Th17 Cytokines and Lung Immunity

细菌性肺炎是重要的临床问题和宿主防御机制

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.