Role of fluid flow on Chlamydia pneumoniae-exacerbated atherosclerosis

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DESCRIPTION (provided by applicant): Systemic bacterial infections elicit inflammatory response that can result in acute or chronic complications. Our current approach to this problem has largely been limited from static systems though it is now well established that the dynamics of blood flow can seriously influence cellular response. A clear demonstration of such an interaction is that atherosclerotic plaques are almost invariably found in regions of disturbed flow fields such as arterial bends or branch points. Of interest, multiple lines of evidence from in vitro experimental, seroepidemiological, histopathological, animal models and limited clinical interventional studies suggest that infection due to a common intracellular respiratory pathogen, Chlamydia pneumoniae is a highly likely risk factor for atherosclerosis. However, the mechanism is poorly understood. Thus, understanding the complex interaction between C. pneumoniae infection and blood flow at cellular and molecular levels is important in exploring options for anti-infective intervention in the prevention or treatment of cardiovascular diseases. We hypothesize that fluid shear stress modulates the risk of atherosclerosis due to C. pneumoniae infection. We will use a systems bioengineering approach to test our hypothesis as defined by the following three specific aims: (1) Evaluate the biochemical effects of C. pneumoniae infection and shear stress on monocytes; (2) Evaluate the biophysical effects of C. pneumoniae infection and shear stress on monocytes; and (3) Examine the effect of C. pneumoniae infection and shear stress on monocyte adhesion to endothelial cells (EC) and transmigration under flow conditions. Our studies should provide insights into mechanisms by which fluid flow plays a critical role in early stages of C. pneumoniae-exacerbated atherosclerosis. In a larger context, this proposal introduces a new paradigm in our approach to understanding systemic infection and inflammation.