Host Immune Responses to Chlamydia Pneumonaie Infection

Cedars-Sinai Medical Center, West Hollywood CA

Investigators

Abstract

DESCRIPTION (provided by applicant): Chlamydia pneumoniae (CP), an intracellular pathogen, is a frequent cause of respiratory infections and contributes to chronic conditions such as allergic asthma exacerbations, chronic lung diseases, including exacerbating chronic obstructive pulmonary disease, and has been associated with the progression of other chronic inflammatory disease such as atherosclerosis and lung cancer in smokers. While the protective effects of IL-17/TH17 against certain microbial agents have been demonstrated, little is known about the role of IL- 17/TH17 in host defenses against CP infection and its role in CP-induced chronic lung inflammation. Better understanding of the role of IL-17 in pathogenesis of chronic lung infections and COPD associated with CP infection may lead to novel strategies for prevention and therapy. We previously investigated the contribution of NOD1, NOD2, and the RIP2 adapter protein on innate immune responses to CP lung infection in mice and discovered that Rip2 was critically required for host defenses and bacterial clearance, as Rip2-/- mice that survived initial infection developed a chronic lung inflammation and developed large numbers of inducible bronchus associated lymphoid tissues (iBALTs). Importantly, we discovered that the NODs/RIP2 pathway also regulates T cells and that TH17 responses in Rip2-/- mice are significantly upregulated. Preliminary data indicates that increased ROR? may be responsible for the enhanced TH17 skewing in Rip2-/- T-cells. A major goal of this project is to define the mechanism of chronic lung inflammation during CP infection, which appears to be driven by IL-17, and enhanced in the absence of Rip2 signaling. The main focus will be to investigate the novel mechanism that we discovered by which Rip2 deficiency results in enhanced Th17 skewing and the molecular mechanism of this regulation. The central hypothesis is that TH17 cells promote chronic inflammation following CP infection, and that lack of NODs/RIP2 signaling leads to increased IL-17 production, which in turn can induce severe chronic lung inflammation. We hypothesize that it is the upregulated ROR? in Rip2-/- T-cells that results in enhanced Th17 skewing. To define the mechanisms by which CP induced IL- 17/TH17 responses lead to chronic lung inflammation, and to investigate the novel cross-talk between Rip2 and Th17 regulation and the role of ROR?, we propose the following three Specific Aims: Aim1 is to determine the role of IL-17 in host defenses in CP lung infection and chronic lung inflammation. Aim 2 is to determine the mechanism of CP-induced increased chronic lung inflammation in Rip2-null mice and the role of Rip2/IL-17 cross-talk. Aim 3 is to investigate the mechanism of Rip2-induced regulation of Th17 skewing.