Viral Manipulation of Myeloid Cell Function

病毒操纵骨髓细胞功能

基本信息

批准号：
8226379
负责人：
Christopher C Norbury
金额：
$ 19.13万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8226379
关键词：
Affect Antigen Presentation Antiviral Agents Attenuated Cell physiology Cells Cowpox Dendritic Cells Dermal Development Dose Down-Regulation Equilibrium Gene Deletion Genes Glucocorticoid Receptor Glucocorticoids Goals Grant Health Heterogeneity Hormones Immune Immune response Immune system Immunity Immunosuppressive Agents Infection Infiltration Inflammation Inflammatory Influenza Knowledge Mediating Mediator of activation protein Molecular Monkeypox Monkeypox virus Mus Myelogenous Myeloid Cells Natural Immunity Peripheral Phase Population Poxviridae Production Proteins Publishing Reactive Oxygen Species Reporting Research Research Personnel Resolution Role Safety Site Skin Smallpox Specificity T cell response T-Cell Immunologic Specificity T-Lymphocyte Tissues Treatment Efficacy Vaccinia Vaccinia virus Vaccinium Viral Virus Virus Diseases Virus Replication Work adaptive immunity cell type cytokine design human disease immune activation immune function in vivo migration monocyte pathogen prevent programs regenerative response therapeutic target transmission process vector vaccine

项目摘要

DESCRIPTION (provided by applicant): The innate immune system responds rapidly to virus infection and aims to contain a virus infection in the periphery prior to the initiation of an adaptive immune response that can clear the infection. However, an unintended consequence of innate immune activity is potentially dangerous tissue damage mediated by the cells of the innate response that the proinflammatory mediators that they produce. To prevent or reduce tissue damage an infected host will initiate a number of strategies to reduce the inflammation induced upon innate immune activation, including the downregulation of the innate and adaptive immune systems and the initiation of tissue protective or "pro-resolving" strategies. Such strategies represent and attractive target for viruses to manipulate to reduce immune activity directed against a virus and to preserve tissue integrity to allow enhanced virus replication. One mechanism used to downregulate the immune response and promote tissue integrity by the host is the production of glucocorticoids. A number of viruses, including influenza and vaccinia (VACV), the virus used here, promote the production of glucocorticoids upon infection. VACV induces glucocorticoid production by expression of the A44L gene product, and deletion of this gene attenuates the virus in vivo and results in a reduction of tissue damage in the skin. However, the mechanisms by which A44L mediates these effects are unknown and are the focus of this application. In Aim 1 we will investigate the effect of A44L-derived glucocorticoids on infiltration of different populations of myeloid cells, including a recently identified population of pro-resolving myeloid cells during VACV infection, and the function (production of cytokines and reactive oxygen species) of these myeloid populations. In Aim 2 we will examine the effects of A44L-derived GC upon dendritic cell heterogeneity, numbers, infiltration, migration, antigen presentation and cytokine production, as our previous results indicate that an effect of GC upon dendritic cells is responsible for a reduction in T cell responsiveness. In both Aim 1 and 2 we will identify the target cell directly affected by A44L-derived glucocorticoids to modulate the immune response. At the conclusion of these studies we will have gained a deeper understanding of the mechanisms that VACV and other viruses deploy to prevent or slow the immune response and preserve tissue integrity, as well as the mechanisms of action of GC upon various components of the innate and adaptive immune response.

描述（由申请人提供）：先天免疫系统对病毒感染的反应迅速，并旨在在启动适应性免疫反应之前在周围含有病毒感染，以清除感染。然而，先天免疫活性的意外后果是由它们产生的促炎性介体的先天反应细胞介导的潜在危险的组织损害。为了防止或减少组织损害，感染的宿主将启动多种策略，以减少先天免疫激活后诱发的炎症，包括先天和适应性免疫系统的下调以及启动组织保护性或“促进”策略。这些策略代表了操纵病毒以减少针对病毒的免疫活性并保留组织完整性以允许病毒复制增强的免疫活性的吸引力。一种用于下调免疫反应并促进宿主组织完整性的机制是糖皮质激素的产生。这里使用的病毒在内的许多病毒，包括流感和离甲酸（VACV），在感染后促进了糖皮质激素的产生。 VACV通过A44L基因产物的表达诱导糖皮质激素的产生，该基因的缺失减弱了体内病毒，并导致皮肤中组织损伤的减少。但是，A44L介导这些作用的机制尚不清楚，并且是该应用的重点。在AIM 1中，我们将研究A44L衍生的糖皮质激素对髓样细胞不同种群的浸润的影响，包括在VACV感染过程中近期鉴定出的促髓样细胞的种群，以及这些髓样群体的功能（细胞因子和活性氧的产生）。在AIM 2中，我们将检查A44L衍生的GC对树突状细胞异质性，数量，浸润，迁移，抗原表现和细胞因子产生的影响，因为我们先前的结果表明，GC对树突状细胞的影响负责降低T细胞响应能力。在AIM 1和2中，我们将确定直接受A44L衍生的糖皮质激素影响的靶细胞以调节免疫反应。在这些研究的结论结束时，我们将对VAVV和其他病毒进行预防或减慢免疫反应并保留组织完整性的机制有更深入的了解，以及GC对先天性和适应性免疫反应的各种组成部分的作用机制。