Pathogenesis of Mumps Virus

描述（由申请人提供）：腮腺炎病毒引起人类急性感染，约10%的感染导致无菌性脑膜炎。虽然已知几种腮腺炎病毒的基因组序列，但腮腺炎病毒发病机制的分子基础尚不清楚。本研究的长期目标是了解病毒如何克服宿主防御机制，特别是病毒蛋白如何在组织培养细胞和动物的分子水平上克服宿主先天免疫。猿猴病毒5 （SV5）是一种与腮腺炎病毒密切相关的病毒，其小疏水蛋白（SH）在抑制肿瘤坏死因子(TNF)- α激活的凋亡通路中发挥重要作用，SH的缺失导致体内病毒的减毒。假设病毒感染细胞对细胞凋亡的抑制有助于病毒的发病机制，腮腺炎病毒小疏水蛋白（SH）在抑制病毒感染细胞（如SV5的SH）的细胞死亡中起重要作用，尽管这两种SH蛋白没有序列同源性。为了验证这些假设，(1)将建立一个从临床分离物的cDNA中获得传染性腮腺炎病毒的反向遗传系统，(2)将产生缺乏SH基因的腮腺炎病毒（rMuVdeltaSH），(3)在组织培养细胞和大鼠模型系统中与其亲本腮腺炎病毒进行比较。自2001年加入宾夕法尼亚州立大学担任病毒学终身助理教授以来，我们已经确定了导致缺乏SH的SV5 （rSV5deltaSH）或缺乏V的保守c -末端的SV5 （rSVSVdeltaC）感染细胞凋亡的途径。我希望建立一个研究项目，了解流行性腮腺炎病毒的致病性与单个流行性腮腺炎病毒蛋白的功能之间的关系。本应用程序中提出的工作建立在我们目前对副粘病毒SV5 SH功能的工作基础上，将我们目前的工作从SV5 SH扩展到腮腺炎病毒SH，并将我们对病毒蛋白在组织培养系统中的功能的关注重新定向到动物模型系统以及组织培养细胞中的功能。

DESCRIPTION (provided by applicant): Mumps virus causes acute infections in humans and about 10% of infection leads to aseptic meningitis. Although several mumps virus genome sequences are known, molecular bases of mumps virus pathogenesis are not clear. Long-term goal of this proposal is to understand how virus overcomes host defense mechanisms, especially how viral proteins overcome host innate immunity at molecular levels in tissue culture cells as well as in animals. The small hydrophobic protein (SH) of simian virus 5 (SV5), a virus closely related to mumps virus, plays an important role in inhibiting tumor necrosis factor (TNF)-alpha activated apoptotic pathway and the deletion of SH results in an attenuated virus in vivo. It is hypothesized that inhibition of apoptosis by virus-infected cells contributes to viral pathogenesis and mumps virus small hydrophobic protein (SH) plays essential roles in inhibition of cell death in virus-infected cells like SH of SV5 even though both SH proteins have no sequence homologies. To test these hypothesis, (1) a reverse genetics system in which infectious mumps virus from cDNA of a clinical isolate will be obtained will be established, (2) mumps virus lacking SH gene (rMuVdeltaSH) will be generated and (3) compared with its parental mumps virus in tissue culture cells and in a rat model system. Since my joining Penn State University in 2001 as a tenure-track assistant professor of virology, we have identified pathways leading to apoptosis in SV5 lacking SH (rSV5deltaSH) or in SV5 lacking the conserved C-terminus of V (rSVSVdeltaC)- infected cells. I hope to establish a research program in understanding the relationship between pathogenicity of mumps virus and functions of individual mumps virus proteins. The proposed work in this application builds on our current work on paramyxovirus SV5 SH function, expands our current work from SV5 SH to mumps virus SH and redirects our focus on functions of viral proteins in tissue culture system to that in an animal model system as well as in tissue culture cells.