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.
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