Th17 Cytokines and Lung Immunity

细菌性肺炎是一个重要的临床问题和宿主防御机制， 肺炎并不完全清楚。使用克雷伯氏菌属小鼠模型的上一个资助期数据 肺炎感染表明，肺中的细菌沉积导致T细胞的释放， 衍生的细胞因子1 L-17 A和1 L-17 F，两者都可以介导中性粒细胞募集到肺中。 IL-22的产生可激活上皮细胞内的STATS，增强上皮屏障 功能以及抗菌蛋白的诱导。早期IL-17的关键来源是γδ T细胞， 接种后，IL-17的细胞来源转移到Th 17细胞。这些细胞不仅识别血清型2 K.肺炎克雷伯氏菌也能对其它血清型的克雷伯氏菌产生应答而增殖。肺炎，但也对其他 遗传学上相关的细菌，如肠杆菌科的成员。因此，Th 17细胞可以 提供针对细菌分支的血清型非依赖性免疫。在这次更新中，我们测试了假设 疫苗诱导的Th 17细胞能够介导非血清型的抗K.肺炎（和 其它相关病原体）通过肺上皮细胞发出信号。我们也会检查这些疫苗 免疫应答可由特异性亚单位抗原如外膜蛋白引起 细菌外泌体总之，这项研究将促进新的治疗细菌感染的发展。 这些感染已经显示出明显的耐药性问题。此外，拟议的工作将 继续推进我们对肺粘膜免疫的理解。 相关性（参见说明）： 细菌性肺炎仍然是一个重大的公共卫生问题。这项建议的扩展将研究 肺部的抵抗机制。通过了解正常的抵抗途径，我们希望这些 可以将这些途径用于预防或治疗细菌性肺炎的新疗法。

Bacterial pneumonia is an important clinical problem and host defense mechanisms against pneumonia are not fully understood. Data from the prior funding period using a murine model of Klebsiella pneumoniae infection has shown that bacterial deposition in the lung results in the release of the T-cell derived cytokines 1L-17A and 1L-17F, both of which can mediate neutrophil recruitment into the lung. Moreover, IL-22 is produced which can activate STATS in epithelial cells and augment epithelial barrier function as well as the induction of antimicrobial proteins. A critical source of early IL-17 is γδ T-cells but upon vaccination the cellular source of IL-17 shifts to Th17 cells. These cells not only recognize serotype 2 K. pneumoniae but also proliferate in response to other serotypes of K. pneumoniae but also to other phylogenetlcally related bacteria such as members of the enterobacteriaceae family. Thus Th17 cells can provide serotype independent immunity against clades of bacteria. In this renewal we test the hypothesis that vaccine induced Th17 cells can mediate serotype independent immunity against K. pneumoniae (and other related pathogens) by signaling through the lung epithelium. We also examine if these vaccine responses can be elicited by specific subunit antigens such as outer membrane proteins as well as secreted bacterial exososmes. Taken together the research will foster the development of new treatment for bacterial infections that have demonstrated a clear issue of drug resistance. Moreover the proposed work will continue to advance our understanding of mucosal immunity in the lung. RELEVANCE (See instructions): Bacterial pneumonia remains a significant public health concern. The extension of this proposal will study resistance mechanisms in the lung. By understanding normal resistance pathways, we hope that these pathways can be exploited for new therapies to prevent or treat bacterial pneumonia.