Mouse model of post-infection atherosclerosis

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PROJECT SUMMARY Atherosclerotic cardiovascular disease (ASCVD) is the number one cause of mortality worldwide, leading to approximately 18 million deaths each year. Besides traditional risk factors, emerging data implicate certain prevalent infections as important contributors of ASCVD risk. We have shown that a globally-prevalent infection such as tuberculosis (TB) carries a 2-fold increased risk of developing ASCVD. Furthermore, TB survivors have a 3-fold increased risk of long-term all-cause mortality compared to the general population, with most deaths attributable to ASCVD. A considerable gap in knowledge is that the mechanisms driving the increased ASCVD risk after recovery from TB and similar chronic infections are unknown. Studies aimed to fill this gap are expected to result in a positive impact in our ability to design interventions to mitigate ASCVD risk after recovery from TB and other chronic infections. We will leverage proof-of-concept mouse experiments conducted by our group which showed that mycobacterial infection enhances inflammation and atherosclerosis development to further establish and characterize a mouse model of post-infection atherosclerosis. Thus, in Aim 1 we will establish the progression of atherosclerosis in mice after mycobacterial-infection clearance with standard antibiotics. In Aim 2, we will profile the activation and function of monocytes post-infection and their contribution to atherosclerosis, as monocytes are key players in atherosclerosis development and our preliminary data indicate that they remain primed after infection clearance. Successful accomplishment of the proposed research will allow the development of an essential mouse model providing a foundation to study mechanisms of post-infection atherosclerosis. We will use the proposed model and findings to support an R01 application aimed at deciphering post-infection progression of atherosclerosis and underlying immune mechanisms. Our results will have a broad translational science impact by providing a model to investigate mechanisms of ASCVD risk and other inflammation-driven diseases among survivors of post-treated chronic infections.