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

ABSTRACT

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.

KEYWORDS:

• Talaromyces marneffei
• liver damage
• pyroptosis
• inflammation
• opportunistic infection

Acknowledgements

Gratitude is expressed to all participants who have been dedicated to this study, and to the individuals who volunteered to participate. This study was supported by the National Natural Science Foundation of China (NSFC; 31970167, 81971934, 81803295, 81760602, 81960602), Guangxi Science Fund for Distinguished Young Scholars (2018GXNSFFA281001), Guangxi Youth Science Fund Project (2021GXNSFBA196004, to Wudi Wei), China Postdoctoral Science Foundation (2020M683212, to Wudi Wei), Guangxi Bagui Scholar (to Junjun Jiang), and Guangxi Medical University Training Program for Distinguished Young Scholars (to Junjun Jiang). We are appreciative of Dr.Wu for her critical reading and language polishing in this paper. Moreover, the authors would like to express their gratitude to all those who have dedicated to the prevention and control of infectious diseases.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The datasets generated for this study are available on request to the corresponding author.

Supplementary materials

Supplemental data for this article can be accessed online at https://doi.org/10.1080/21505594.2022.2080904

Additional information

Funding

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].