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Updated: Sep 21, 2025
Evaluation of Caspase Activation to Assess Innate Immune Cell Death
Published on: January 20, 2023
Talaromyces marneffei activates the AIM2-caspase-1/-4-GSDMD axis to induce pyroptosis in hepatocytes
Gang Wang1, Wudi Wei1, Zhongsheng Jiang2
1Guangxi Key Laboratory of AIDS Prevention and Treatment, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China.
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.
Insights
Talaromyces marneffei infection causes liver damage in immunocompromised individuals by inducing pyroptosis in hepatocytes. This cell death pathway involves AIM2, caspase-1/-4, and Gasdermin D, leading to abnormal liver function.
Area of Science:
- Mycology
- Immunology
- Hepatology
Background:
- Talaromyces marneffei causes systemic infections, particularly in immunocompromised individuals, leading to high mortality.
- The molecular mechanisms behind T. marneffei-induced liver dysfunction remain unclear.
- Clinical observations show T. marneffei infection is associated with reduced albumin and elevated liver enzymes (AST, ALT).
Purpose of the Study:
- To investigate the mechanisms of Talaromyces marneffei-induced liver injury.
- To determine the role of programmed cell death pathways in T. marneffei-related hepatotoxicity.
Main Methods:
- Infection of C57BL/6J mice and AML-12 hepatocytes with Talaromyces marneffei.
- Analysis of liver function markers, including albumin, AST, and ALT.
- Assessment of pyroptosis, necroptosis, and apoptosis markers (AIM2, caspase-1/-4, GSDMD, cytokines).
- Treatment with VX765, a caspase-1/-4 inhibitor, to evaluate its effect on cell death.
Main Results:
- T. marneffei infection led to abnormal liver function in both mice and AML-12 cells.
- Hepatocytes exhibited pyroptosis, evidenced by increased AIM2, caspase-1/-4, GSDMD, and related cytokines.
- Inhibition of caspase-1/-4 with VX765 significantly suppressed T. marneffei-induced pyroptosis and cell death.
- Necroptosis and apoptosis were also observed in later stages of infection in the animal model.
Conclusions:
- Talaromyces marneffei induces pyroptosis in hepatocytes via the AIM2-caspase-1/-4-GSDMD pathway, contributing to liver damage.
- This pyroptotic cell death is a key mechanism underlying T. marneffei-induced liver dysfunction.
- Necroptosis and apoptosis may play a role in the later phases of T. marneffei infection and liver injury.
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