Initiation and regulation of antibacterial innate immunity

描述(申请人提供)：中性粒细胞(PMN)是一种强大的抗微生物细胞，可以迅速动员并招募到感染组织和组织损伤部位。一旦进入组织，PMN就可以进行许多活动来清除病原体和/或受损细胞。这些事件的失调会给宿主带来严重的后果，并导致多种疾病的病理变化，包括糖尿病、血栓形成和狼疮。越来越多的人认识到，免疫细胞通过称为微簇的多蛋白平台整合来自受体的各种信号，从而产生适当的反应。这种信号整合在T细胞中已经得到了广泛的研究，但一种细胞类型的整合和细胞结果的特定规则不一定适用于其他细胞，因为每种细胞类型在免疫中扮演着不同的角色。PMN如何整合来自宿主和细菌的信号，以在受感染的组织中产生正确的反应，目前还知之甚少。这项应用旨在揭示和了解PMN使用细菌病原体Yersinia及其效应蛋白YopH和YOPO触发杀菌反应的关键分子机制。根据我们的初步数据表明，YopH通过失活由微簇发出的Skap-2、PRAM-1和SLP-76调节的通路来扰乱信号的整合，我们将重点了解SKAP2在PMN反应中的作用。我们的中心假设是，YopH和YOPO通过调节SKAP2依赖的系统来协调PMN触发的各种不同类型的受体的抗微生物功能，从而损害PMN对细菌的反应。我们的目标是(1)确定YopH在组织感染中的关键功能；(2)剖析SKAP2在PMN抗微生物反应中的作用；(3)了解YOPO在受体刺激后对中性粒细胞信号转导的影响。通过拟议的研究，我们期望对PMN抗微生物反应的关键分子机制有更好的理解。了解YOPs是如何在感染组织中灭活PMN的，将揭示PMN部署其抗微生物和组织破坏性武器库的机制，并导致在自身免疫综合征中阻止这种部署的新方法。

DESCRIPTION (provided by applicant): Neutrophils (PMNs) are powerful anti-microbial cells that are rapidly mobilized and recruited to infected tissues and sites of tissue damage. Once within tissues, PMNs can deploy many activities to remove pathogens and/or damaged cells. Dysregulation of these events can have severe consequences for the host and contribute to the pathology a variety of diseases, including diabetes, thrombus formation and lupus. It has been increasingly recognized that immune cells generate appropriate responses by integrating a variety signals from receptors through multi-protein platforms, called microclusters. This signal integration has been studied extensively in T cells, but the specific rules of integration and cellular outcomes for one cell type do not necessarily apply to other cells because each cell type plays distinct roles in immunity. How PMNs integrate signals from the host and bacteria to generate the correct response in infected tissues is very poorly understood. This application seeks to uncover and understand critical molecular mechanisms PMNs employ to trigger bactericidal responses, using the bacterial pathogen, Yersinia, and its effector proteins, YopH and YopO. Based on our preliminary data indicating that YopH disrupts integration of signals by inactivating SKAP-2, PRAM-1 and SLP- 76-regulated pathways that emanate from micro-clusters, we will focus on understanding the role of SKAP2 in PMN responses. Our central hypothesis is that YopH and YopO impair PMN responses to bacteria by modulating a SKAP2-dependent system that coordinates the anti-microbial functions of PMNs triggered a variety of different types of receptors. Our aims are (1) to determine the critical functions of YopH in tissu infection; (2) dissect the role of SKAP2 in the anti-microbial responses of PMNs; and (3) understand the effects of YopO on neutrophil signaling after receptor stimulation. Through the proposed research, we expect to contribute a better understanding of the molecular mechanisms critical for PMNs anti-microbial responses. An understanding of how PMNs are inactivated by Yops in infected tissues will reveal the mechanisms by which PMNs deploy their anti-microbial and tissue damaging arsenal and lead to new ways to stop this deployment in auto-immune syndromes.