Microbial Pattern Recognition and Signaling by the Adhesion GPCR BAI1

通过粘附 GPCR BAI1 进行微生物模式识别和信号传导

• 批准号: 8495901
• 负责人: James E. Casanova
• 金额: $ 35.93万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8495901
• 关键词: Adhesions; Adopted; Amino Acids; Antibiotics; Apoptotic; BAI1 gene; Bacteria; Bacterial Infections; Binding; Binding Sites; Biochemical; Biological Assay; C Type Lectin Receptors; C-terminal; Calorimetry; Cells; Charge; Communicable Diseases; Complex; Cytoplasmic Tail; Data; Development; Ectopic Expression; Elements; Exhibits; Extracellular Domain; Family; Fibroblasts; G Protein-Coupled Receptor Genes; Goals; Gram-Negative Bacteria; Gram-Positive Bacteria; Health; Host Defense; Immune response; Immune system; In Vitro; Infection; Infectious Agent; Inflammation; Inflammatory; Inflammatory Response; Interferons; Invaded; Ligand Binding; Ligands; Ligation; Lipopolysaccharides; Liver; MAP Kinase Modules; Mediating; Microbe; Monomeric GTP-Binding Proteins; Mus; Nature; Organism; Orphan; Pathway interactions; Pattern Recognition; Pattern recognition receptor; Phagocytes; Phagocytosis; Physiological; Predisposition; Proteins; Reactive Oxygen Species; Receptor Activation; Receptor Signaling; Research; Role; Salmonella; Salmonella infections; Salmonella typhimurium; Sentinel; Series; Side; Signal Pathway; Signal Transduction; Specificity; Spleen; Structure; Surface; TLR4 gene; Tissues; Toll-like receptors; Work; base; chemokine; cytokine; in vivo; insight; intraperitoneal; macrophage; member; microbial; microorganism; mouse model; next generation; novel; pathogen; pathogenic bacteria; receptor; response; scavenger receptor; uptake

DESCRIPTION (provided by applicant): The innate immune system forms the first line of specific host defense against invading microbial pathogens. Integral to the innate immune response are Pattern Recognition Receptors (PRRs) that recognize conserved determinants expressed by a broad range of pathogenic microorganisms. Among these are the Toll-like receptors, which promote inflammatory signaling and phagocyte recruitment in response to pathogen recognition, and several families of phagocytic PRRs, including scavenger receptors and C-type lectin receptors that mediate phagocytic clearance of microbes from infected tissues. Each receptor family contains multiple members that recognize a unique spectrum of microbial components, and collectively they provide protection against a wide range of infectious organisms. We have identified a novel pattern recognition receptor, BAI1, that is expressed on macrophages and recognizes the surface lipopolysaccharide (LPS) of Gram-negative bacteria using an array of thrombospondin repeats (TSRs) in its extracellular domain. TSRs in several secreted proteins have been shown to bind microbial products, but this is the first evidence of a transmembrane receptor that uses TSRs to mediate the phagocytic clearance of specific pathogens. Binding of bacteria to BAI1 triggers phagocytosis through a mechanism involving activation of the small GTPase Rac by the Elmo/Dock180 GEF complex, which interacts directly with BAI1. An emerging theme is that pattern recognition receptors often cooperate with each other to enhance downstream signaling responses. Our preliminary data suggest that BAI1 acts synergistically with the Toll-like receptor TLR4 to promote the synthesis of inflammatory cytokines/chemokines. BAI1 is an orphan GPCR-like receptor and apart from its ability to activate Rac, almost nothing is known about how it transmits signals to the cell interior or which signaling pathways are activated in response to BAI1 ligation. The overall goal of the proposed research is to define the role of BAI1 in host defense against bacterial infection. In Aim 1, we will define the mode of interaction of LPS with the BAI1 TSRs, using a combination of biochemical, biophysical and structural approaches. In Aim 2, we will identify components of the signaling machinery that interact with BAI1, define the signaling pathways activated in response to LPS or bacterial activation of the receptor, and elucidate the mechanisms of crosstalk between BAI1 and TLR4. In Aim 3, we will characterize the role of BAI1 in host defense in vivo, using a mouse model of Salmonella infection. Together these studies will provide unique structural, biochemical and physiological insights into a new class of pattern recognition receptor that may have important functions in the innate immune response to bacterial pathogens.

描述（由申请人提供）：先天免疫系统形成特异性宿主防御入侵微生物病原体的第一道防线。固有免疫反应的组成部分是模式识别受体（PRRs），它识别由广泛的病原微生物表达的保守决定因子。其中包括toll样受体，其促进炎症信号传导和吞噬细胞募集以响应病原体识别，以及几个吞噬PRRs家族，包括清道夫受体和c型凝集素受体，它们介导被感染组织中的微生物的吞噬清除。每个受体家族都包含多个成员，这些成员识别独特的微生物成分光谱，它们共同提供针对各种传染性生物体的保护。我们已经发现了一种新的模式识别受体BAI1，它在巨噬细胞上表达，并利用其细胞外结构域的一系列血栓反应蛋白重复序列（TSRs）识别革兰氏阴性细菌的表面脂多糖（LPS）。一些分泌蛋白中的tsr已被证明与微生物产物结合，但这是跨膜受体利用tsr介导特定病原体的吞噬清除的第一个证据。细菌与BAI1的结合通过Elmo/Dock180 GEF复合物激活小GTPase Rac的机制触发吞噬，该复合物直接与BAI1相互作用。一个新兴的主题是模式识别受体经常相互合作，以增强下游信号反应。我们的初步数据表明，BAI1与toll样受体TLR4协同作用，促进炎症细胞因子/趋化因子的合成。BAI1是一种罕见的gpcr样受体，除了其激活Rac的能力外，几乎不知道它如何将信号传递到细胞内部或哪些信号通路被激活以响应BAI1连接。本研究的总体目标是确定BAI1在宿主防御细菌感染中的作用。在目标1中，我们将结合生化、生物物理和结构方法，定义LPS与BAI1 TSRs的相互作用模式。在Aim 2中，我们将确定与BAI1相互作用的信号机制的组成部分，定义响应LPS或细菌激活受体而激活的信号通路，并阐明BAI1和TLR4之间串扰的机制。在Aim 3中，我们将使用沙门氏菌感染的小鼠模型来描述BAI1在体内宿主防御中的作用。总之，这些研究将提供独特的结构，生化和生理学的见解，为一类新的模式识别受体，可能在先天免疫应答细菌病原体的重要功能。