Rhinovirus Pathogenesis and Host Range

描述(由申请人提供)：大约一半的普通感冒，其中之一 最常见的人类感染，是由人类鼻病毒引起的。这些 病毒是短小航行虫科的成员，这个家族由小的， 无包膜正链RNA病毒。鼻病毒的致病机制 对感染的了解很少，因为病毒只在较高的 灵长类动物。鼻病毒感染的小鼠模型将提供信息 关于鼻病毒致病机制和刺激抗病毒的鉴定 消炎药。我们建议分离鼻病毒变种，使其能够 在小鼠细胞中复制，确定导致宿主变化的突变 范围，并研究这些突变的作用机制。鼠标适配 鼻病毒将用于感染表达人ICAM-1的转基因小鼠， 主要人类鼻病毒的细胞受体。两个具体目标是 建议。目的1：确定鼻病毒宿主范围的分子基础。 已发现16型鼻病毒在表达该病毒的小鼠细胞中复制 选择病毒受体、人ICAM-1和复制的病毒变异体 在这些细胞中更有效，并导致广泛的细胞死亡。突变 这种寄主范围表型位于病毒非结构 多肽2B和2C。实验的设计是为了确定这些 突变通过确定它们对病毒RNA的影响来影响病毒复制 和蛋白质合成，以及它们对宿主细胞膜的影响。宿主细胞 将确定与2B和2C相互作用的蛋白质以确定 寄主范围突变的作用机制。目标2：开发转基因产品 小鼠鼻病毒感染模型。表达人细胞间黏附分子-1的转基因小鼠 在呼吸道中将会发展。人ICAM-1转基因小鼠将 感染16型鼻病毒和适应于小鼠的16型鼻病毒 表达人细胞间黏附分子-1的细胞研究鼻病毒的发病机制 感染，包括呼吸道内病毒复制的部位 肠道，宿主细胞损伤的程度，免疫的性质 免疫应答，以及免疫应答在发病机制中的作用。

DESCRIPTION (provided by applicant): About half of all common colds, one of the most frequent infections of humans, are caused by the human rhinoviruses. These viruses are members of the Picornaviridae, a family composed of small, non-enveloped positive strand RNA viruses. The pathogenesis of rhinovirus infection is poorly understood because the viruses replicate only in higher primates. A mouse model for rhinovirus infection would provide information about rhinovirus pathogenesis and stimulate the identification of antiviral and anti-inflammatory drugs. We propose to isolate rhinovirus variants that can replicate in mouse cells, identify mutations responsible for the change in host range, and study the mechanism of action of these mutations. Mouse-adapted rhinoviruses will be used to infect transgenic mice expressing human ICAM-1, the cellular receptor for major group human rhinoviruses. Two specific aims are proposed. Aim 1: Determine the molecular basis of rhinovirus host range. Rhinovirus type 16 has been found to replicate in mouse cells expressing the viral receptor, human ICAM-1, and a viral variant was selected that replicates more efficiently in these cells and causes extensive cell death. The mutations that confer this host range phenotype are located in viral nonstructural polypeptides 2B and 2C. Experiments are designed to determine how these mutations influence viral replication, by determining their effect on viral RNA and protein synthesis, and their effects on the host cell membranes. Host cell proteins that interact with 2B and 2C will be identified to determine the mechanism of action of the host range mutations. Aim 2: Develop a transgenic mouse model for rhinovirus infection. Transgenic mice that express human ICAM-1 in the respiratory tract will be developed. Human ICAM-1 transgenic mice will be infected with rhinovirus type 16 and rhinovirus type 16 adapted to mouse cells expressing human ICAM-1 to study the pathogenesis of rhinovirus infection, including the sites of virus replication within the respiratory tract, the extent of cell damage in the host, the nature of the immune response, and the role of the immune response in pathogenesis.