Immune Mechanisms That Control Ectromelia Virus Infection

控制Ectromelia病毒感染的免疫机制

• 批准号: 7680613
• 负责人: Luis J Sigal
• 金额: $ 193.58万
• 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/7680613
• 关键词: Immune; Mechanisms; Control; Ectromelia; Virus

DESCRIPTION (provided by applicant): Viruses and their hosts have co-evolved an intricate interplay that is delicately balanced during the course of infection. The value of exploring such a natural relationship, rather than the mismatched experimental systems that currently prevail, is becoming increasingly clear. This program will focus squarely upon ectromelia virus (ECTV), a genuine mouse pathogen with several attractive properties. First, routes of transmission are similar to those of other orthopoxviridae in their natural hosts. Second, mousepox disease is remarkably similar to that of human monkeypox and smallpox. Third, some mouse strains are resistant to ECTV while others are highly susceptible, analogous to natural variations within human populations. None of this is true for vaccinia virus (VACV), an orthopoxvirus of unknown origin, frequently used in mouse models of immunity, and made all the more suspect by preliminary results presented below. Headed by three PIs with extensive experience in host defense against poxviruses, the program will comprehensively dissect the interplay between ECTV and resistant/susceptible strains of mice, referencing to VACV when appropriate. Project 1 will examine the cells and cytokines of the innate system that play critical roles in keeping the virus in check at the site of infection. Project 2 continues inspection of innate/natural immunity by examining the mechanisms by which type 1 interferons limit spread of the virus beyond the draining lymph node. Finally, Projects 2 and 3 will investigate all three major arms of the adaptive immune system to understand how they defend against primary infection and establish protection from subsequent challenge. All three projects will examine strategies by ECTV to thwart these different levels of host defense. Administrative, Biological Reagent, and Imaging Core Components will provide a wide range of support to the program, with the latter two carrying out their own exploratory projects. Our goal with this hypothesis-driven, highly interactive program is to develop an understanding of virus-host relationships that provides a framework for many other natural virus infections. PROJECT 1: THE INNATE IMMUNE RESPONSE TO MOUSEPOX AT THE SITE OF INFECTION (Norbury, C) PROJECT 1 DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：病毒及其宿主共同进化出一种复杂的相互作用，在感染过程中保持微妙的平衡。探索这种自然关系的价值，而不是目前流行的不匹配的实验系统，正变得越来越明显。该计划将直接关注鼠痘病毒（ECTV），这是一种真正的小鼠病原体，具有几个吸引人的特性。首先，传播途径与其他正痘病毒科在其自然宿主中的传播途径相似。其次，鼠痘病与人类的猴痘和天花非常相似。第三，一些小鼠品系对ECTV具有抗性，而另一些小鼠品系则高度易感，类似于人类群体中的自然变异。但对于牛痘病毒（VACV）来说，这一切都不是真的，VACV是一种来源不明的正痘病毒，经常用于小鼠免疫模型，下面给出的初步结果使其更加可疑。该项目由三名在痘病毒宿主防御方面具有丰富经验的PI领导，将全面剖析ECTV与耐药/敏感小鼠品系之间的相互作用，并在适当时参考VACV。项目1将检查先天系统的细胞和细胞因子，这些细胞和细胞因子在控制感染部位的病毒方面发挥着关键作用。项目2通过检查1型干扰素限制病毒扩散到引流淋巴结以外的机制，继续检查先天/自然免疫。最后，项目2和3将研究适应性免疫系统的所有三个主要分支，以了解它们如何防御原发性感染并建立对后续挑战的保护。这三个项目都将研究ECTV的策略，以挫败这些不同级别的主机防御。行政、生物试剂和成像核心组件将为该计划提供广泛的支持，后两者将开展自己的探索性项目。我们的目标是这个假设驱动的，高度互动的程序是开发一个病毒宿主关系的理解，为许多其他自然病毒感染提供了一个框架。 项目1：感染部位对鼠痘的天然免疫应答（Norbury，C） 项目1描述（由申请人提供）：在自然病毒感染期间，小剂量的感染性病毒沉积在外周感染部位，然后进行“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。这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，介导其迁移到感染部位的化学引诱物以及病毒和免疫系统在病毒-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，以及吸引先天效应细胞所必需的趋化因子，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，是ECTV挑战生存所必需的。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。