烟曲霉钙信号蛋白Vac14影响宿主天然免疫的调控机制研究

侵袭性曲霉病（IA）是严重影响人类健康的真菌性疾病，在免疫缺陷的病人中具有极高的致病率和死亡率。烟曲霉是引起IA最主要的病原真菌。宿主通过免疫细胞表面的特异性模式识别受体（PPRs）识别烟曲霉的病原相关分子模式（PAMPs）引起免疫反应以清除病原菌，期间免疫细胞的数量及细胞因子的浓度至关重要。由于大量耐药菌株的出现及烟曲霉孢子的免疫惰性给临床治疗曲霉病带来巨大的困难。钙信号通路与烟曲霉的耐药性以及细胞壁PAMPs密切相关。新近研究发现一个全新的蛋白Vac14影响细胞内钙离子平衡及细胞壁PAMPs，而Vac14调控钙平衡机制及其对病原菌耐药性和宿主免疫反应的影响并不清楚。本项目拟对烟曲霉Vac14调控钙离子平衡机制展开研究，并探究Vac14及相关钙信号蛋白对曲霉耐药性和宿主免疫反应的影响。丰富和完善钙离子信号通路并为开发以钙离子为“佐剂”联合抗真菌药物治疗曲霉病的新策略提供理论基础。

Invasive aspergillosis (IA), one of the most important life-threatening fungal diseases, has high morbidity and mortality in immunocompromised individuals. Aspergillus fumigatus, a filamentous fungus, is the most common pathogen that causes IA. The interactions between A. fumigatus and the host environment are dynamic and complex. The host can recognize the pathogen-associated molecule patterns (PAMPs) of the pathogens by corresponding pattern recognition receptors (PRRs) on the immune cell surface, triggering an immune response to clear pathogens. The number of immune cells and cytokine concentrations are essential for the host to defense against pathogenic fungus during A. fumigatus infection. However, the emergence of extensively drug-resistant strains and immunological inertness of A. fumigatus conidia bring an obstruction to clinical treatment of aspergillosis. Numerous studies reported that a conserved calcium signaling pathway contributes to resistance to antifungal agents and associates with the biosynthesis of the cell wall PAMPs in filamentous fungi. Our previous study found a novel calcium signal-related protein, Vac14, involved in the calcium ions homeostasis in cytoplasm and vacuole, and the integrity of the cell wall. However, the underline mechanism of the relationship between Vac14 and other calcium-related proteins and the host’s innate immunity is still unclear. In this project, we aim to explore the roles of Vac14 in regulating calcium ions homeostasis to enrich the calcium signaling pathway; and investigating the roles of Vac14 in biosynthesis and organization of PAMPs and in the host innate immunity to provide an important theoretical basis for new treatment strategies for fungal diseases.