Chlamydia pneumoniae is an etiological agent of human respiratory disease, causing 5-10% of pneumoniae bronchitis and sinusitis. This pathogen has also been associated with atheroscleroisis and its related clinical manifestations such as coronary heart disease, the leading cause of morbidity and mortality in the U.S. C. pneumoniae has been found in atherosclerotic lesions but rarely in normal tissues The biological plausibility of a role in atherosclerosis has been indicated by in vitro experiments demonstrating that C. pneumoniae induces the expression of proatherogenic factors and affects cellular pathways that to atherosclerosis. In hyperlipidemic animal models, C. pneumoniae infection accelerates atherosclerotic lesion formation. Key to pathogenesis and development of strategies to prevent infection is identification for how this obligate intracellular parasite is internalized. We have shown that the chlamydial glycan, a high mannose oligosaccharide, is critical for infectivity and that C. pneumoniae uses the mannose-6-phosphate receptor while C. trachomatis uses the mannose receptor for entry into the host. We also have preliminary results demonstrating that C. pneumoniae may bind to the lectin-like scavenger receptor for oxidized LDL (LOX-1). Expression of this receptor is induced by ox-LDL resulting in increased uptake of ox-LDL and expression of proatherogenic factors. C. pneumoniae has been found to induce the same factors, but the mechanism by which it does so is unknown. The novel hypotheses to be tested is that C. pneumoniae induces expression of the LOX-1 receptor resulting in endocytosis of the organism and in the expression of proatherogenic factors, which contribute to C. pneumoniae accelerated atherosclerosis and that treatment with agents that act through inhibition of LOX-1 will prevent C. pneumoniae accelerated atherosclerosis. Overall, the mechanisms by which chlamydiae enter the host cell have remained elusive and may involve more than one pathway. Our studies demonstrating that the chlamydiae spp. can use either the MR or M6PR for entry, both of which are internalized through clathrin mediated endocytosis, suggest that chlamydiae can enter through this pathway. Using inhibitors of clathrin and ubiqutin endocytosis, we have shown that the infectivity of C. pneumoniae could be inhibited. Thus, we will test the hypothesis that chlamydiae may use these pathways for entry into the host.

Public Health Relevance

Chlamydia pneumoniae is a ubiquitous respiratory pathogen and everyone is infected and re-infected during his/her lifetime. This proposal seeks to identify how the organism attaches and enters into host cells to establish infection. If this organism contributes to the pathology of cardiovascular disease, identification of targets for intervention or prevention is of paramount importance to public health.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Host Interactions with Bacterial Pathogens Study Section (HIBP)
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Taylor, Christopher E,
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University of Washington
Schools of Public Health
United States
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Campbell, Lee Ann; Rosenfeld, Michael E (2015) Infection and Atherosclerosis Development. Arch Med Res 46:339-50
Cabbage, Sarah; Ieronimakis, Nicholas; Preusch, Michael et al. (2014) Chlamydia pneumoniae infection of lungs and macrophages indirectly stimulates the phenotypic conversion of smooth muscle cells and mesenchymal stem cells: potential roles in vascular calcification and fibrosis. Pathog Dis 72:61-9
Campbell, Lee A; Lee, Amy W; Rosenfeld, Michael E et al. (2013) Chlamydia pneumoniae induces expression of pro-atherogenic factors through activation of the lectin-like oxidized LDL receptor-1. Pathog Dis 69:1-6
Campbell, Lee Ann; Puolakkainen, Mirja; Lee, Amy et al. (2012) Chlamydia pneumoniae binds to the lectin-like oxidized LDL receptor for infection of endothelial cells. Microbes Infect 14:43-9
Jiang, Shinn-Jong; Kuo, Cho-Chou; Berry, Mark W et al. (2008) Identification and characterization of Chlamydia pneumoniae-specific proteins that activate tumor necrosis factor alpha production in RAW 264.7 murine macrophages. Infect Immun 76:1558-64
Takaoka, Naohisa; Campbell, Lee Ann; Lee, Amy et al. (2008) Chlamydia pneumoniae infection increases adherence of mouse macrophages to mouse endothelial cells in vitro and to aortas ex vivo. Infect Immun 76:510-4
Puolakkainen, Mirja; Lee, Amy; Nosaka, Tadayoshi et al. (2008) Retinoic acid inhibits the infectivity and growth of Chlamydia pneumoniae in epithelial and endothelial cells through different receptors. Microb Pathog 44:410-6
Kuo, Cho-Chou; Lee, Amy; Jiang, Shinn-Jong et al. (2007) Inoculation of Chlamydia pneumoniae or Chlamydia trachomatis with ligands that inhibit attachment to host cells reduces infectivity in the mouse model of lung infection: implication for anti-adhesive therapy. Microbes Infect 9:1139-41
Campbell, Lee Ann; Lee, Amy; Kuo, Cho-chou (2006) Cleavage of the N-linked oligosaccharide from the surfaces of Chlamydia species affects infectivity in the mouse model of lung infection. Infect Immun 74:3027-9
Puolakkainen, Mirja; Kuo, Cho-Chou; Campbell, Lee Ann (2005) Chlamydia pneumoniae uses the mannose 6-phosphate/insulin-like growth factor 2 receptor for infection of endothelial cells. Infect Immun 73:4620-5

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