Abstract P85: Studying the role of a Mycobacterium tuberculosis virulent factor on liver pathology and cancer

Tuberculosis (TB) is a communicable disease which causes liver pathogenesis and may increase liver cancer risk by yet unknown mechanism. The granulomas, composed of Mycobacterium tuberculosis (Mtb) infected macrophages and other immune cells share characteristics of tumor microenvironment such as hijacking macrophage polarization toward anti-inflammatory M2 phenotype and T cell exhaustion. Mtb is believed to induce liver inflammation and pathology which may lead to hepatocellular carcinoma (HCC). Hence, it is important to identify the Mtb etiological factors which may help designing therapeutics to ameliorate TB-associated liver pathology and cancer. One of the virulent Mtb protein (protein-X) is specifically present in pathogenic mycobacteria but is absent in non-pathogenic M. smegmatis. Its expression is also increased in Mtb-infected macrophages and in active TB patients. Mice infected with M. smegmatis expressing Mtb protein-X (Msmeg-X) showed rapid death compared to the M. smegmatis vector control (Msmeg-pVV) implying multi-organ failure. Importantly, we have observed that expression of pro-inflammatory markers such as NLRP3, IL-1β, IL-6, CCL3, CCL2 were higher in Msmeg-X infected mice livers as compared to Msmeg-pVV. Furthermore, higher expression of iNOS and MPO in Msmeg-X-infected mice indicated oxidative stress induction. H&E analysis revealed abnormal hepatocyte lobule structure, fat accumulation and increased immune cells infiltration in Msmeg-X-infected mice. qRT-PCR analysis showed higher expression of CD11b, Ly6C, F4/80, CD64, IL-17A and CCR2 in Msmeg-X-infected livers indicating immune cell infiltration. Importantly, our results showing increased expression of TGF-β, α-SMA, collagen III, TIMP1 and CTGF in Msmeg-X-infected mice livers suggest stellate cell activation which is a central event leading to HCC. In conclusion, we identified this protein-X to be one of the Mtb etiological factors which may be responsible for stellate cell activation, liver pathology, and HCC. Citation Format: Supriya Borah and Sangita Mukhopadhyay. Studying the role of a Mycobacterium tuberculosis virulent factor on liver pathology and cancer [abstract]. In: Proceedings of Frontiers in Cancer Science 2024; 2024 Nov 13-15; Singapore. Philadelphia (PA): AACR; Cancer Res 2025;85(15_Suppl):Abstract nr P85.