从TLR7对巨噬细胞的调控探讨侵袭性肺曲霉病的发病机制及治疗

侵袭性肺曲霉病（IPA）预后差，死亡率高，是医学界亟待解决的难题之一。曲霉菌与宿主相互作用对IPA的发病起着关键作用，但机制不清。预实验发现：在IPA动物模型中，TLR7与现有报道的TLRs作用可能不同，TLR7基因缺陷小鼠肺部清除曲霉菌的能力显著增强，死亡率明显降低。进一步研究显示：TLR7表达缺失下，巨噬细胞吞噬杀伤曲霉菌的能力显著增强。鉴于巨噬细胞是宿主抗曲霉菌感染的关键免疫效应细胞，因此提出“曲霉菌侵入肺脏时，TLR7通过抑制巨噬细胞的吞噬杀菌功能，破坏肺脏区域免疫稳态，降低宿主对曲霉菌的清除，促进IPA的发病”的科学假说。本项目拟体内揭示“TLR7介导巨噬细胞抗曲霉菌功能下调”在IPA发病中的作用，体外阐明“TLR7介导巨噬细胞抗曲霉菌功能下调”的细胞内信号调控分子，最后用临床IPA患者病例探讨TLR7表达及其基因多态性与IPA发病的相关性，为IPA的防治提供新思路。

Invasive pulmonary aspergillosis is a life-threatening disease with poor prognosis, which is one of the greatest challenges in clinical medicine. The interaction between Aspergillus and host has been considered to play an essential role in the pathogenesis of IPA. However, its molecular mechanisms remain to be elucidated. Our previous work has demonstrated that the functions of TLR7 were not similar with other TLRs as reported in the animal model of IPA. As compared to wild-type (WT) mice, TLR7–deficient mice developed less severe infection when challenged with A. fumigatus conidia, as evidenced by the decreased fungal colonization and the increased survival. Furthermore, the anti- aspergillosis activity of TLR7-deficient alveolar macrophages was significantly enhanced when compared to WT macrophages. Therefore, we hypothesized that “TLR7 regulates immune dysfunction of macrophages during IPA, which disrupts immune homestasis in the lung and promotes MRSA escape from macrophage-mediated phagocytosis and conidiocidal activity, leading to the development of IPA”. This project will study the role of TLR7-mediated dysfunction of macrophages in the development of IPA in vivo and its intracellular signaling molecules in vitro, and analyze the association of TLR7 expression and TLR7 gene polymorphisms with disease severity in IPA patients. Our work will provide new strategies for the treatment of IPA.