Initiation and regulation of antibacterial innate immunity

描述（由申请人提供）：中性粒细胞（PMN）是一种强大的抗微生物细胞，可快速动员并募集到感染组织和组织损伤部位。一旦在组织内，PMNs可以部署许多活动以去除病原体和/或受损细胞。这些事件的失调可能对宿主产生严重后果，并导致多种疾病的病理学，包括糖尿病、血栓形成和狼疮。人们越来越认识到，免疫细胞通过多蛋白平台（称为微簇）整合来自受体的各种信号来产生适当的反应。这种信号整合已经在T细胞中进行了广泛的研究，但是一种细胞类型的特定整合规则和细胞结果不一定适用于其他细胞，因为每种细胞类型在免疫中起着不同的作用。PMNs如何整合来自宿主和细菌的信号，以在感染组织中产生正确的反应，目前还知之甚少。本申请旨在揭示和理解关键的分子机制PMNs采用触发杀菌反应，使用细菌病原体，耶尔森氏菌，及其效应蛋白，YopH和YopO。基于我们的初步数据表明，YopH通过灭活SKAP-2，PRAM-1和SLP- 76调节的途径，从微簇发出中断信号的整合，我们将专注于了解SKAP 2在PMN反应中的作用。我们的中心假设是，YopH和YopO通过调节SKAP 2依赖性系统来损害PMN对细菌的反应，SKAP 2依赖性系统协调PMN的抗微生物功能，触发了各种不同类型的受体。我们的目的是（1）确定YopH在组织感染中的关键功能;（2）剖析SKAP 2在PMN的抗微生物应答中的作用;以及（3）了解YopO在受体刺激后对中性粒细胞信号传导的影响。通过这项研究，我们希望能够更好地了解PMN抗微生物反应的分子机制。了解感染组织中的Yops如何灭活PMNs将揭示PMNs部署其抗微生物和组织损伤武器库的机制，并导致新的方法来阻止这种部署在自身免疫综合征中。

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.