Immunopathology of pulmonary orthopox infections

人类感染天花病毒的主要途径是通过肺部，但对正痘病毒与肺部的相互作用知之甚少。该项目的重点是确定牛痘病毒（一种啮齿动物正痘病毒）在对该病毒表现出不同程度易感性的小鼠品系中引起的肺免疫病理的性质。该系统将被用作正痘病毒肺部感染的模型。在这项研究中，我们将描述病毒在肺部复制的位点和动力学；宿主对感染的反应类型；以及病毒免疫调节辅助蛋白在肺部病毒复制和病毒发病机制中的意义。具体来说，这个项目将：目标1。确定牛痘病毒与驻留肺细胞包括上皮细胞、肺泡巨噬细胞（AM）和树突状细胞（DCs）的相互作用。

The primary route of variola virus in infection in humans is via the lungs, yet remarkably little is known about orthopoxvirus-lung interactions. The focus of this project is to determine the nature of pulmonary immunopathology induced by cowpox virus, a rodent orthopoxvirus, in strains of mice that exhibit various levels of susceptibility to this virus. This system will be used as a model of orthopoxvirus-lung infections. In this study, we will characterize the sites and kinetics of viral replication in the lungs; the types of host responses to infection; and the significance of viral immunomodulatory accessory proteins for viral replication and viral pathogenesis in the lungs. Specifically this project will: Aim 1. Define the interaction of cowpox virus with resident lung cells including epithelial cells, alveolar macrophages (AM) and dendritic cells (DCs) in vitro.. Aim 2. Determine the cellular and cytokine response elicited to pulmonary cowpox in resistant and susceptible strains of mice in vivo. Aim 3. Determine the roles of cowpox virus proteins in viral replication, host immune responses, and pulmonary immunopathology in the mouse. Our determination of the host responses to virus infection will indicate which responses are important for effective protection against viral infection, and which responses may contribute to the pathogenesis. We hypothesize that whilst most host responses are likely to be beneficial to the host, abnormal types of response, such as inappropriate Th1/Th2 responses or unusual cytokine responses may be major factors in poxvirus-induced disease. Therefore, this study will be valuable in several important health-related areas including: the identification of molecular mechanisms of orthopoxvirus pathogenesis; the development of therapeutics targeting either viral proteins or host responses contributing to symptoms of disease; and the identification of ways to both attenuate vaccinia virus vaccines and increase the immunogenicity of these vaccines.