肠道病毒71型（EV71）诱导线粒体自噬的分子机制研究

Hand foot and mouth disease (HFMD) has been posed a heavy threat to children’s health and social stability in China in the past few years. Enterovirus 71(EV71) is the major causative pathogen of HFMD and is responsible for most severe and death cases of HFMD. However, the specific antiviral medicine against EV71 is unavailable to date. The uncertain pathogenesis is the major obstacle that restricted the development of effective antiviral medicine. It has been reported that EV71 could induce autophagy in infected cells and this process has been regarded as a factor of viral pathogenesis. Previously, we had reported EV71 infection could cause mitochondrial morphological and functional abnormality and we speculated the life cycle of EV71 is associated with cellular mitochondrion. The latest research showed that HBV and HCV could cause mitochondrial damage and induce mitophagy that contributed to viral pathogenesis in infected cells. Our preliminary data have shown that EV71 infection could also cause mitophagy and the mechanism way different from that of HCV and HBV. On these bases, we will hence further define the characteristics of EV71 induced mitophagy and clarify the specific mechanisms through comprehensive study of all possible pathways. The results would be helpful to further understanding of the EV71 pathogenesis and could provide theoretical basis for the design and development of antiviral therapy.

手足口病严重威胁着婴幼儿健康和社会稳定。特异性抗病毒药物的缺乏严重影响了该病的防治，而发病机制不清是制约抗病毒药物研发的主要因素。EV71是引起手足口病的重要病原体，其感染细胞后可以引起细胞自噬且该过程被证明和其致病性相关。本课题组在前期研究中首次提出了线粒体可能参与EV71在细胞内的复制，而最近的研究也表明，乙型和丙型肝炎病毒（HBV and HCV）可以通过损伤的线粒体诱导线粒体自噬参与病毒的致病机理。因此，本课题拟对EV71诱导的线粒体自噬进行深入研究，初步实验结果显示EV71可以诱导细胞发生线粒体自噬，且其发生机制可能不同于已经报道的HBV和HCV。在此基础上，本课题将进一步明确EV71诱导线粒体自噬的特点，并通过对多种可能机制进行全面检测而最终明确EV71诱导线粒体自噬的分子机制，为进一步阐明EV71的致病机理及设计和研发有效抗病毒药物提供理论依据。

手足口病严重威胁着婴幼儿健康和社会稳定。特异性抗病毒药物的缺乏严重影响了该病的防治，而发病机制不清是制约抗病毒药物研发的主要因素。EV71是引起手足口病的重要病原体，其感染细胞后可以引起细胞自噬且该过程被证明和其致病性相关。本课题组在前期研究中首次提出了线粒体可能参与EV71在细胞内的复制，而其它文献也报道EV71可以诱导细胞内的内质网应激。因此，本课题对EV71导致的线粒体和内质网改变进行了研究。研究结果发现EV71可以诱导非PINK1-Parkin依赖的线粒体自噬，并明确了EV71不依赖PINK1诱导线粒体自噬的分子机制在于其编码的2A蛋白酶可以有效抑制PINK1在线粒体上的聚集。EV71诱导的线粒体自噬具有完整的自噬流，其不依赖于宿主蛋白而是依靠病毒自身编码的蛋白作为线粒体自噬的受体。对EV71感染细胞中内质网的研究发现EV71可以抑制宿主细胞内质网相关的降解途径（endoplasmic reticulum-associated degradation, ERAD）,导致多种ERAD底物在内质网腔内的聚集。EV71通过其编码的病毒蛋白酶2A和3C以不同机制作用于ERAD的不同靶分子而抑制ERAD途径。其中，3C蛋白可作用于ERAD途径中关键的E2泛素偶联酶Ubc6e并多位点切割Ubc6e； EV71 2A蛋白酶则在蛋白翻译水平抑制ERAD关键分子Herp和VIMP的表达。研究还进一步发现EV71可挟持ERAD途径的关键分子p97进行自身复制，该分子和病毒蛋白2C共定位于细胞浆中的病毒复制复合体。上述研究揭示了EV71对宿主细胞线粒体自噬和ERAD途径的调控机制，进一步丰富了病毒与宿主细胞蛋白质质量控制系统相互调控的认识，发现了新的潜在的抗EV71感染靶点，也进一步丰富了对EV71的致病机制的了解。

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