Immunopathology of pulmonary orthopox infections

肺部正痘感染的免疫病理学

• 批准号: 6857533
• 负责人: David J Pickup
• 金额: $ 39.74万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6857533
• 关键词: Poxviridae; alveolar macrophages; bioterrorism /chemical warfare; cytokine; dendritic cells; disease /disorder model; genetic susceptibility; host organism interaction; laboratory mouse; lymphocyte; microorganism immunology; respiratory epithelium; respiratory infections; virus infection mechanism; virus protein; virus replication

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.

天花病毒感染人类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。本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诱导的肺免疫病理学的性质。该系统将用作正痘病毒-肺感染的模型。在这项研究中，我们将表征的网站和动力学的病毒复制在肺中的宿主对感染的反应的类型;和病毒的免疫调节辅助蛋白的病毒复制和病毒的发病机制在肺中的意义。具体而言，该项目将：目标1。明确牛痘病毒与肺上皮细胞、肺泡巨噬细胞（AM）和树突状细胞（DCs）的体外相互作用。 目标2.测定体内抗和易感小鼠品系对肺牛痘引起的细胞和细胞因子反应。目标3.确定牛痘病毒蛋白在病毒复制、宿主免疫反应和小鼠肺免疫病理学中的作用。 我们确定的宿主对病毒感染的反应将表明哪些反应是重要的有效保护免受病毒感染，哪些反应可能有助于发病机制。我们假设，虽然大多数主机的反应可能是有益的主机，异常类型的反应，如不适当的Th 1/Th 2反应或不寻常的细胞因子反应可能是痘病毒引起的疾病的主要因素。因此，本研究将在几个重要的健康相关领域具有价值，包括：鉴定正痘病毒发病机制的分子机制;开发靶向病毒蛋白或导致疾病症状的宿主反应的治疗剂;以及鉴定减毒牛痘病毒疫苗并增加其免疫原性的方法。 疫苗。