Viral Manipulation of Myeloid Cell Function

描述（由申请方提供）：先天免疫系统对病毒感染快速响应，目的是在启动可清除感染的适应性免疫应答之前将病毒感染控制在外周。然而，先天免疫活性的一个意外后果是由它们产生的促炎介质的先天反应细胞介导的潜在危险的组织损伤。为了预防或减少组织损伤，感染的宿主将启动许多策略以减少先天免疫激活时诱导的炎症，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。这样的策略代表了病毒的有吸引力的靶标，以操纵以降低针对病毒的免疫活性并保持组织完整性以允许增强的病毒复制。宿主用于下调免疫应答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，包括流感和牛痘（VACV），这里使用的病毒，在感染时促进糖皮质激素的产生。VACV通过表达A44L基因产物诱导糖皮质激素产生，并且该基因的缺失在体内减弱病毒并导致皮肤中组织损伤的减少。然而，A44L介导这些效应的机制是未知的，并且是本申请的焦点。在目标1中，我们将研究A44 L衍生的糖皮质激素对不同髓样细胞群体浸润的影响，包括最近鉴定的VACV感染期间促消退髓样细胞群体，以及这些髓样细胞群体的功能（细胞因子和活性氧的产生）。在目标2中，我们将研究A44 L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，因为我们先前的结果表明GC对树突状细胞的影响是导致T细胞反应性降低的原因。在目标1和2中，我们将鉴定直接受A44L衍生的糖皮质激素影响以调节免疫应答的靶细胞。在这些研究的结论中，我们将更深入地了解VACV和其他病毒用于预防或减缓免疫反应并保持组织完整性的机制，以及GC对先天性和适应性免疫反应的各种组分的作用机制。

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.