Mucosal Innate Immunity to Salmonella Infection

粘膜对沙门氏菌感染的先天免疫

• 批准号: 7342842
• 负责人: Kelly D Smith
• 金额: $ 33.43万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7342842
• 关键词: Acute; Address; Agonist; Applications Grants; Attenuated; B-Lymphocytes; Bacteria; Bacterial Infections; C57BL/6 Mouse; Cell Line; Cells; Cellular Immunity; Colitis; Complex; Data; Diaminopimelic Acid; Epithelial Cells; Event; Family; Flagella; Flagellin; Genes; Germ Lines; Helicobacter pylori; Hematopoietic; Histologic; Human; Immune; Immune response; Immune system; Immunologic Receptors; Infection; Inflammatory Response; Intestines; Ligands; Lipopolysaccharides; Lipoproteins; Livestock; Localized; M cell; Mastigophora; Mediating; Messenger RNA; Modeling; Mononuclear; Mus; Natural Immunity; Oral; Outcome; Output; Pattern; Peptides; Peptidoglycan; Phagocytes; Phase; Property; Receptor Cell; Receptor Signaling; Research Personnel; Role; Salmonella; Salmonella infections; Salmonella typhi; Salmonella typhimurium; Signal Transduction; Site; Specialized Epithelial Cell; Streptomycin; Surface; Systemic disease; TLR1 gene; TLR2 gene; TLR4 gene; TLR5 gene; Tissues; Toll-Like Receptor 5; Toll-like receptors; Typhoid Fever; Vaccination; Virulence; Virulence Factors; cell motility; cell type; defined contribution; enteric pathogen; in vitro Model; in vivo; in vivo Model; macrophage; microbial; microorganism interaction; monomer; mouse model; oral infection; pathogen; programs; receptor; receptor expression; response

This grant application addresses the mucosal innate immune recognition and response to the flagellated mucosal pathogen, Salmonella typhimurium. The innate immune response is the product of both multiple cell types and multiple receptors; this combination of events results in a tailored" inflammatory response to the pathogen. We hypothesize that innate immune receptors have specific and redundant functions that regulate a plethora of outputs, which are responsible for controlling bacterial infection. Toll-like receptors (TLR) constitute a prototypic family of innate immune receptorsthat recognize specific microbial components. We identified bacterial flagellin as the ligand for TLR5, defined the TLR5 recognition site on flagellin as a highly conserved region that is required for bacterial motility, demonstrated physical association of TLR5 and flagellin, and recently characterizedtwo major subclasses of bacteria that have evaded TLR5 recognition. Our studies and those of others suggest that TLR5 is a critical receptor for innate immune defense against flagellated pathogens at mucosal surfaces. The NOD family of immune receptors recognizesbacterial peptidoglycans, and we present data demonstrating that NOD1 recognizes S. typhimurium and synergistically interacts with TLRs. Although a detailed model of ligand recognition and signaling is emerging for TLRS and NOD1, little is know about the significance of these innate immune receptorsin vivo. In this proposal we aim to extend our studies into in vivo models of bacterial infection, using Salmonella as the model pathogen. Our efforts are focused on the roles of TLRS and NOD1 in regulating inflammatory responses and bacterial colonization during the early phases of oral infection. We will use in vivo and directed in vitro models of Salmonella infection to determine specific contributions of TLRS recognition of bacterial flagellin (Aim 1), NOD1 recognition of diaminopimelic acid containing peptidoglycans (Aim 2), and specific host cell types (Aim3) to mucosal innate defense against Salmonella.

该赠款申请介绍了粘膜先天免疫识别和对鞭毛的反应 粘膜病原体，沙门氏菌伤寒。先天免疫反应是两个多个细胞的产物 类型和多个受体；这种事件的结合导致量身定制的“对 病原。我们假设先天免疫受体具有调节的特定和冗余功能 大量输出，负责控制细菌感染。 Toll样受体（TLR） 构成了先天免疫受体的原型家族，这些家族识别特定的微生物成分。我们 将细菌鞭毛蛋白鉴定为TLR5的配体，将TLR5识别位点定义为高度 细菌运动所需的保守区域，表现出TLR5和 鞭毛蛋白，最近表征了逃避TLR5识别的细菌的主要子类。 我们的研究和其他研究表明，TLR5是天生免疫防御的关键受体 粘膜表面的鞭毛病原体。免疫受体的点头家族识别细菌 肽二聚糖，我们提供的数据表明NOD1识别鼠伤寒链虫和 协同与TLR相互作用。尽管出现了配体识别和信号传导的详细模型 对于TLR和NOD1，几乎不了解这些先天免疫受体在体内的重要性。在这个 提案我们旨在将研究扩展到细菌感染的体内模型，以沙门氏菌为 模型病原体。我们的努力集中于TLR和NOD1在调节炎症中的作用 口腔感染早期阶段的反应和细菌定植。我们将在体内使用 定向在体外的沙门氏菌感染模型，以确定TLR识别的特定贡献 细菌鞭毛蛋白（AIM 1），NOD1识别含有肽二聚糖（AIM 2）的二氨基二二酰酸（AIM 2）和 特定的宿主细胞类型（AIM3）以粘膜先天防御沙门氏菌。