<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.马尔尼菲篮状菌（Talaromyces marneffei）易在免疫功能低下个体中引发全身性感染，是导致高死亡率的诱因之一。目前，马尔尼菲篮状菌诱导肝功能异常的潜在分子机制仍未被充分阐明。 本研究发现，马尔尼菲篮状菌感染患者可出现肝功能异常，表现为白蛋白水平降低、天冬氨酸转氨酶（aspartate aminotransferase, AST）及AST/丙氨酸转氨酶（alanine aminotransferase, ALT）比值升高。马尔尼菲篮状菌感染小鼠也呈现出相似的特征。 体外实验显示，马尔尼菲篮状菌可诱导AML-12细胞死亡。进一步研究证实，马尔尼菲篮状菌感染可诱导C57BL/6J小鼠肝细胞及AML-12细胞发生焦亡（pyroptosis），具体表现为感染小鼠/细胞中AIM2（AIM2）、半胱天冬酶-1/-4（caspase-1/-4）、Gasdermin D（GSDMD）及焦亡相关细胞因子水平上调。值得注意的是，使用半胱天冬酶-1/-4抑制剂VX765处理后，细胞死亡现象被显著抑制，同时马尔尼菲篮状菌诱导的焦亡过程也被阻断。 在感染后14天的动物模型中，同时检测到了坏死性凋亡（necroptosis）与细胞凋亡（apoptosis）。综上，马尔尼菲篮状菌可通过激活AIM2-半胱天冬酶-1/-4-GSDMD通路诱导肝细胞焦亡，这可能是肝损伤的重要致病原因之一；而坏死性凋亡、细胞凋亡等其他细胞死亡途径，也可能参与感染后期的病理过程。