Mycobacterial Phthiocerol Dimycocerosate Induces Galectin-3 Upregulation to Impair Proinflammatory Responses and Favor Immune Evasion in vivo

Abstract

Mycobacterium tuberculosis (Mtb), a typical intracellular parasite that cause tuberculosis (TB), which rank the top infectious killer for human death. Pathogenic mycobacterium has evolved numerous strategies to favor their intracellular survival including a unique lipid-rich cell wall component and granuloma formation during early infection [1]. 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 [2-7], but the mechanisms are still remains questionable. We used an AACT/SILAC-based quantitative proteomic approach to determine PDIM-responded proteome profiles during Mm early infection. A major difference was the high abundance of galectin3 (Gal-3) in WT Mm-infected cells and not with PDIM-deficient. 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. Silencing of Gal-3 effectively relieved tissue damage induced in mice by PDIM-expressing Mm. We found upregulated Gal-3 in the serum and BALF of confirmed clinical tuberculosis cases, while 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 in vivo, but also that target-Gal-3 therapy is a promising anti-tuberculosis strategy in the future. Funding Statement: This work was supported in part by the National Natural Science Foundation of China (Grant Nos. 31772709 and 31572485 to D.W), the new faculty startup research fund of China Three Gorges University (KJ2014B023 to D.W), Health Commission of Hubei Province in China (WJ2019H528 to D.W; WJ2019F080 to D.L), and in part by the intramural research program of NIAID, NIH (Bethesda MD, USA). Z.L was supported by grants from the China’s 13th Five Year Programs for the prevention and cure of great infectious diseases (2017ZX10201301-005) and Open Fund of Shanghai Key Laboratory of Tuberculosis (2018kf03). XY.Fan is the recipient of National Natural Science Foundation of China (31771004). Declaration of Interests: The authors declare no competing financial interests. Ethics Approval Statement: The case-control study of TB was reviewed and approved by the Ethics Committee of the Third People’s Hospital of Yichang (2017008H). Written informed consent was obtained from all participants. The animal experiments were reviewed and approved by the Animal Care and Use Committee of China Three Gorges University (2017010M).