<i>Talaromyces marneffei</i> activates the AIM2-caspase-1/-4-GSDMD axis to induce pyroptosis in hepatocytes

<i>Talaromyces marneffei</i> tends to induce systemic infection in immunocompromised individuals, which is one of the causes of the high mortality. The underlying molecular mechanisms of <i>T.marneffei</i>-induced abnormal liver function are still poorly understood. In this study, we found that <i>T.marneffei</i>-infected patients could develop abnormal liver function, evidenced by reduced albumin and increased levels of aspartate aminotransferase (AST) and AST/alanine aminotransferase (ALT). <i>T. marneffei</i>-infected mice exhibited similar characteristics. <i>In vitro</i> investigations showed that <i>T.marneffei</i> induced the death of AML-12 cells. Furthermore, we determined that <i>T.marneffei</i> infection induced pyroptosis in hepatocytes of C57BL/6J mice and AML-12 cells, demonstrated by the increase of AIM2, caspase-1/-4, Gasdermin D(GSDMD) and pyroptosis-related cytokines in <i>T.marneffei</i>-infected mice/cells. Importantly, cell death was markedly suppressed in the presence of VX765 (an inhibitor of caspase-1/-4). Furthermore, in the presence of VX765, <i>T.marneffei</i>-induced pyroptosis was blocked. Nevertheless, necroptosis and apoptosis were also detected in infected animal model at 14 days post-infection. In conclusion, <i>T.marneffei</i> induces pyroptosis in hepatocytes through activation of the AIM2-caspase-1/-4-GSDMD axis, which may be an important cause of liver damage, and other death pathways including necroptosis and apoptosis may also be involved in the later stage of infection.