The long-term objective of this project is to understand interactions between cellular and soluble factors in host defense against bacterial pneumonia. Preliminary data from our laboratory indicate that deposition of bacteria (Klebsiella pneumoniae) into the lungs of mice stimulates the release of one such soluble factor- the lymphocyte- derived cytokine, Interleukin-17 (IL-17). Additional experiments in IL- 17 receptor """"""""knock-out"""""""" mice show increased mortality and impaired neutrophil recruitment after K. Pneumoniae challenge. In this project, we will test the experimental hypothesis that IL-17 released from lung T-lymphocytes amplifies the host response to bacterial infection through stimulated release of C-X-C chemokines for neutrophils and enhanced release of other proinflammatory cytokines.
In Specific Aim 1, we will localize IL-17 to CD4+ and CD8+ T- lymphocytes in the interstitium or alveolar space at serial intervals after bacterial challenge using flow cytometry and laser capture microdissection.
In Specific Aim 2, we will show that IL-17 enhances host release of CXC chemokines and recruitment of neutrophils in response to K. Pneumoniae. We will utilize IL-17 receptor knock-out mice and mice administered a neutralizing IL-17 receptor/FC fusion construct by gene transfer.
In Specific Aim 3, we will investigate the interactions between IL-17 and other pro-inflammatory and anti-inflammatory cytokines released into lung tissue in response to K. Pneumoniae. These experiments will focus on TNF-alpha, IL-12, IFN-gamma, and IL-10.
In Specific Aim 4, we will upregulate IL-17 in lung tissue with gene transfer of the murine IL-17 gene using an adenoviral vector and demonstrate increased bacterial clearance and enhanced recruitment of neutrophils. The results of these experiments will provide new information on how IL-17 participates in host defense against bacterial pneumonia and may lead to novel approaches to augment immune function in the immunocompromised host.
|Ruan, Sanbao; McKinley, Laura; Zheng, Mingquan et al. (2008) Interleukin-12 and host defense against murine Pneumocystis pneumonia. Infect Immun 76:2130-7|
|Rudner, Xiaowen L; Happel, Kyle I; Young, Erana A et al. (2007) Interleukin-23 (IL-23)-IL-17 cytokine axis in murine Pneumocystis carinii infection. Infect Immun 75:3055-61|
|Happel, Kyle I; Dubin, Patricia J; Zheng, Mingquan et al. (2005) Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae. J Exp Med 202:761-9|
|Happel, Kyle I; Zheng, Mingquan; Young, Erana et al. (2003) Cutting edge: roles of Toll-like receptor 4 and IL-23 in IL-17 expression in response to Klebsiella pneumoniae infection. J Immunol 170:4432-6|