Overexpressed Rv0222 in M. smegmatis suppresses host innate immunity by downregulating miR-9 target SIRT1

Tuberculosis (TB) remains one of the most fatal infectious diseases, the pathogenic bacterium Mycobacterium tuberculosis (Mtb) has a thick wall to resist the invasion of extracellular substances and secretes a variety of virulence proteins to antagonize host innate immunity. Rv0222, a protein encoded by the gene Rv0222 in the RD4 region of Mtb, is a critical virulence factor in the pathogenicity of Mtb. However, the mechanism of its regulation of miRNAs during bacterial infection is unclear. We used Rv0222 gene and Mycobacterium smegmatis (M. smegmatis), which is highly homologous to Mtb, to construct Rv0222 recombinant M. smegmatis Ms_Rv0222. Ms_Rv0222 induced down-regulation of miR-9 expression and up-regulation of SIRT1 in RAW264.7 cells and mice post-infection. Up-regulation of SIRT1 caused down-regulation of p65 activity and decreased the expression of pro-inflammatory cytokine, which increased the intracellular survival of M. smegmatis. Si-SIRT1 induced up-regulation of p65 activity and increased the expression of pro-inflammatory cytokine, then decreased the intracellular survival of M. smegmatis. This study reveals that Mtb Rv0222 mediates the suppression of host innate immunity by miR-9 and its target SIRT1, and may provide a potential site for the development of new anti-TB drugs targeting Rv0222.