Talaromyces marneffei activates the AIM2-caspase-1/-4-GSDMD axis to induce pyroptosis in hepatocytes.
Talaromyces marneffei activates the AIM2-caspase-1/-4-GSDMD axis to induce pyroptosis in hepatocytes.
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DOI：
10.1080/21505594.2022.2080904
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发表时间：
2022-12
期刊：
影响因子：
5.2
通讯作者：
Ye, Li
中科院分区：
文献类型：
--
作者：
Wang, Gang;Wei, Wudi;Jiang, Zhongsheng;Jiang, Junjun;Han, Jing;Zhang, Hong;Hu, Jiaguang;Zhang, Peng;Li, Xu;Chen, Tao;He, Jinhao;Li, Zhen;Lai, Jingzhen;Liang, Hao;Ning, Chuanyi;Ye, Li
马尔尼菲篮状菌易引起免疫功能低下个体的全身感染，这是其高死亡率的原因之一。马尔尼菲弓形虫引起肝功能异常的潜在分子机制仍知之甚少。在这项研究中，我们发现马尔尼菲弓形虫感染的患者可能会出现肝功能异常，表现为白蛋白降低和天冬氨酸转氨酶（AST）和AST/丙氨酸转氨酶（ALT）水平升高。T.马尔尼菲感染的小鼠表现出类似的特征。体外研究表明，马尔尼菲毛癣菌诱导AML-12细胞死亡。此外，我们确定马尔尼菲毛癣菌感染诱导C57 BL/6 J小鼠和AML-12细胞肝细胞中的焦亡，通过马尔尼菲毛癣菌感染的小鼠/细胞中AIM 2、半胱天冬酶-1/-4、Gasdermin D（GSDMD）和焦亡相关细胞因子的增加来证明。重要的是，在VX 765（半胱天冬酶-1/-4的抑制剂）存在下，细胞死亡被显著抑制。此外，在VX 765的存在下，马尔尼菲锥虫诱导的焦亡被阻断。然而，在感染后14天，在感染动物模型中也检测到坏死性凋亡和凋亡。结论：马尔尼菲毛癣菌通过激活AIM 2-caspase-1/-4-GSDMD轴诱导肝细胞发生焦亡，这可能是导致肝损伤的重要原因之一，感染后期可能还参与了其他死亡途径，包括坏死性凋亡和细胞凋亡。
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.
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影响因子：
7.3
作者：
Jiang W;Deng Z;Dai X;Zhao W
通讯作者：
Zhao W
影响因子：
64.5
作者：
Karki R;Lee E;Place D;Samir P;Mavuluri J;Sharma BR;Balakrishnan A;Malireddi RKS;Geiger R;Zhu Q;Neale G;Kanneganti TD
通讯作者：
Kanneganti TD
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影响因子：
11.1
作者：
Guo, Xiaoli;Zhong, Wen;Gao, Ai
通讯作者：
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影响因子：
15.9
作者：
Kupz, Andreas;Zedler, Ulrike;Kaufmann, Stefan H. E.
通讯作者：
Kaufmann, Stefan H. E.
影响因子：
10
作者：
Floto RA;Olivier KN;Saiman L;Daley CL;Herrmann JL;Nick JA;Noone PG;Bilton D;Corris P;Gibson RL;Hempstead SE;Koetz K;Sabadosa KA;Sermet-Gaudelus I;Smyth AR;van Ingen J;Wallace RJ;Winthrop KL;Marshall BC;Haworth CS;US Cystic Fibrosis Foundation and European Cystic Fibrosis Society
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US Cystic Fibrosis Foundation and European Cystic Fibrosis Society