Chlamydia pneumoniae, a causative agent in human community acquired pneumonia, also has been implicated in a variety of sequelae associated with chronic disease and re-exposure to the organism. One important sequel associated with C. pneumoniae infection is the development of atherosclerotic lesions that define the pathology of cardiovascular disease in people. Cardiovascular disease due to atherogenic processes is a major health problem in most of the world, accounting for about 50% of all deaths. It is clear that vascular injury is crucial in the development and progression of atherosclerosis and that this injury can result from a variety of causes, including infection. Several lines of evidence support the hypothesis that C. pneumoniae infection is linked to the development of atherosclerosis. Initially, seroepidemiological evidence was generated to establish a relationship between C. pneumoniae and cardiovascular disease. Subsequently, evidence for the presence of the organism in atherosclerotic lesions was obtained using either direct antigen detection methods or probes specific for C. pneumoniae nucleic acids. In addition, the organism has been isolated from an aortic lesion and grown in cell culture. Finally, two pilot secondary prevention antibiotic treatment trials have provided evidence to suggest that treatment of C. pneumoniae in individuals with coronary heart disease significantly reduces cardiac events in treated versus placebo administered populations. Thus, although the association of C. pneumoniae and atherosclerosis is well-established, existing data do not prove an etiology or pathogenic role for the organism in disease, although both rabbit and murine animal models have been developed to determine if C. pneumoniae is causally associated with development or progression of atherosclerotic lesions in vivo. Activation and modification of mononuclear phagocyte function is associated with atherosclerotic lesion development. Characteristic changes include development of cholesteryl ester-laden monocytes (foam cells) and oxidation of lipids to form tissue-damaging derivatives. The hypothesis to be tested here is that infection of human monocytes, monocyte-derived macrophages or murine monocyte cell lines with C. pneumoniae results in changes in macrophage morphology and function that are consistent with a role for C. pneumoniae in the pathogenesis of atherosclerosis. This hypothesis will be tested by determining if C. pneumoniae causes mononuclear phagocytes to form foam cells in the presence of low density lipoprotein (LDL) or other cholesterol-containing serum lipoprotein complexes. Studies also will be conducted to determine if C. pneumoniae contributes to the oxidative modification of LDL and molecular characterization of C. pneumoniae antigens involved in these processes will be identified. Finally, a murine model will be developed to provide in vivo correlates to cell culture observations. Results will help establish links between C. pneumoniae infection and the atherosclerotic disease process.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042790-02
Application #
6149880
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Taylor, Christopher E,
Project Start
1999-02-15
Project End
2004-01-31
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
2
Fiscal Year
2000
Total Cost
$235,857
Indirect Cost
Name
University of Wisconsin Madison
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Grayston, J Thomas; Belland, Robert J; Byrne, Gerald I et al. (2015) Infection with Chlamydia pneumoniae as a cause of coronary heart disease: the hypothesis is still untested. Pathog Dis 73:1-9
Cao, Fei; Castrillo, Antonio; Tontonoz, Peter et al. (2007) Chlamydia pneumoniae--induced macrophage foam cell formation is mediated by Toll-like receptor 2. Infect Immun 75:753-9
Ouellette, Scot P; Abdelrahman, Yasser M; Belland, Robert J et al. (2005) The Chlamydia pneumoniae type III secretion-related lcrH gene clusters are developmentally expressed operons. J Bacteriol 187:7853-6
Gieffers, Jens; Durling, Luke; Ouellette, Scot P et al. (2003) Genotypic differences in the Chlamydia pneumoniae tyrP locus related to vascular tropism and pathogenicity. J Infect Dis 188:1085-93
Byrne, Gerald I (2003) Chlamydia uncloaked. Proc Natl Acad Sci U S A 100:8040-2
Gieffers, Jens; Belland, Robert J; Whitmire, William et al. (2002) Isolation of Chlamydia pneumoniae clonal variants by a focus-forming assay. Infect Immun 70:5827-34
Byrne, G I; Ouellette, S P; Wang, Z et al. (2001) Chlamydia pneumoniae expresses genes required for DNA replication but not cytokinesis during persistent infection of HEp-2 cells. Infect Immun 69:5423-9
Kalayoglu, M V; Indrawati; Morrison, R P et al. (2000) Chlamydial virulence determinants in atherogenesis: the role of chlamydial lipopolysaccharide and heat shock protein 60 in macrophage-lipoprotein interactions. J Infect Dis 181 Suppl 3:S483-9
LaVerda, D; Kalayoglu, M V; Byrne, G I (1999) Chlamydial heat shock proteins and disease pathology: new paradigms for old problems? Infect Dis Obstet Gynecol 7:64-71
Kalayoglu, M V; Miranpuri, G S; Golenbock, D T et al. (1999) Characterization of low-density lipoprotein uptake by murine macrophages exposed to Chlamydia pneumoniae. Microbes Infect 1:409-18

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