Chlamydia pneumoniae is the third most common cause of community acquired pneumonia and may cause chronic persistent disease, which leads to chronic inflammatory lung diseases such as asthma and COPD as well as acceleration of atherosclerosis. The overall goals of this study are to determine the role of the innate immune system in C. pneumonia induced pneumonitis and define the mechanisms by which C. pneumoniae and Chlamydia HSP60 (criSP60) interact with the innate immune system receptors, Toll-like Receptor-4 (TLR4), TLR2 and MyD88 and lead to acute and chronic lung infection, inflammation and airway reactivity. We have shown earlier that criSP60 activates endothelial cells through TLR4. In preliminary data we now show that C. pneumoniae induces acute lung infection and severe inflammation in wild type MyD88+/+, TLR4+/+ and TLR4-/-. However, MyD88 -/- mice develops significantly less inflammation after 5 days of infection despite same bacterial load in the lungs. In addition we have shown that Chlamydia pneumoniae induced activation of inflammatory cytokines are significantly higher in lung homogenate and BAL of wild type MyD88+/+, TLR4+/+ and TLR4-/-mice compared to MyD88-/- mice at 5 days. The hypothesis: We hypothesize that C. pneumoniae induces lung inflammation via both TRL4, and TLR2 in a MyD88-dependent pathway, while criSP60 utilizes only TLR4 and MyD88. We also hypothesize that the bacterial clearance later on (days 14-30 and 60) will be significantly delayed in the lungs of MyD88-/- animals and this will lead to increased lung damage.
Specific Aims are: 1- To investigate the role of TLR4, TLR2 and MyD88 in C. pneumoniae induced acute and chronic lung infection and inflammation in a mouse model. 2a) To generate a recombinant cHSP60-induced lung inflammation model to determine the specific contributions of criSP60 in C. pneumoniae induced lung inflammation. ? 2b) To dissect the role of TLR4, TLR2 and MyD88 in live-, UV killed- Chlamydia pneumonia, and 2e) to determine the role of TLR4, TLR2 and MyD88 in cHSP60-induced in-vitro cellular activation of endothelial cells, macrophages and lung epithelial cells. Significance: Improved understanding of the role of the innate immune system and TLR4, TLR2 and MyD88 in C .pneumoniae and criSP60 induced acute and chronic lung disease may provide new targets for intervention and prevention of chronic inflammatory lung disease. ? ? ?
| Bulut, Yonca; Shimada, Kenichi; Wong, Michelle H et al. (2009) Chlamydial heat shock protein 60 induces acute pulmonary inflammation in mice via the Toll-like receptor 4- and MyD88-dependent pathway. Infect Immun 77:2683-90 |
