The innate Immune Response to Mousepox at the Site - Associated Project

现场对鼠痘的先天免疫反应 - 相关项目

• 批准号: 7982868
• 负责人: CYNTHIA A LEIFER
• 金额: $ 6.23万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7982868
• 关键词: Actins; Animals; Antigen Presentation; Antiviral Agents; Binding Proteins; Biological; Categories; Cells; Cellular Infiltration; Cessation of life; Chemotactic Factors; Chickenpox; Clathrin; Complex; Deposition; Development; Disease; Dose; Effector Cell; Enterovirus; Environment; Flavivirus; Foot-and-Mouth Disease; Gene Targeting; Genetic Models; Goals; Growth; Health; Human; Immigration; Immune; Immune response; Immune system; Immunity; In Vitro; Inbred BALB C Mice; Infection; Infectious Ectromelia; Infiltration; Instruction; Leucocytic infiltrate; Leukocytes; Measles; Mediating; Molecular; Morbillivirus; Mouse Pox Virus; Mouse Strains; Mumps; Mus; Natural Immunity; Nitrogen; Orthopoxvirus; Oxygen; Pathway interactions; Peripheral; Phase; Phenotype; Play; Poliomyelitis; Population; Poxviridae Infections; Process; Proteins; Race; Research; Resistance; Rest; Role; Rubella; Rubivirus; Rubulavirus; Sampling; Signal Transduction; Site; Skin; System; Time; Vaccinia virus; Viral; Virus; Virus Diseases; Virus Replication; Virus-Cell Membrane Interaction; West Nile virus; Yellow Fever; cell motility; cell type; chemokine; chemokine receptor; cytokine; extracellular; falls; in vivo; insight; migration; mutant; pathogen; polymerization; prevent; programs; receptor; response; sensor; solute; trafficking; virus pathogenesis

PROJECT SUMMARY (See instructions): During a natural virus infection small doses of infectious virus are deposited at a peripheral infection site and then a "race" ensues, in which the replicating virus attempts to "outpace" the host's immune system. In the early phases of infection, the innate immune system must contain the infection prior to the development of an adaptive response. In Project 1 we will examine the mechanisms that are used by the innate immune system to contain infection with mousepox, a lethal mouse disease caused by ectromelia virus (ECTV), an exclusive mouse pathogen. This system is unique because it allows us to examine the innate response in susceptible and resistant mouse strains. The three Specific Aims will examine the cells that are required to slow the systemic spread of ECTV at the site of infection, the chemoattractants that mediate their migration to the site of infection and the cell biological mechanisms that are used by both the virus and the immune system during virus-cell interaction. In Aim 1 we will characterize the cellular infiltrate to the site of ECTV infection in resistant or susceptible mice and identify the innate immune effector cell types that are required to slow the systemic spread of ECTV and allow the development of an adaptive response that can clear the infection. In this aim we will also examine the effector functions that are required by innate immune cells to retard ECTV infection. In Aim 2 we will determine the chemokines and chemokine receptors expressed at the site of ECTV infection in resistant or susceptible mice, and the chemokines that are essential to attract innate effector cells that slow replication and spread of the virus. We will also study the role of immune modifiers of cellular migration encoded by ECTV in the innate response to the virus, and will identify the targets of these genes in vivo. In Aim 3 we will study the interaction of ECTV and innate immune cells in vitro, focusing primarily upon macropinocytosis, which has recently been described as the mode of infection of orthopoxviruses. Macropinocytosis has an important role in the sampling of extracellular solute for initiation of an adaptive immune response and we will examine its contribution to sampling of the environment for initiation of an innate response. We will also examine the trafficking to macropinosomes of TLR9;,an innate receptor that is required for survival from ECTV challenge. The results from this Project will provide a comprehensive picture of the innate response to a peripheral virus infection.

项目摘要（请参阅说明）： 在天然病毒感染期间，小剂量的感染性病毒沉积在外围感染部位，然后随后发生“种族”，其中复制病毒试图“超过”宿主的免疫系统。 在感染的早期阶段，先天免疫系统必须在自适应反应发展之前包含感染。在项目1中，我们将研究先天免疫系统使用的机制，该机制含有莫斯波克（Mousepox）感染，这是一种由Ectromelia病毒（ECTV）引起的致命小鼠疾病，一种是一种独特的小鼠病原体。该系统是独一无二的，因为它使我们能够检查易感和抗性小鼠菌株中的先天反应。这三个特定目的将检查降低ECTV在感染部位的全身传播所需的细胞，即趋化因子 介导其迁移到感染部位以及病毒相互作用期间病毒和免疫系统使用的细胞生物学机制。在AIM 1中，我们将表征耐药或易感小鼠ECTV感染部位的细胞浸润，并确定降低ECTV系统性扩散并允许自适应反应的固有免疫效应细胞类型，并允许可以清除感染的适应性反应。在此目标中，我们还将检查先天免疫细胞延迟ECTV感染所需的效应子功能。在AIM 2中，我们将确定在耐药或易感小鼠中ECTV感染部位表达的趋化因子和趋化因子受体，以及 趋化因子对于吸引天生效应细胞的必不可少的因子，这些细胞会缓慢复制和传播病毒。 我们还将研究由ECTV在对病毒的先天反应中编码的细胞迁移的免疫修饰剂的作用，并将在体内识别这些基因的靶标。在AIM 3中，我们将在体外研究ECTV和先天免疫细胞的相互作用，主要集中于大胞刺病，最近已被描述为正蛋白的感染方式。大型细胞增多症在启动适应性免疫反应的细胞外溶质中具有重要作用，我们将研究其对启动先天反应的环境采样的贡献。我们还将检查TLR9的大斑点体的贩运； ECTV挑战。该项目的结果将为周围病毒感染的先天反应提供全面的了解。