C. pneumoniae and atherosclerotic plaque destabilization

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Infection with Chlamydia pneumonias (C. pneumoniae) is associatedwith an increased risk of cardiovascular disease morbidity and mortality and antibody titers are elevated in those with unstable angina. The prevalence of C. pneumoniae antibodies is also highest in the elderly, the population at greatest risk of mortality from established cardiovascular disease. C. pneumoniae infection is disseminated from the lungs to the artery wall by infected macrophages. Sustained infection occurs in endothelial cells, smooth muscle cells, and macrophages within atherosclerotic plaques but rarely within normal arteries. We, and others, have demonstrated that C. pneumoniae infection accelerates the development of fatty streaks in hypercholesterolemic animal models. However, to date little is known about whether C. pneumoniae infection contributes to the advanced stages of the disease process. Furthermore, it is still unclear whether there are indirect effects of C. pneumoniae infection of epithelial cells and macrophages in the lungs on lesion progression or whether any effects on advanced lesions requires direct infection of vascular cells. In this proposal, we will focus on modeling the effects of C. pneumoniae on the advanced stages of atherosclerosis. In addition, we will follow-up on the observation that the toll-like receptor-2 largely mediates the responses of macrophages to C. pneumoniae. We hypothesize that C. pneumoniae infection of macrophages contributes via activation of TLR-2 to the progression of advanced atherosclerotic lesions by both directly and indirectly potentiating the ongoing inflammatory response within the diseased blood vessel. The potentitation of the inflammatory response in turn leads to increased cell death and expansion of the necrotic core followed by a wound healing fibrotic conversion and increased vascular calcification. To test these hypotheses we will pursue the following specific aims: 1. To determine the mechanisms by which C. pneumoniae induces a caspase independent death and concurrently stimulates production of ATP in mouse macrophages. 2. To determine whether the absence of toll-like receptors TLR-2 and TLR-4 and the accessory protein MyD88 alters the acute phase response and prevents the acceleration of atherosclerosis induced by C. pneumoniae infection in C57BI/6 and Apo E-/- mice. 3. To determine how C. pneumoniae infection of macrophages contributes to vascular calcification in vitro and in vivo. 4. To determine whether exposure of young versus old mice to air pollution increases the susceptibility of the mice to C. pneumoniae infection and accelerates the development and progression of atherosclerosis.