HPV11E7通过激活HTRA1介导的线粒体自噬抑制角质形成细胞免疫应答的机制研究

尖锐湿疣是低危型人类乳头瘤病毒(HPV)感染引起的性传播疾病。HPVE7蛋白通过破坏角质形成细胞的免疫平衡，导致病毒持续感染是尖锐湿疣难以治愈的重要原因，其关键机制尚未明确。最新研究显示线粒体自噬作为细胞选择性清除受损线粒体的现象是病毒抑制宿主免疫应答的关键环节。我们前期研究发现HPV11E7促进角质形成细胞中HTRA1基因的表达，进而激活PINK1/Parkin通路介导的线粒体自噬，抑制细胞I型干扰素分泌。本项目拟进一步通过免疫共沉淀、蛋白质谱、基因敲除小鼠模型等技术，深入阐述HPV11E7激活HTRA1介导的线粒体自噬在病毒免疫逃逸中的机制，包括明确HTRA1调控线粒体自噬的具体分子机制，检测HTRA1敲除小鼠上皮细胞中线粒体自噬相关基因及固有免疫相关因子表达情况，探究干预线粒体自噬对HPV感染细胞固有免疫相关因子分泌的影响等，为临床防治HPV感染相关疾病提供新的思路和理论依据。

Condyloma acuminata is one of the common sexually transmitted diseases caused by low-risk human papillomavirus (HPV) infection. Accumulating evidence suggests that HPV E7 protein can impair the immune system of keratinocytes, which is crucial for persistent infection of HPV and refractory of condyloma acuminatum. However, the underlying mechanisms are still poorly understood. The latest researches show that mitophagy is a sticking point for viruses to suppress the host immune response. In the preliminary experiment, we found HPV11E7 can promote the expression of HTRA1 in keratinocytes. The enhanced HTRA1 expression subsequently activated mitophagy mediated by the PINK1/Parkin pathway and inhibited the secretion of type I interferon. Based on our previous work, we further intend to evaluate the role of HPV11E7 activating mitophagy during viral immune escape including the mechanism of HTRA1 regulating mitophagy, the expression of mitophagy-related genes and innate immune factors in epithelial cells of HTRA1(-/-)mice, the effect of mitophagy inhibitor on secretion of innate immune factors in HPV-infected cells. Immunoprecipitation assay, protein profile assay and knockout mice will be used to confirm the results. Above all, this study will contribute to clarify the underlying mechanims and develop novel therapeutic approaches for HPV related diseases in the future.