Chlamydia pneumoniae is a common human respiratory pathogen. In recent years the scope of C. pneumoniae in human diseases has been extended to the cardiovascular diseases. The studies on seroepidemiology, detection of the organism, and animal models have provided a strong evidence indicating that C. pneumoniae and hyperlipidemia are co-risk factor of atherosclerosis. Because coronary heart disease is a leading cause of death in this country and worldwide, the overall goal of this proposal is to investigate the immunopathogenic mechanisms by which C. pneumoniae promotes the development of vascular disease and to develop the secondary preventive measures for C. pneumoniae-associated atherosclerosis. This research proposal will exploit the recent findings from our studies on the mouse models of C. pneumoniae and atherosclerosis and cell cultures on C. pneumoniae infection using arterial wall cells.
The specific aims are to 1) test the hypothesis that the tropism of C. pneumoniae is dependent on previous activation of the endothelium and expression of adhesion molecules, which facilitates C. pneumoniae homing to and establishing persistent infection at the lesion site to accelerate atherosclerosis; 2) analyze gene expression in foam cell macrophages induced by C. pneumoniae infection by the microarray technique; 3) determine whether infection of hyperlipidemic mice with C. pneumoniae increases expression of Egr-1 responsive genes in the artery wall and whether infection accelerates development of atherosclerotic lesions in Egr-1 knockout mice; and 4) evaluate the ligand-receptor based therapy for prevention of C. pneumoniae-associated atherosclerosis in mice by administering food or water supplemented with mannose 6-phosphate/mannan and retinoic acid. The proposed studies should contribute to the understanding of the disease process and development of better eradication or preventive measures for C. pneumoniae infection and reduction of atherosclerosis and coronary heart disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-BM-1 (01))
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Tolunay, Eser
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University of Washington
Schools of Public Health
United States
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Campbell, Lee Ann; Yaraei, Kambiz; Van Lenten, Brian et al. (2010) The acute phase reactant response to respiratory infection with Chlamydia pneumoniae: implications for the pathogenesis of atherosclerosis. Microbes Infect 12:598-606
Jiang, Shinn-Jong; Campbell, Lee Ann; Berry, Mark W et al. (2008) Retinoic acid prevents Chlamydia pneumoniae-induced foam cell development in a mouse model of atherosclerosis. Microbes Infect 10:1393-7
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
Yaraei, Kambiz; Campbell, Lee Ann; Zhu, Xiaodong et al. (2005) Effect of Chlamydia pneumoniae on cellular ATP content in mouse macrophages: role of Toll-like receptor 2. Infect Immun 73:4323-6
Blessing, E; Campbell, L A; Rosenfeld, M E et al. (2005) A 6 week course of azithromycin treatment has no beneficial effect on atherosclerotic lesion development in apolipoprotein E-deficient mice chronically infected with Chlamydia pneumoniae. J Antimicrob Chemother 55:1037-40
Campbell, Lee Ann; Nosaka, Tadayoshi; Rosenfeld, Michael E et al. (2005) Tumor necrosis factor alpha plays a role in the acceleration of atherosclerosis by Chlamydia pneumoniae in mice. Infect Immun 73:3164-5
Yaraei, Kambiz; Campbell, Lee Ann; Zhu, Xiaodong et al. (2005) Chlamydia pneumoniae augments the oxidized low-density lipoprotein-induced death of mouse macrophages by a caspase-independent pathway. Infect Immun 73:4315-22
Puolakkainen, Mirja; Campbell, Lee Ann; Lin, Tsun-Mei et al. (2003) Cell-to-cell contact of human monocytes with infected arterial smooth-muscle cells enhances growth of Chlamydia pneumoniae. J Infect Dis 187:435-40
Chesebro, Brian B; Blessing, Erwin; Kuo, Cho-Chou et al. (2003) Nitric oxide synthase plays a role in Chlamydia pneumoniae-induced atherosclerosis. Cardiovasc Res 60:170-4

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