Viral Manipulation of Myeloid Cell Function

描述（由申请人提供）：先天免疫系统对病毒感染反应迅速，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，先天免疫活动的一个意想不到的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。为了防止或减少组织损伤，受感染的宿主会启动许多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“促解决”策略。这些策略为病毒提供了一个有吸引力的靶标，可以用来降低针对病毒的免疫活性，并保持组织的完整性，从而增强病毒的复制。宿主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，包括流感病毒和牛痘病毒（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的产生，该基因的缺失在体内减弱病毒并导致皮肤组织损伤的减少。然而，A44L介导这些作用的机制是未知的，也是本应用的重点。在Aim 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，包括最近发现的在VACV感染期间的促溶解髓系细胞群，以及这些髓系细胞群的功能（细胞因子和活性氧的产生）。在Aim 2中，我们将研究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是T细胞反应性降低的原因。在Aim 1和Aim 2中，我们将确定受a44l衍生糖皮质激素直接影响的靶细胞，以调节免疫反应。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和保持组织完整性的机制，以及GC对先天和适应性免疫反应的各种组成部分的作用机制。

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.