隐球菌转录因子Zap103通过抑制过氧化物酶调控其巨噬细胞胞内生存与播散感染的机制研究

隐球菌感染导致的皮肤隐球菌病、隐球菌肺炎和隐球菌性脑膜炎暂无有效治疗手段，预后差、死亡率高。巨噬细胞是抵御隐球菌感染的第一道屏障，但隐球菌强大的胞内生存力可介导其逃避巨噬细胞杀伤作用。申请人前期发现转录因子Zap103可抑制隐球菌毒力和致病性，全转录组测序和KEGG分析提示Zap103可能负向调控过氧化物酶体介导的氧化应激耐受，细胞实验发现过氧化氢酶缺失可回复ZAP103缺失菌株的氧化应激敏感性，因此推测Zap103可能通过抑制隐球菌过氧化物酶体生成，继而调控其巨噬细胞胞内生存与宿主体内免疫逃逸。为证实以上假说，本研究拟通过动物和细胞模型探讨ZAP103基因缺失对隐球菌巨噬细胞胞内生存和致病能力的影响；体外实验明确ZAP103在隐球菌过氧化物酶体形成中的作用；最后探讨Zap103介导过氧化物酶体形成在隐球菌免疫逃逸中的功能，以加深对隐球菌致病机制理解，为隐球菌感染治疗药物开发提供新的切入点

Cutaneous Cryptococcosis, Cryptococcal pneumonia and meningoencephalitis have a poor prognosis and a high mortality rate, and there is no effective treatment. Macrophages are a first-line barrier against cryptococcal infection, however, the strong intracellular viability of C. neoformans can mediate its ability to escape macrophage killing. Our previous work found that the transcription factor Zap103 can inhibit the virulence and pathogenicity of C. neoformans. Transcriptomic sequencing and KEGG analysis found that Zap103 may negatively regulate peroxisome-mediated oxidative stress tolerance, and cell experiments showed catalase deficiency could restore the effect of Zap103 deletion on oxidative stress tolerance in C. neoformans. Therefore, we speculated that Zap103 might inhibit cryptococcal peroxisome production and thus regulate its intracellular survival inside macrophages and immune escape in vivo. The effects of ZAP103 gene knockout on the intracellular survival and pathogenicity of C. neoformans were explored in animal and cell models, and the role of ZAP103 in the formation and function of cryptococcal peroxisomes was clarified via in vitro experiments. Finally, the function of Zap103-mediated peroxisome formation in cryptococcal immune escape was explored. Our work will further deepen the understanding of the pathogenic mechanism of C. neoformans, and provide a new direction for developing novel therapeutic drugs against cryptococcosis.