MECHANISMS OF MOUSE HEPATITIS VIRUS HOST RANGE EXPANSION

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 模型小鼠肝炎病毒(MHV)依赖于其刺突蛋白与靶细胞结合。一旦结合，Spike引导随后的病毒-细胞膜融合，从而导致进入并通过延伸调节宿主范围。Spike蛋白表现出I类融合蛋白的特征，类似于流感的融合蛋白。以前对MHV和其他I类病毒的研究已经证明，保守的七肽重复区域(对融合过程至关重要的区域)及其附近的突变可以导致宿主范围的改变。假说是，Spike蛋白在融合机制中有一个固有的“松弛”，可能在某些选择性环境下暴露，导致宿主范围改变。这个项目有两个目标。第一个是检测以前分离的MHV宿主范围突变株的Spike蛋白的生化特性。第二项研究将研究当使用一种融合抑制肽(类似于药物Fuzeon)对七肽重复序列施加选择性压力时，如果有任何突变会导致什么结果。通过将这些研究结合起来，应该可以更清楚地了解MHV如何跨越物种障碍，并可能扩展到其他I类病毒。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The model coronavirus Mouse Hepatitis Virus (MHV) is dependent upon its Spike protein for target cell binding. Once bound, Spike directs subsequent virus-cell membrane fusion thus leading to entry and by extension regulating host range. Spike protein displays the features of a Class I fusion protein, similar to the fusion proteins of Influenza. Prior research with MHV and other Class I viruses has demonstrated that mutations in and adjacent to conserved heptad repeat regions (regions vital to the fusion process) can lead to altered host range. The hypothesis is that the Spike protein has an inherent "slack" in the fusion mechanism that may be exposed under certain selective environments leading to altered host range. This project has two goals. The first is to examine the biochemical properties of Spike proteins from previously isolated MHV host range mutants. The second will examine what, if any, mutations result when selective pressure is applied to the heptad repeats using a fusion inhibiting peptide, similar to the drug Fuzeon. By combining these studies, a clearer picture of how MHV can cross the species barrier should be developed and possibly extended to other Class I viruses.