Chlamydia pneumoniae is an important cause of community acquired pneumonia that also significantly contributes to allergic airway disease and exacerbation of asthma. Emerging evidence suggests that Toll-Like Receptors (TLRs) may play a role in host defenses against C. pneumoniae infection. Our studies show that MyD88-/- mice were unable to mount an early inflammatory response, failed to clear the bacteria from their lungs, and developed a delayed and sustained lung inflammation that led to increased mortality compared to wild type mice, but wild-type (MyD88+/+) littermate control mice rapidly recovered from infection. These results indicate that TLR signaling via MyD88 is an essential component of host defenses against C. pneumoniae. While C. pneumoniae -induced cytokine release in vitro from bone marrow derived macrophages and dendritic cells are TLR2-dependent, we did not observe a significant defect in bacterial clearance or resolution of lung inflammation in TLR2-/- and TLR4-/- mice. These observations suggest that MyD88 is critical to host defense against C. pneumoniae, but also indicate that MyD88- and/or TLR-independent pathways lead to the delayed and chronic lung inflammation in MyD88-/- mice. TLR/MyD88-independent pathways which include NOD1 and NOD2 may also be involved in innate host defenses against this obligate intracellular organism. We also observed that UV killed or live C. pneumoniae infection sensitizes the mice for allergens and exacerbates allergen-mediated eosinophilic airway inflammation with a Th2 type response in the lung. These studies have driven hypotheses that we will critically test in studies proposed here and that are organized around a central hypothesis: Host response to C. pneumoniae lung infection and inflammation is mediated through TLR2/MyD88 pathways that trigger innate and adaptive immune defenses which in turn play an important role in the pathogenesis of C. pneumoniae infection and host responses to clear the bacteria from the lungs. The resulting initial inflammation which is associated with intense cytokine responses to clear the acute infection, including IFN-y but also enhances allergen-mediated sensitization and eosinophilic airway inflammation and allergic asthma triggered by allergen challenge by promoting a Th2 bias in the lung.
Specific Aims are: 1- To investigate the role of TLR2/TLR4 and MyD88-dependent and-independent signaling pathways in innate and adaptive host responses against C. pneumoniae- induced lung infection and inflammation in mice;2- To determine and compare the roles of hematopoietic and lung epithelial cells in C. pneumoniae- induced immune responses and lung inflammation 3- To determine the impact of C, pneumoniae infection on the development of allergen-mediated eosinophilic airway inflammation of the lung. Significance: Our proposed studies will lead to improved understanding of the role of innate and adaptive immune responses in host defenses against C. pneumoniae infection, including the role of TLR/MyD88 pathway and NOD1/NOD2 receptors, as well as the molecular mechanisms by which C. pneumoniae infection exacerbates allergen- mediated eosinophilic airway inflammation, and may provide new targets for treatment and/or prevention of allergic asthma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI067995-05
Application #
7880013
Study Section
Special Emphasis Panel (ZRG1-IDM-G (02))
Program Officer
Taylor, Christopher E,
Project Start
2006-07-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
5
Fiscal Year
2010
Total Cost
$367,781
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
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