Viral Manipulation of Myeloid Cell Function

病毒操纵骨髓细胞功能

基本信息

批准号：
8450749
负责人：
Christopher C Norbury
金额：
$ 22.95万
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 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8450749
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做出快速反应，旨在在启动可清除感染的适应性免疫反应之前将病毒感染遏制在周围。然而，先天免疫活动的一个意想不到的后果是细胞产生的促炎介质的先天反应所介导的潜在危险的组织损伤。为了防止或减少组织损伤，受感染的宿主将启动多种策略来减少先天免疫激活引起的炎症，包括下调先天和适应性免疫系统以及启动组织保护或“促消退”策略。这些策略代表了病毒的有吸引力的目标，可操纵其降低针对病毒的免疫活性并保持组织完整性以增强病毒复制。宿主用于下调免疫反应和促进组织完整性的一种机制是糖皮质激素的产生。许多病毒，包括此处使用的流感病毒和痘苗病毒 (VACV)，在感染后会促进糖皮质激素的产生。 VACV 通过 A44L 基因产物的表达诱导糖皮质激素产生，删除该基因可在体内减弱病毒并减少皮肤组织损伤。然而，A44L 介导这些作用的机制尚不清楚，也是本申请的重点。在目标 1 中，我们将研究 A44L 衍生的糖皮质激素对不同髓系细胞群浸润的影响，包括最近在 VACV 感染期间发现的促解髓系细胞群，以及 A44L 衍生的糖皮质激素的功能（细胞因子和活性氧的产生）。这些骨髓细胞群。在目标 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、抗原呈递和细胞因子产生的影响，因为我们之前的结果表明 GC 对树突状细胞的影响导致 T 细胞减少细胞反应性。在目标 1 和 2 中，我们将鉴定直接受 A44L 衍生糖皮质激素影响的靶细胞，以调节免疫反应。在这些研究结束时，我们将更深入地了解 VACV 和其他病毒预防或减缓免疫反应并保持组织完整性的机制，以及 GC 对先天和免疫系统各种成分的作用机制。适应性免疫反应。