IRAK Family Function in Bacterial Infection

描述(由申请人提供)：感染是最常见的 对主机完整性的根本威胁。当细菌病原体侵入 上皮屏障，宿主先天免疫系统检测到攻击并 触发响应以遏制和消灭入侵者。蜂窝传感器， 如巨噬细胞和树突状细胞，通过受体检测病原体 识别细菌大分子。然后这些细胞就会形成促炎因子 导致细胞反应的反应，该反应包含和消除 感染。因此，先天免疫反应包含传入 (病原体感应)和传出(促炎)肢体。Toll/IL-1信号 转导通路介导了这种先天感染反应的两个臂。 这一保守的信号级联由MyD88、 白介素1受体相关激酶(IRAK)分子家族(IRAK， IRAK2和IRAK-M)和肿瘤坏死因子相关因子6。它 处理至少10个Toll样受体(TLRs)和3个IL-1的信号 受体家族成员(IL-1、IL-18和T1/ST2)，将它们分布到 多个下游靶点，包括核因子-kB和几个激活的有丝分裂原 蛋白激酶级联反应。我们已经从基因上删除了IRAK，原发的近端 在小鼠体内，这条通路中有一条激活酶。IRAK基因缺陷的动物和巨噬细胞 对脂多糖(LPS)、肽聚糖(PGN)的反应受损，以及 脂磷壁酸(LTA)和CpG DNA，这两种细菌分子可以激活 通过TLR4和TLR2的先天免疫传入臂。这些老鼠还展示了 IL-1和IL-18被破坏所致的(传出)炎症反应减弱 发信号。这项提案的总体目标是确定伊拉克的功能 在宿主对革兰氏阴性和革兰氏阳性感染的反应中。目标1是 确定IRAK在革兰氏阴性杆菌急性体内反应中的作用 革兰氏阳性感染。我们将让伊拉克淘汰赛(KO)动物 使用毒素挑战的这些感染的日益复杂的模型， 热灭活菌、大肠杆菌和肺炎链球菌的刺激 腹膜炎和败血症。目标2是将伊拉克的功能从基因上分离出来 TLR4或IL-1受体通路，并比较Double和 单只KO小鼠对内毒素刺激，热致死大肠杆菌和大肠杆菌 腹膜炎。目标3是确定IRAK2和IRAK-M对 IRAK缺失细胞中残留的TLR信号，因为IRAK的缺失受损， 但并不完全废除信令。这些研究将提供 关于IRAK在先天免疫中作用的基本新信息 对急性细菌感染的反应，并可能最终导致 制定战略，以调节这种反应的有害方面。

DESCRIPTION (provided by applicant): Infection represents one of the most fundamental threats to host integrity. When a bacterial pathogen breaches an epithelial barrier, the host innate immune system detects the attack and triggers a response to contain and eliminate the invader. Cellular sensors, such as macrophages and dendritic cells, detect pathogen through receptors that recognize bacterial macromolecules. These cells then mount a proinflammatory reaction that leads to cellular responses that contain and eliminate the infection. Thus, the innate immune response contains both afferent (pathogen-sensing) and efferent (proinflammatory) limbs. The Toll/IL-1 signal transduction pathway mediates both arms of this innate response to infection. This conserved signaling cascade consists of the proteins MyD88, the interleukin-1 receptor-associated kinase (IRAK) family of molecules (IRAK, IRAK2, and IRAK-M) and the tumor necrosis factor associated factor 6. It processes signals from at least 10 Toll-like receptors (TLRs) and three IL-1 receptor family members (IL-1, IL-18, and T1/ST2), distributing them to multiple downstream targets, including NF-kB and several mitogen activated protein kinase cascades. We have genetically deleted IRAK, the primary proximal kinase in this pathway, in mice. IRAK-deficient animals and macrophages exhibit impaired responses to lipopolysaccharide (LPS), peptidoglycan (PGN), and lipotechoic acid (LTA), and CpG DNA, bacterial molecules that activate the afferent arm of innate immunity through TLR4 and TLR2. These mice also exhibit attenuated proinflammatory (efferent) responses due to disrupted IL-1 and IL-18 signaling. The overall objective of this proposal is to determine IRAK function in the host response to Gram-negative and Gram-positive infections. Aim 1 is to determine the role of IRAK in the acute in vivo response to Gram-negative and Gram-positive infections. We will subject IRAK knockout (KO) animals to increasingly complex models of these infections using toxin challenges, stimulation with heat-killed bacteria, and E. coli and S. pneumoniae peritonitis and sepsis. Aim 2 is to isolate IRAK function genetically to either the TLR4 or lL-1 receptor pathway and compare the responses of double and single KO mice to LPS stimulation, heat killed E. coli, and E. coli peritonitis. Aim 3 is to determine the contributions of IRAK2 and IRAK-M to residual TLR signaling in IRAK-deficient cells, as deletion of IRAK impairs, but does not completely abrogate signaling. These studies will provide fundamental new information about the role of IRAK in the innate immune response to acute bacterial infection and may eventually lead to the development of strategies to modulate deleterious aspects of this response.