Influence of infection with Chlamydia pneumoniae on structure, function and interaction of vascular cells and its relation on atherogenesis

In epidemiologic, immunohistochemical and electron microscopic studies an infection of the vascular wall with Chlamydia pneumoniae (C. pneumoniae) has been linked with coronary heart disease, myocardial infarction and stroke. In addition striking evidence for an active role of C. pneumoniae but not Chlamydia trachomatis in atherogenesis has been provided in animal models and from preliminary data of intervention trials. Although these observations strongly indicate an involvement of C. pneumoniae in the pathogenesis of vascular complications and atherosclerosis, our knowledge on the molecular mechanisms contributing to the proposed effect of C. pneumoniae on the vascular wall homeostasis is very limited. Therefore, the proposed project is designed to elucidate the molecular mechanisms how an infection with C. pneumoniae affects the vascular wall to initiate or facilitate vascular dysfunction. Using freshly isolated endothelial cells and vascular smooth muscle cells from the human uterine artery and umbilical vein and immortalised cell lines we intent to study the effect of an infection with C. pneumoniae on the architectural organisation of the cytoskeleton and microtubular network cytokine expression, free radical release, nitric oxide production/bioactivity, activity of transcription factors and gene expression, cell-to-cell interaction with vascular cells, and cell derived oxidation of low density lipoproteins. To know how an infection of C. pneumoniae affects endothelial and smooth muscle cell integrity, release of vasoactive molecules and cell function, will provide essential knowledge to understand the role of C. pneumoniae in initiation or promotion of vascular dysfunction and vascular complications. These fundamental findings might contribute to the development of new strategies for therapeutic intervention for the prevention and treatment of atherosclerosis, the leading cause of mortality in the Western world.

Recently there has been increasing evidence that chronic infections, especially those with the intracellular bacterium Chlamydia pneumoniae, are involved in atherogenesis as trigger or promotor of the disease. Chlamydia pneumoniae causes infections of the respiratory tract from harmless pharyngitis up to severe pneumoniae. Statistically every human gets infected several times during live with this pathogen. The organism is found in blood vessels affected with atherosclerosis. The question, if Chlamydia pneumoniae is causally involved in atherogenesis has not been answered yet and our knowledge on the molecular mechanisms contributing to the proposed effect of Chlamydia pneumoniae on the vascular wall homeostasis is very limited. The aim of this project was to elucidate in cell culture experiments the molecular mechanisms of how an infection with Chlamydia pneumoniae affects the various cells of the vascular wall to iniciate or facilitate changes in cellular structure or vascular dysfunction. In conclusion our results elucidate the interaction between Chlamydia pneumoniae and the host cell. In this case the activation of the transcription factor NFkappaB seems not to be part of the defense mechanism, as it is in infections with other pathogens. In contrast, Chlamydia pneumoniae seems to use this mechanism to promote its own developmental cycle in the cell. As shown by electron microscopy, the inhibition of NFkappaB causes a retardation in the growth of the bacterium, but there is no obvious direct toxic effect. These results are of special interest because the NFkappaB inhibitor acetyl salicylic acid shows a strong concentration dependent inhibition of chlamydial growth in the cells. It is known since years that acetyl salicylic acid has a protective effect in the secondary prophylaxis of atherosclerosis. This has been attributed to the inhibition of platelet aggregation. Our results suggest this protective effect might be, at least in part, due to an inhibition of the infection with Chlamydia pneumoniae in the arteriosclerotic leasions of the blood vessels.