The overall goal of the proposed studies is to determine the molecular mechanisms by which microbial agents such as Chlamydia pneumoniae induced infections accelerate the progression of atherosclerosis. In the previous funding cycle, our studies investigated how Innate Immune Receptors, TLR4, TLR2 and the adaptor molecule MyD88 signaling promote development of high fat diet-induced atherosclerosis as well as C. pneumoniae-induced acceleration of plaque formation in hypercholesterolemic mouse model. Here we propose to further elucidate the molecular mechanisms of C. pneumoniae-induced progression of atherosclerosis in the ApoE-/- mouse model. We hypothesize that both hematopoietic lineage cells including Dendritic cells (DCs) as well as stromal cells including endothelial cells (ECs) play an important role in C. pneumoniae-induced acceleration of atherosclerosis. Our central hypothesis is that signaling by both major arms downstream of TLRs, MyD88-dependent and MyD88-independent pathways contribute to C. pneumoniae-induced acceleration of atherosclerosis, but do so in mechanistically distinct ways. Given the cross talk between the TLR and the Liver X Receptor (LXR) pathways converge on the MyD88-independent TRIF and IRF3 signaling, we hypothesize that both the LXR and the IRF3 pathways participate in C. pneumoniae-mediated acceleration of atherosclerosis. We will test these hypotheses by the following aims.
Specific Aims : 1- Determine the relative contributions of BM-derived hematopoietic and stromal cells (i.e. EC) in the protection provided by MyD88 deficiency in Apo-MyD88 double KO mice with hypercholesterolemia with and without C. pneumonia infection using BM chimeric mice;2- Define the specific role of DCs and the role of intact MyD88 signaling in DCs in C. pneumoniae-induced acceleration of atherosclerosis;3- Determine the contribution of LXR and the MyD88-independent IRF3 pathway in C. pneumonia-induced acceleration of the lesion and define the cross talk between TLRs, LXRs and IRF3 in a setting of infection-mediated progression of atherosclerosis. Significance: These studies will thus elucidate interactive mechanisms by which infection with C. pneumoniae, cholesterol metabolism, and innate immune pattern recognition receptors from the TLR and LRX family converge to impact development of atherosclerotic plaque, the biological substrate for cardiovascular events that continue to exact a tremendous toll on human health around the globe. These studies will thus improve our understanding of how innate immune defenses contribute to atherosclerosis and its consequences, and in particular will shed important new light on how infection with a specific and widely- prevalent pathogen might exacerbate atherosclerotic disease.
Innate immune responses play a role in Chlamydia pneumoniae infection-mediated acceleration of atherosclerosis in hypercholesterolemic mice. Atherosclerosis- based coronary heart diseases strike without warning and account for the third of all deaths in the United States. Fatal myocardial infarctions or strokes occur at a rate of about one every 33 seconds in the U.S. One of the major participants in atherosclerosis are immune cells and their mediators, which directly cause the chronic arterial inflammation that is the hallmark of the disease. While it is clear that hypercholesterolemia and the host immune defenses are key participants in development and progression of atherosclerosis, it is far less clear how infections might accelerate this disease process. The major goal of this application is to understand the molecular mechanisms that explain exactly how infections such as a common lung infection (Chlamydia pneumoniae) accelerates the atherosclerotic disease process. The successful completion of the proposed studies may allow us to develop novel treatment or preventive approaches to infection-mediated progression of atherosclerotic heart disease.
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