Chlamydia pneumoniae (CP) is an important respiratory pathogen associated with community acquired pneumonia and bronchitis and significantly contributes to chronic debilitating pulmonary conditions such as bronchial asthma and COPD. However, the exact molecular mechanisms involved in CP-induced chronic lung inflammation and allergic airway inflammation are not clearly understood. While the protective effects of Th-17/IL-17 against certain microbial agents have been demonstrated, little is known about the role of Th17/IL-17 in host defenses against CP infection and their role in CP-induced chronic lung inflammation or allergic airway sensitization. Better understanding of the role of Th17IL-17 in the pathogenesis of COPD and allergic airway inflammation associated with CP infection may result in much needed new preventive and therapeutic approaches. During the last funding period we investigated the role of the innate immune receptors such as TLRs/MyD88 and NOD/RIP2 in host defenses against CP as well as their role in CP-induced allergic airway sensitization. We discovered that Rip2 signaling was critically required for efficient host defenses and bacterial clearance, and that Rip2-/- mice that survived initial infection developed a chronic lung inflammation. Importantly, we found that TH17 responses in Rip2-/- mice were significantly upregulated. A major goal of this project is to define the mechanism and cross talk between IL-17 production and lack of NOD/RIP2 signaling pathway in chronic lung inflammation during CP pulmonary infection. We also observed that allergic sensitization was dependent on infection severity with Tregs playing a critical role in determining the likelihood of sensitization, and that CP-induced IL-6 levels critically modulated Allergic Sensitization. Based upon these key findings, we now propose the following studies in this renewal application focused around the central hypothesis that TH17 cells promote chronic inflammation following CP infection, exacerbate asthmatic responses, and that lack of RIP2 signaling leads to increased IL-17 production, which in turn can induce severe chronic lung inflammation with granuloma-like lesions. Furthermore, IL-6 induced during the early stages of CP infection counteracts the suppressive effects of Tregs resulting in infection induced allergic sensitization. To define the mechanisms by which CP induced Th17/IL-17 responses lead to chronic lung inflammation, granuloma lesion, and to investigate the role of CP infection induced IL-6 in allergic airway sensitization, we propose the following three Specific Aims:
Aim1 is to determine the role of IL-17 in host defenses in CP lung infection and allergic airway sensitization.
Aim 2 is to determine the role of Rip2/IL-17 cross-talk in CP-induced chronic lung inflammation and allergic airway sensitization.
Aim 3 is to determine the role of IL-6 in CP-induced allergic airway sensitization.

Public Health Relevance

Chlamydia pneumoniae (CP) is an important respiratory pathogen that is responsible for a significant percentage of community acquired pneumonia and plays a role in chronic lung diseases such as asthma and COPD (chronic obstructive pulmonary disease), at least in part by instigating long term structural changes in airways (airway remodeling). The major goal of this application is to understand the cellular and molecular mechanisms that explain how CP infections may lead to chronic lung inflammation, and hence contribute to COPD and allergic asthma. Our studies may allow us to develop novel treatments or preventive approaches to these diseases, and may also produce new insights into other types of inflammatory diseases where C. pneumoniae infection is thought to be a contributing or causative factor.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
High Priority, Short Term Project Award (R56)
Project #
Application #
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Taylor, Christopher E,
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cedars-Sinai Medical Center
Los Angeles
United States
Zip Code
Shimada, Kenichi; Porritt, Rebecca A; Markman, Janet L et al. (2018) T-Cell-Intrinsic Receptor Interacting Protein 2 Regulates Pathogenic T Helper 17 Cell Differentiation. Immunity 49:873-885.e7
Chiba, Norika; Shimada, Kenichi; Chen, Shuang et al. (2015) Mast cells play an important role in chlamydia pneumoniae lung infection by facilitating immune cell recruitment into the airway. J Immunol 194:3840-51
Dagvadorj, Jargalsaikhan; Shimada, Kenichi; Chen, Shuang et al. (2015) Lipopolysaccharide Induces Alveolar Macrophage Necrosis via CD14 and the P2X7 Receptor Leading to Interleukin-1? Release. Immunity 42:640-53
Tumurkhuu, Gantsetseg; Dagvadorj, Jargalsaikhan; Jones, Heather D et al. (2015) Alternatively spliced myeloid differentiation protein-2 inhibits TLR4-mediated lung inflammation. J Immunol 194:1686-94
Jones, Heather D; Crother, Timothy R; Gonzalez-Villalobos, Romer A et al. (2014) The NLRP3 inflammasome is required for the development of hypoxemia in LPS/mechanical ventilation acute lung injury. Am J Respir Cell Mol Biol 50:270-80
Jupelli, Madhulika; Shimada, Kenichi; Chiba, Norika et al. (2013) Chlamydia pneumoniae infection in mice induces chronic lung inflammation, iBALT formation, and fibrosis. PLoS One 8:e77447
Shimada, Kenichi; Crother, Timothy R; Karlin, Justin et al. (2012) Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36:401-14
Crother, Timothy R; Ma, Jun; Jupelli, Madhulika et al. (2012) Plasmacytoid dendritic cells play a role for effective innate immune responses during Chlamydia pneumoniae infection in mice. PLoS One 7:e48655
Shimada, Kenichi; Crother, Timothy R; Arditi, Moshe (2012) Innate immune responses to Chlamydia pneumoniae infection: role of TLRs, NLRs, and the inflammasome. Microbes Infect 14:1301-7
Shimada, Kenichi; Crother, Timothy R; Karlin, Justin et al. (2011) Caspase-1 dependent IL-1? secretion is critical for host defense in a mouse model of Chlamydia pneumoniae lung infection. PLoS One 6:e21477

Showing the most recent 10 out of 15 publications