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

项目总结（见说明）： 在自然病毒感染过程中，小剂量的感染性病毒沉积在外周感染部位，然后是“竞赛”，其中复制病毒试图“超越”宿主的免疫系统。 在感染的早期阶段，先天免疫系统必须在适应性反应发展之前控制感染。在项目1中，我们将研究先天免疫系统用于控制鼠痘感染的机制，鼠痘是一种由鼠痘病毒（ECTV）引起的致命性小鼠疾病，ECTV是一种唯一的小鼠病原体。这个系统是独一无二的，因为它使我们能够检查易感和耐药小鼠品系的先天反应。三个特定目的将检查在感染部位减缓ECTV全身传播所需的细胞， 介导它们迁移到感染部位以及在病毒-细胞相互作用期间由病毒和免疫系统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感染部位的细胞浸润，并确定减缓ECTV全身传播所需的先天免疫效应细胞类型，并允许发展可以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子功能，以延缓ECTV感染。在目标2中，我们将确定在抗性或易感小鼠中ECTV感染部位表达的趋化因子和趋化因子受体，以及在ECTV感染部位表达的趋化因子受体。 趋化因子是吸引先天效应细胞所必需的，这些细胞减缓病毒的复制和传播。 我们还将研究ECTV编码的细胞迁移的免疫调节剂在对病毒的先天反应中的作用，并将确定这些基因在体内的靶点。在目标3中，我们将研究ECTV和先天性免疫细胞在体外的相互作用，主要集中在巨胞饮，这是最近被描述为正痘病毒的感染模式。巨胞饮在细胞外溶质的采样启动适应性免疫反应中起着重要作用，我们将研究其对环境采样的贡献，以启动先天性反应。我们还将研究TLR 9向巨胞饮体的运输，TLR 9是一种先天性受体， ECTV激发。该项目的结果将提供对外周病毒感染的先天反应的全面了解。

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.