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.
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.
|Campbell, Lee Ann; Rosenfeld, Michael E (2015) Infection and Atherosclerosis Development. Arch Med Res 46:339-50|
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|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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