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ABSTRACTTalaromyces marneffeitends 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 vitroinvestigations showed that T.marneffeiinduced the death of AML-12 cells. Furthermore, we determined that T.marneffeiinfection 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.marneffeiinduces 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.

ABSTRACTLittle is known about how Talaromyces marneffei, a thermally dimorphic fungus that causes substantial morbidity and mortality in Southeast Asia, evades the human immune system. Polarization of macrophages into fungal-inhibiting M1-like and fungal-promoting M2-like types has been shown to play an important role in the innate immune response against fungal pathogens. This mechanism has not been defined for T. marneffei. Here, we demonstrated that T. marneffeipromotes its survival in human macrophages by inducing them toward M2-like polarization. Our investigations of the mechanism revealed that T. marneffeiinfection led to SOCS3 protein degradation by inducing tyrosine phosphorylation, thereby relieving the inhibitory effect of SOCS3 on p-STAT6, a key factor for M2-like polarization. Our SOCS3-overexpression experiments showed that SOCS3 is a positive regulator of M1-like polarization and plays an important role in limiting M2-like polarization. Furthermore, we found that inhibition of the TLR9 pathway partially blocked T. marneffei-induced M2-like polarization and significantly enhanced the killing activity of macrophages against T. marneffei. Collectively, these results reveal a novel mechanism by which T. marneffeievades the immune response of human macrophages.

China has become an emerging destination for international migration, especially in some Association of South East Asian Nations countries, but the situation of migrants seeking medical care in China remains unclear. A retrospective cross-sectional study was conducted in a hospital in Chongzuo, which provides medical services for foreigners, to investigate the situation of Vietnamese people seeking health care in Guangxi, China. Vietnamese patients who visited the hospital between 2018 and 2020 were included in the study. Demographic characteristics, clinical characteristics, characteristics of payment for medical costs, and characteristics of hospitalization were compared between outpatients and inpatients. In total, 778 Vietnamese outpatients and 173 inpatients were included in this study. The percentages of female outpatients and inpatients were 93.44% and 88.44% (χ2= 5.133, P = .023), respectively. Approximately 30% of outpatients and 47% of inpatients visited the hospital due to obstetric needs. The proportions of outpatients with basic medical insurance for urban residents, basic medical insurance for urban employees, and new cooperative medical schemes were 28.02%, 3.21%, and 2.31%, respectively. In comparison, the proportion of inpatients with the above 3 types of medical insurance was 16.76%, 1.73%, and 2.31%, respectively. The proportion of different payments for medical costs between outpatients and inpatients were significantly different (χ2= 24.404, P < .01). Middle-aged Vietnamese females in Guangxi, China, may have much greater healthcare needs. Their main medical demand is for obstetric services. Measurements should be taken to improve the health services targeting Vietnamese female, but the legitimacy of Vietnamese in Guangxi is a major prerequisite for them to access more and better healthcare services.