Th17 Cytokines and Lung Immunity

细菌性肺炎是一种重要的临床问题和宿主防御机制。 对肺炎的认识还不完全。使用克雷伯氏菌小鼠模型的前一个资助期的数据 肺炎杆菌感染表明，细菌沉积在肺部会导致T细胞的释放 衍生细胞因子1L-17A和1L-17F均可介导中性粒细胞向肺内募集。 此外，IL-22还可以激活上皮细胞中的STAT，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γδT细胞，但 一旦接种，IL-17的细胞来源就转移到Th17细胞。这些细胞不仅识别2型血清 肺炎克雷伯菌不仅对其他血清型肺炎克雷伯菌有反应，而且对其他血清型也有反应。 与系统发育相关的细菌，如肠杆菌科的成员。因此Th17细胞可以 针对细菌分支提供独立于血清型的免疫力。在这次更新中，我们检验了假设 疫苗诱导的Th17细胞可介导对肺炎克雷伯菌的非血清型免疫(和 其他相关病原体)通过肺上皮细胞发出信号。我们还检查这些疫苗是否 反应可以由特定的亚单位抗原，如外膜蛋白以及分泌的 细菌外切体。综上所述，这项研究将促进细菌新疗法的发展 感染表现出明显的抗药性问题。此外，拟议的工作将 继续推进我们对肺粘膜免疫的了解。 相关性(请参阅说明)： 细菌性肺炎仍然是一个重大的公共卫生问题。这项建议的延期将研究 肺部的耐药机制。通过了解正常的耐药途径，我们希望这些 可以开发新的治疗方法来预防或治疗细菌性肺炎。

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.