigated the role of Rv3425 in stress adaption in vitro and in the virulence of M. tuberculosis avirulent strain in cellular and murine infection models. We found that Rv3425 enhances the stress resistance of M. tuberculosis under conditions of 0.05% SDS, pH3.0 or hydrogen peroxide treatment in vitro. The knockout of rv3425 resulted in a phenotypic alteration of the mycobacterial colony morphology from the typical rough and dry appearance to an atypical smooth and moist phenotype. Further, Rv3425 localizes to the host cell nucleus, the knockout of rv3425 attenuated the survival of M. tuberculosis in THP-1 cells and in C57BL/6 mice. The transcriptional analysis identified 1370 differentially expressed genes that were enriched in cytokines production and associated signaling pathways. Notably, Rv3425 significantly suppressed the expression of IFN-α while promoting the expression of IFN-γ in infected mice. T-cell recall (IFN-γ) assay showed that Rv3425 substantially increased the antigenicity of M. tuberculosis. Altogether, we found that Rv3425 enhances survival of M. tuberculosis avirulent in macrophages and mice, and exerting immunomodulatory effects, indicating that Rv3425 is a potential target for the development of new diagnostic techniques or therapeutic strategies against tuberculosis.