Mycobacterial phthiocerol dimycocerosate induces Galectin-3 upregulation to impair proinflammatory responses and favor immune evasion.

Mycobacterium tuberculosis, a typical intracellular parasite that causes tuberculosis, is ranked as the top infectious killer for humans in annual WHO reports. Pathogenic mycobacterium has evolved numerous strategies to favor their intracellular survival including a unique lipid-rich-cell-wall and granuloma formation during infection. Phthiocerol dimycocerosate (PDIM) is a critical virulence factor of mycobacteria including Mycobacterium marinum (Mm), which manipulate host immune responses and granuloma induction and facilitate immune evasion, but the mechanisms still remain unclear. We used an AACT/SILAC-based-quantitative proteomic approach to determine PDIM-responsive proteomics during Mm-infection. A major difference was the high abundance of Gal-3 in WT_Mm-infected cells not observed in PDIM-deficient infections. Gal-3 induction by PDIM-replete bacteria was primarily via Toll-like-receptor 2, and also engaged TGF-β non-classical-pathway. Elevated Gal-3 in macrophages prevented the turnover and translocation of NF-κB to effectively modulate the profile of inflammatory cytokines. Gal-3 Silencing effectively reduced tissue damage induced in mice by PDIM-expressing Mm. We found upregulated Gal-3 in the serum and BALF of clinical tuberculosis cases, which decreased significantly after effective chemotherapy. Our findings demonstrated that upregulated Gal-3 not only plays an important role in regulating host immune response and granuloma formation, but also suggests that targeting-Gal-3 therapy could be a promising anti-tuberculosis strategy.