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PANoptosis-mediated mechanisms underlying AST elevation in Talaromyces marneffei infection
Wudi Wei1, Baili Zhan1, Lixiang Chen2
1Joint Laboratory for Emerging Infectious Diseases in China (Guangxi)-ASEAN, Life Sciences Institute, Guangxi Medical University, Guangxi. China.
Background:
Talaromyces marneffei (T. marneffei), a life-threatening opportunistic fungal pathogen, is endemic to Southeast Asia. Although elevated aspartate aminotransferase (AST) levels are commonly observed in infected individuals, the origin and mechanism of this phenomenon remain unclear. This study aimed to determine whether AST is a specific clinical indicator of T. marneffei infection and to investigate the underlying mechanisms associated with tissue damage and cell death.
Methods:
We retrospectively analyzed clinical and laboratory data of HIV/AIDS patients with or without T. marneffei infection from the Fourth People's Hospital of Nanning, Guangxi. A murine model of T. marneffei infection was constructed to investigate AST distribution in tissues. Additionally, PANoptosis-related proteins expression and inflammatory cytokines levels were assessed using ELISA, qPCR, and Western blotting.
Results:
Patients with HIV/ T. marneffei co-infection demonstrated significantly higher serum AST levels than HIV-only individuals, which declined following antifungal therapy. In infected mice, AST levels increased progressively in plasma and organs, with hepatic levels elevated throughout days 7, 14, and 21 post-infection. The liver exhibited the highest AST concentration, while the spleen showed the greatest fold increase. PANoptosis markers, including P-RIP, RIPK1, RIPK3, P-MLKL, GSDME, GSDMD, cleaved GSDMD, caspase-3, caspase-7, caspase-8, caspase-9, were markedly upregulated in liver tissues. Concurrently, proinflammatory cytokines Tnf-α, Il-1β, and Il-18 were consistently elevated in the liver but suppressed in the spleen, indicating organ-specific immune responses.
Conclusions:
Our findings demonstrate that T. marneffei infection triggers PANoptosis- mediated hepatocyte death and hepatic inflammatory activation, which contributes to AST elevation. AST may serve as a potential auxiliary biomarker for early diagnosis and therapeutic monitoring in Talaromycosis.
Insights
Talaromyces marneffei infection elevates aspartate aminotransferase (AST) by triggering PANoptosis-mediated liver cell death and inflammation. AST may help diagnose and monitor Talaromycosis in HIV patients.
Area of Science:
- Mycology
- Immunology
- Pathology
Background:
- Talaromyces marneffei is an opportunistic fungal pathogen causing severe infections, particularly in Southeast Asia.
- Elevated aspartate aminotransferase (AST) is common in T. marneffei infections, but its origin and significance are unclear.
- Investigating AST's role could improve diagnosis and understanding of T. marneffei pathogenesis.
Purpose of the Study:
- To determine if AST is a specific indicator of T. marneffei infection.
- To elucidate the mechanisms behind AST elevation, tissue damage, and cell death in T. marneffei infection.
Main Methods:
- Retrospective analysis of clinical data from HIV/AIDS patients with and without T. marneffei infection.
- Establishment of a murine model to track AST distribution in tissues.
- Assessment of PANoptosis markers and inflammatory cytokines using ELISA, qPCR, and Western blotting.
Main Results:
- HIV/T. marneffei co-infected patients showed significantly higher AST than HIV-only patients; levels decreased with treatment.
- In mice, AST increased in plasma and organs, with the liver showing the highest concentration and the spleen the greatest fold increase.
- Liver tissues displayed upregulated PANoptosis markers and elevated pro-inflammatory cytokines (Tnf-α, Il-1β, Il-18), while the spleen showed suppressed inflammation.
Conclusions:
- T. marneffei infection induces PANoptosis-mediated hepatocyte death and liver inflammation, leading to AST elevation.
- AST shows potential as an auxiliary biomarker for early diagnosis and treatment monitoring of Talaromycosis.
- Understanding the link between PANoptosis, inflammation, and AST is crucial for managing T. marneffei infections.
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