The goal of this K08 proposal is to allow the candidate the opportunity to: 1) develop into an independent investigator, 2) gain laboratory experience in molecular techniques, in vivo models of infection and cell sorting and FACS analysis and 3) focus on the role of IL-23 in Pseudomonas aeruginosa pneumonia. The candidate will draw on the expertise of her mentor Dr. Jay K. Kolls and her Career Development Committee. She will benefit from the resources available in the Lung Immunology Laboratory, Ranges Research Center and the School of Medicine. This proposal will examine the role of IL-23 in both chronic and acute P. aeruginosa pulmonary infection. P. Aeruginosa is the most significant cause of chronic endobronchial infection in individuals with cystic fibrosis and is also a significant cause of morbidity and mortality related to acute pneumonia in other, immunocompromised groups. The host response is characterized by neutrophilic infiltration and significant pulmonary damage. Preliminary data suggest that IL-23 is produced in response to P. aeruginosa infection and that this results in elevated IL-17, CXC chemokines and a neutrophilic response. In addition, preliminary data suggest that IL-23 is regulated by STAT-1 and that this regulation may be altered in the face of infection. This has led to the proposed hypothesis that: P. aeruginosa, signaling through TLR4 on antigen presenting cells in the lung, elicits IL-23 production, subsequent IL-17 production and an ongoing granulopoietic response;STAT1 activation by Type I IFN down-regulates this IL-23 production, effecting a negative feedback loop. This hypothesis will be investigated by the following specific aims: 1) To investigate the capacity of alveolar macrophages and lung DC subsets to produce IL-23 in response to P. aeruginosa in a TLR4 dependent fashion, 2) To determine if experimental P. aeruginosa infection elicits IL-23 production by lung antigen presenting cells and results in IL-17, G-CSF and CXC chemokine production as well as subsequent neutrophil recruitment and 3) To determine if STAT1 is activated by Type I IFN, down-regulating IL-23 production.
|Dubin, Patricia J; Martz, Ashley; Eisenstatt, Jessica R et al. (2012) Interleukin-23-mediated inflammation in Pseudomonas aeruginosa pulmonary infection. Infect Immun 80:398-409|
|Dubin, Patricia J; Kolls, Jay K (2011) IL-17 in cystic fibrosis: more than just Th17 cells. Am J Respir Crit Care Med 184:155-7|