Innate immune response to bacterial flagellans

对细菌鞭毛的先天免疫反应

• 批准号: 7843571
• 负责人: STEPHEN J MCSORLEY
• 金额: $ 37.75万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-16 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7843571
• 关键词: Adjuvant; Affect; Antigen Presentation; Antigen-Presenting Cells; Bacteria; Bacterial Proteins; Biological; Blood; Bone Marrow; Cell Line; Cells; Characteristics; Communicable Diseases; Confusion; Connecticut; Dendritic Cells; Developing Countries; Development; Epitopes; Event; Flagellin; Funding; Future; Hematopoietic; Histocompatibility; Immune response; Immune system; Immunity; In Vitro; Inflammatory disease of the intestine; Intestines; Knowledge; Laboratories; Lamina Propria; Ligands; Ligation; Link; Major Groove; Mastigophora; Natural Immunity; Oral; Pathogenesis; Peptides; Population; Program Research Project Grants; Proteins; Published Comment; Reagent; Reporting; Research Project Grants; Salmonella; Salmonella infections; Sampling; Stimulus; Structure of aggregated lymphoid follicle of small intestine; Surface; T cell response; Testing; Toll-Like Receptor 5; Toll-like receptors; Typhoid Fever; Universities; Vaccine Adjuvant; Vaccines; Work; adaptive immunity; base; cell motility; in vivo; killings; microbial; migration; novel vaccines; oral infection; pathogen; pre-clinical; receptor; response; uptake

Bacterial flagellins are unusual microbial products that can be directly recognized by receptors of both the innate and adaptive immune system. Since flagellins initiate an innate immune response, they have the potential to function as molecularly defined adjuvants, and are being studied in preclinical vaccine studies. Expanding our knowledge about the innate immune response to bacterial flagellins is important for understanding immunity to flagellated pathogens and has the additional potential to influence future vaccine and adjuvant development. Mucosal dendritic cells (DC) are the only hematopoietic population known to constitutively express the flagellin receptor, TLR5. The effect of bacterial flagellins on intestinal DC antigen presentation and migration have not previously been examined but have the potential to influence bacterial pathogenesis and host immunity. Our overall hypothesis is that Salmonella flagellin recognition by intestinal DCs enhances the presentation of flagellin epitopes and initiates rapid intestinal DC migration. We expect the rapid response of TLR5' DCs is beneficial to host immunity but is also beneficial to the bacteria since it enables efficient pathogen dissemination. It is not known if TLR5 ligation on intestinal DCs can influence the presentation of flagellin peptides on surface MHC molecules. Our working hypothesis in Specific Aim 1 is that activation of intestinal DCs via TLR5 preferentially enhances the display of flagellin peptides on surface MHC molecules. This hypothesis predicts a direct link between surface TLR ligation and subsequent antigen presentation, and could explain the notable dominance of flagellin-specific T cell responses in infectious and inflammatory diseases of the intestine. We propose to examine this hypothesis using new reagents that we have developed to directly track presentation of flagellin epitopes on antigen presenting cells in vitro and in vivo. Reports suggest that Salmonella provoke rapid migration of an unusual DC population in the intestinal lamina propria to enter the host. However, the bacterial stimulus provoking these early DC migration events are undefined. Our hypothesis in Specific Aim 2 is that recognition of bacterial flagellins causes rapid DC migration in the intestine. We propose to examine this hypothesis using reagents that will allow us to physically track DC migration from the lamina propria.

细菌鞭毛是不寻常的微生物产品，可以直接识别 先天和适应性免疫系统的受体。由于鞭毛启动了先天 免疫反应，它们有可能充当分子定义的佐剂，并且 正在临床前疫苗研究中研究。扩大我们对先天的知识 对细菌鞭毛蛋白的免疫反应对于理解免疫力很重要 鞭毛病原体，并具有影响未来疫苗和 辅助发展。 粘膜树突状细胞（DC）是唯一已知的造血人群 组成性表达鞭毛蛋白受体TLR5。细菌鞭毛蛋白对 肠道直流抗原表现和迁移以前尚未被检查，但 有可能影响细菌发病机理和宿主免疫。我们的整体 假设是肠道DC识别沙门氏菌鞭毛蛋白会增强 鞭毛蛋白表位和引发快速肠道直流迁移的表现。我们期望 TLR5'DCS的快速响应对宿主免疫有益，但也对 细菌因为它可以有效地传播病原体。 尚不清楚TLR5在肠道DC上的结扎是否会影响 表面MHC分子上的鞭毛蛋白肽。我们在特定目标中的工作假设1 是通过TLR5激活肠道DC可以优先增强 表面MHC分子上的鞭毛蛋白肽。该假设预测了直接链接 在表面TLR连接和随后的抗原表现之间，可以解释 感染性和炎症中鞭毛蛋白特异性T细胞反应的显着优势 肠道疾病。我们建议使用新试剂来检查这一假设 我们已经开发了直接跟踪抗原呈现鞭毛蛋白表位的表现 细胞体外和体内。 报告表明沙门氏菌会激发不寻常的DC的快速迁移 肠道层中的人口进入宿主。但是，细菌刺激 激发这些早期的DC迁移事件是不确定的。我们在特定目的中的假设 2是对细菌鞭毛蛋白的识别会导致肠道快速的直流迁移。 我们建议使用试剂来检查这一假设，以使我们能够物理跟踪 DC从固有层迁移。