表皮生长因子受体（EGFR）调控烟曲霉内化侵入肺泡上皮细胞的作用及机制研究

Although the internalization of Aspergillus fumigatus into alveolar epithelial cell is an important step in the pulmonary infection, the specific regulatory mechanism is unclear. EGFR is a transmembrane protein, which widely distributes on epithelial cells. Activated EGFR stimulates various signaling cascades that regulate multiple cell functions including cytoskeleton reorganization. It is reported that EGFR was involved in the invasion of many pathogenic microorganisms into host cells, such as herpes simplex virus-1 and cytomegalovirus ect.. Our previous study confirmed that cofilin modulated the internalization of A. fumigatus into alveolar epithelial cells by regulating the cytoskeleton reorganization. And this process was controlled by ROCK-LIMK signal pathway, which were activated by EGFR. Therefore, on the basis of these results, we will discuss the expression, distribution changes of EGFR during A. fumigatus internalization into alveolar epithelial cells in vivo and in vitro, respectively. And then we will further analyze the signal pathway. These will help us to extend our knowledge about the role of EGFR in A. fumigatus internalization into alveolar epithelial cells, and will be of great importance in further clarifying the pathogenesis of invasive aspergillosis and looking for potential drug targets.

烟曲霉诱发细胞形态改变从而内化侵入肺泡上皮细胞是其引起肺部感染的关键步骤之一，但具体调控机制尚不清楚。表皮生长因子受体（EGFR）是广泛分布于上皮细胞的一类跨膜糖蛋白，通过激活其下游激酶级联反应从而调节细胞肌动蛋白骨架重排，参与调控多种病原微生物侵袭宿主细胞。我们前期研究发现肺泡上皮细胞cofilin通过磷酸变化调节肌动蛋白骨架重排，从而介导烟曲霉膨胀孢子的内化侵入，这一过程受其上游ROCK-LIMK激酶活性的调控，而ROCK-LIMK属于EGFR下游激酶的一部分。因此本研究拟在此基础上，从体内外实验中探讨细胞EGFR在烟曲霉内化侵入肺泡上皮细胞过程中的作用，并解析该作用是否由EGFR-PI3K-Erk-ROCK-LIMK-cofilin信号通路介导。项目的完成有利于拓展人们对细胞EGFR在烟曲霉内化侵入肺泡上皮细胞过程中作用的认识，为寻找针对宿主因素的抗真菌药物靶点提供一定的理论基础。

烟曲霉诱发细胞形态改变从而内化侵入肺泡上皮细胞是其引起肺部感染的关键步骤之一，但具体调控机制尚不清楚。表皮生长因子受体（EGFR）是广泛分布于上皮细胞的一类跨膜糖蛋白，通过激活其下游激酶级联反应从而调节细胞肌动蛋白骨架重排，参与调控多种病原微生物侵袭宿主细胞。我们前期研究发现肺泡上皮细胞cofilin通过磷酸变化调节肌动蛋白骨架重排，从而介导烟曲霉膨胀孢子的内化侵入，这一过程受其上游ROCK-LIMK激酶活性的调控，而ROCK-LIMK属于EGFR下游激酶的一部分。因此本研究拟在此基础上，从体内外实验中探讨细胞EGFR在烟曲霉内化侵入肺泡上皮细胞过程中的作用。研究结果显示烟曲霉膨胀孢子内化侵入肺泡上皮细胞过程中由EGFR介导，并通过激活下游Erk-ROCK-LIMK-cofilin发挥作用，抑制EGFR活性可减少烟曲霉膨胀孢子对肺泡上皮细胞的内化侵入，从而有利于巨噬细胞的吞噬并起到防治作用。