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Immunol."],"abstract":"<jats:p>To reveal functions of novel <jats:italic>Mycobacterium tuberculosis<\/jats:italic> (<jats:italic>M. tb<\/jats:italic>) proteins responsible for modulating host innate immunity is essential to elucidation of mycobacterial pathogenesis. In this study, we aimed to identify the role of a putative protein Rv0309 encoded within RD8 of <jats:italic>M. tb<\/jats:italic> genome in inhibiting the host inflammatory response and the underlying mechanism, using <jats:italic>in-vitro<\/jats:italic> and <jats:italic>in-vivo<\/jats:italic> experiments. A recombinant <jats:italic>M. smegmatis<\/jats:italic> strain Ms_rv0309 expressing Rv0309 and a mutant Bacillus Calmette-Gu\u00e9rin (BCG)\u0394RS01790 strain with deletion of BCG_RS01790, 100% homologue of Rv0309 in BCG, were constructed. Rv0309 was found to localize in the cell wall and be able to decrease cell wall permeability. Purified recombinant rRv0309 protein inhibited lipopolysaccharide-induced IL-6 release in RAW264.7 cells. BCG_RS01790 in BCG or Rv0309 in Ms_rv0309 strain greatly inhibited production of IL-6, IL-1\u03b2, and TNF-\u03b1 in RAW264.7 cells. Similarly, BCG\u0394RS01790 strongly induced expression of these cytokines compared with wild-type BCG and complement strain, cBCG\u0394RS01790::RS01790. Further BCG_RS01790 or Rv0309 suppressed cytokine production through NF-\u03baB p65\/I\u03baB\u03b1 and MAPK ERK\/JNK signaling. Importantly, BCG_RS01790 in BCG and Rv0309 in Ms_rv0309 strain enhanced mycobacterial survival in macrophages. Mice infected with BCG\u0394RS01790 exhibited high levels of IFN-\u03b3, TNF-\u03b1 and IL-1\u03b2, and large numbers of neutrophils and lymphocytes in the early stage, and minimal lung bacterial load and inflammatory damage in late stage of the experiment. In conclusion, the cell wall protein Rv0309 or BCG_RS01790 enhanced mycobacterial intracellular survival after infection likely through inhibition of the pro-inflammatory response and decrease of bacterial cell wall permeability, thereby contributing to mycobacterial pathogenesis.<\/jats:p>","DOI":"10.3389\/fimmu.2022.829410","type":"journal-article","created":{"date-parts":[[2022,2,24]],"date-time":"2022-02-24T04:27:27Z","timestamp":1645676847000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Mycobacterium tuberculosis Rv0309 Dampens the Inflammatory Response and Enhances Mycobacterial 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