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.

项目总结(见说明)： 在自然病毒感染期间，小剂量的传染性病毒沉积在外周感染部位，然后发生一场“竞赛”，在这场竞赛中，复制的病毒试图“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形成适应性反应之前遏制感染。在项目1中，我们将研究先天免疫系统用来遏制鼠痘感染的机制，鼠痘是一种由鼠痘病毒(ECTV)引起的致命小鼠疾病，ECTV是一种独有的老鼠病原体。这个系统是独一无二的，因为它允许我们检查敏感和耐药小鼠品系的先天反应。这三个特定的目标将检查在感染部位减缓ECTV系统性传播所需的细胞，化学诱导剂 调节它们向感染部位的迁移，以及病毒和免疫系统在病毒与细胞相互作用期间使用的细胞生物学机制。在目标1中，我们将描述耐药或易感小鼠中ECTV感染部位的细胞渗透特征，并确定减缓ECTV全身传播所需的先天免疫效应细胞类型，并允许发展出能够清除感染的适应性反应。在这个目标中，我们还将研究先天免疫细胞所需的效应器功能，以延缓ECTV感染。在目标2中，我们将测定耐药或易感小鼠ECTV感染部位表达的趋化因子和趋化因子受体，以及 趋化因子是吸引先天效应细胞所必需的，这些细胞可以减缓病毒的复制和传播。 我们还将研究ECTV编码的细胞迁移免疫调节剂在对病毒的先天反应中的作用，并将在体内确定这些基因的靶点。在目标3中，我们将研究ECTV和天然免疫细胞在体外的相互作用，主要集中在巨噬细胞吞噬，这是最近被描述为正痘病毒的感染方式。巨噬细胞吞噬作用在启动适应性免疫反应的细胞外溶质采样中起着重要作用，我们将检查它对启动先天免疫反应的环境采样的贡献。我们还将研究TLR9；这是一种生存所需的先天受体，它被转运到大胞体。 ECTV挑战赛。该项目的结果将提供对外周病毒感染的先天反应的全面图景。