Innate immune response to bacterial flagellans

细菌鞭毛是一种非同寻常的微生物产物，可以直接被 天然免疫系统和获得性免疫系统的受体。因为鞭毛启动了一种先天的 免疫应答，它们有可能作为分子定义的佐剂发挥作用，并且 正在进行临床前疫苗研究。扩展我们对先天知识的了解 对细菌鞭毛的免疫反应对于理解对 鞭毛化病原体，并有可能影响未来的疫苗和 佐剂发展。 粘膜树突状细胞(DC)是已知的唯一一种造血细胞 组成性表达鞭毛蛋白受体TLR5。细菌鞭毛蛋白对细菌生长发育的影响 以前没有检查过肠道DC抗原的提呈和迁移，但 有可能影响细菌的致病机理和宿主免疫。我们的整体 假说是肠道树突状细胞对沙门氏菌鞭毛蛋白的识别增强了 鞭毛蛋白表位的呈现和启动肠道DC的快速迁移。我们期待着 TLR5树突状细胞的快速反应有利于宿主免疫，但也有利于 细菌，因为它能够有效地传播病原体。 目前尚不清楚结扎肠道树突状细胞上的TLR5是否会影响 表面MHC分子上的鞭毛蛋白多肽。我们在特定目标1中的工作假设 通过TLR5激活肠道DC是否优先增强了对 表面MHC分子上的鞭毛蛋白多肽。这一假设预言了一种直接的联系 表面TLR连接和随后的抗原呈递之间的关系，并可以解释 鞭毛特异性T细胞在感染性和炎症性疾病中的显著优势 肠道疾病。我们建议使用新的试剂来检验这一假设 我们已经开发出在抗原呈递时直接跟踪鞭毛蛋白表位的呈递。 细胞在体外和体内。 报告表明，沙门氏菌引发了一种不同寻常的DC的快速迁移 种群在肠道固有层进入宿主体内。然而，细菌刺激 引发这些早期DC迁移事件的原因不明。我们在特定目标下的假设 2是对细菌鞭毛的识别导致DC在肠道中快速迁移。 我们建议使用试剂来检验这一假说，这种试剂将使我们能够物理跟踪 DC从固有层移行。

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.