Taylor & Francis Group
13 files

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

posted on 2022-05-31, 16:20 authored by Gang Wang, Wudi Wei, Zhongsheng Jiang, Junjun Jiang, Jing Han, Hong Zhang, Jiaguang Hu, Peng Zhang, Xu Li, Tao Chen, Jinhao He, Zhen Li, Jingzhen Lai, Hao Liang, Chuanyi Ning, Li Ye

Talaromyces marneffei tends to induce systemic infection in immunocompromised individuals, which is one of the causes of the high mortality. The underlying molecular mechanisms of T.marneffei-induced abnormal liver function are still poorly understood. In this study, we found that T.marneffei-infected patients could develop abnormal liver function, evidenced by reduced albumin and increased levels of aspartate aminotransferase (AST) and AST/alanine aminotransferase (ALT). T. marneffei-infected mice exhibited similar characteristics. In vitro investigations showed that T.marneffei induced the death of AML-12 cells. Furthermore, we determined that T.marneffei 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 T.marneffei-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, T.marneffei-induced pyroptosis was blocked. Nevertheless, necroptosis and apoptosis were also detected in infected animal model at 14 days post-infection. In conclusion, T.marneffei 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.


The work was supported by the China Postdoctoral Science Foundation [2020M683212]; Guangxi Science Fund for Distinguished Young ScholarsGuangxi [2018GXNSFFA281001]; National Natural Science Foundation of China [81803295]; National Natural Science Foundation of China [81760602]; National Natural Science Foundation of China [81971934]; National Natural Science Foundation of China [31970167]; National Natural Science Foundation of China [81960602]; Guangxi Medical University Training Program for Distinguished YoungScholars [to Junjun Jiang]; Guangxi Bagui Scholar [toJunjun Jiang]; Guangxi Youth Science Fund Project [2021GXNSFBA196004].