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Pathogenesis of spongiform encephalopathy induced by viral infection

病毒感染所致海绵状脑病的发病机制

基本信息

批准号：
22590368
负责人：
WATANABE Rihito
金额：
$ 3万
依托单位：
Soka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2010
资助国家：
日本
起止时间：
2010 至 2012
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22590368/
关键词：
単球海綿状脳症初期病変ウイルス脳神経疾患感染症神経病理

项目摘要

Mouse hepatitis virus (MHV) is a member of the coronavirus family. Spike (S) protein, composed of virion projections, is responsible for binding to a receptor and also for the cell entry mechanism of MHV. Soluble receptor-resistant mutant 7 (srr7) isolated from the highly neuropathogenic JHM strain of MHV, cl-2, shows slightly reduced virulence compared to its maternal virus, inducing spongiotic degeneration at 48 hours post-inoculation (pi) with viral antigens-expression in the periventricular areas.During the course of infection with srr7, small spongiotic lesions appear at 2 days pi,and these spread out to form spongiform encephalopathy by 8 to 10 days pi. In thisstudy, we noted that the neurovirulence of srr7 increases with a shorter incubationperiod, and, in some cases, exhibits infectivity of neurons, similar to the observation incl-2 infection. Through the re-cloning of srr7, we obtained several mutants with singleor double substitutions of amino acids in the S protein rei on. All of these mutantviruses exhibited major MHV receptor (MHVR)-independent infectivity due to themutation of the S-coding region, which was examined by in vitro expression of thegenes. Each mutant virus showed different pattern of invasion into the brainparenchyma, provably due to the difference in the affinity to extracellular matrixemerged after the infection in the brain, which provides a new paradigm to elucidatethe mechanisms of spongiotic degeneration in the brain.

小鼠肝炎病毒（MHV）是冠状病毒家族的一员。刺突(S)蛋白由病毒粒子突起组成，负责与受体结合，也负责MHV的细胞进入机制。从高神经致病性MHV JHM株cl-2中分离出可溶性受体抗性突变体7 (srr7)，其毒力与其母株病毒相比略有降低，在接种后48小时（pi）诱导海绵状变性，病毒抗原在脑室周围表达。在srr7感染的过程中，在第2天出现小的海绵状病变，这些病变在第8至10天扩散形成海绵状脑病。在本研究中，我们注意到srr7的神经毒力随着孵育时间的缩短而增加，并且在某些情况下表现出神经元的感染性，类似于观察到的include -2感染。通过对srr7的再克隆，我们获得了多个S蛋白区氨基酸单或双替换的突变体。所有这些突变病毒都表现出主要的MHV受体（MHVR）不依赖于s编码区突变的感染性，这是通过基因的体外表达来检验的。每种突变病毒侵入脑实质的方式不同，这可能是由于感染后对脑内细胞外基质的亲和力不同，这为阐明脑海绵状变性的机制提供了新的范式。