EV71诱导宿主细胞形成应激颗粒样结构的分子机制研究

发布时间：2018-01-16 18:03

本文关键词：EV71诱导宿主细胞形成应激颗粒样结构的分子机制研究　出处：《北京协和医学院》2016年硕士论文　论文类型：学位论文

【摘要】：肠道病毒71型(EV71)是引起手足口病的重要病原体,其引起的手足口病常伴有中枢神经系统并发症,严重时可造成永久性瘫痪或死亡。近年来,手足口病的发病数和死亡数在我国呈大幅上升趋势,该病的流行已成为影响我国社会安全和稳定的重要因素,是我国迫切需要解决的公共卫生问题。目前,手足口病的治疗仍缺乏特异性抗病毒药物,EV71致病机制不清是其主要制约因素,EV71的致病机制仍需要深入研究。细胞应激颗粒(stress granule, SG)是宿主细胞防御体系的重要组成部分,其形成在抗病毒感染中起着重要的作用。已有多种病毒被报道可通过不同方式诱导并调控SG的形成,提示SG和宿主细胞的相互调控可能和病毒的致病性相关,但目前EV71诱导SG形成的分子机制及其与宿主细胞的相互调控关系还不清楚。本研究对EV71感染细胞中SG的形成情况及其与宿主细胞的相互调控关系进行了深入的研究。通过多色免疫荧光检测SG的各类组分在EV71感染细胞中的分布情况,我们发现EV71可以抑制经典SG的形成而诱导细胞形成一种组成成分和形态上都区别于经典SG的新的RNA颗粒,我们称之为“SG样结构”。进一步的研究发现,EV71诱导SG样结构的形成依赖于PKR和eIF2a磷酸化途径,且需要宿主细胞mRNA的持续合成。通过抑制EV71诱导的SG样结构形成,我们发现SG样结构是一种具有抗病毒功能的颗粒,可促进EV71诱导到的宿主细胞凋亡,并且可以抑制EV71在宿主细胞内的扩增。综上所述,本研究初步阐述了EV71诱导SG样结构形成的分子机制及其对宿主细胞和病毒自身的影响,为进一步研究病毒宿主相互作用及EV71的致病机制提供了新的线索。
[Abstract]:Enterovirus 71 (EV71) is an important pathogen of hand, foot and mouth disease (HFMD), which is often accompanied by central nervous system complications, and can lead to permanent paralysis or death in recent years. The incidence and mortality of HFMD in China is increasing significantly. The prevalence of HFMD has become an important factor affecting the social security and stability of our country, and it is an urgent public health problem to be solved in our country. The lack of specific antiviral drug EV71 in the treatment of hand-foot-mouth disease is the main limiting factor. The pathogenesis of EV71 still needs to be further studied. The cellular stress granule (SGG) is an important part of the host cell defense system. It has been reported that many viruses can induce and regulate the formation of SG in different ways. These results suggest that the interaction between SG and host cells may be related to the pathogenicity of the virus. However, the molecular mechanism of SG formation induced by EV71 and its interaction with host cells are not clear. This study is concerned with the formation of SG in EV71 infected cells and the interaction between SG and host cells. Polychromatic immunofluorescence was used to detect the distribution of SG components in EV71 infected cells. We found that EV71 can inhibit the formation of classical SG and induce cell to form a new RNA particle which is different from the classical SG in composition and morphology. We call it "SG like structure". Further study shows that the formation of SG like structure induced by EV71 depends on the phosphorylation pathway of PKR and eIF2a. By inhibiting the formation of SG-like structure induced by EV71 we found that SG-like structure is a kind of antiviral particles. It can promote the apoptosis of host cells induced by EV71 and inhibit the expansion of EV71 in host cells. In this study, the molecular mechanism of SG-like structure formation induced by EV71 and its effect on host cells and virus itself were discussed. It provides a new clue for the further study of virus host interaction and the pathogenesis of EV71.
【学位授予单位】：北京协和医学院
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R512.5

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