Mechanisms of Cardiovascular Complications in Respiratory Viral Infections

SUMMARY Cardiovascular diseases (CVD) are the leading cause of death, accounting for an estimate of 19.05 million deaths in 2020, representing 32% of global deaths. The coronavirus outbreak highlighted impact of respiratory viral infections on atherosclerotic cardiovascular (CV) disease. Viral infections not only heighten the risk of CVD but also render individuals with pre-existing CVD and/or risk factors more susceptible to severe viral illnesses. However, the extent to which immune-mediated anti-viral response, viral tropism and cytotoxic mechanisms contribute to the increased CV risk remains poorly understood. Defining the mechanisms of viral CV tropism and resulting inflammation is key to understanding and preventing post-acute sequelae (PASC). Our previous work demonstrated that SARS-CoV-2 preferentially infects atherosclerotic plaques, correlating with macrophage infiltration in coronary lesions from patients with acute coronavirus disease. Foam cells, a hallmark of atherosclerosis, showed higher viral burden, delayed clearance, impaired interferon anti-viral responses, and increased secretion of pro-atherogenic cytokines, indicating a link between viral infection, lipid metabolism and inflammation in the context of CVD. Preliminary evidence shows that SARS-CoV-2 directly targets vascular immune cells, particularly macrophages altering their metabolism and inflammatory programs that contribute to atherosclerosis and post-viral CV sequelae. Building on our previous findings and promising preliminary data, this project aims to define how viral infection drives macrophage metabolic and inflammatory reprogramming that accelerates atherosclerosis progression and establishes long-lasting vascular inflammation. Aim 1 will define how SARS-CoV-2 infection reprograms macrophages toward a pro-atherogenic state, promoting foam-cell formation, defective efferocytosis, and plaque inflammation, and whether this accelerates atherosclerosis progression. Aim 2 will determine how viral infection induces long-lived myeloid reprogramming that sustains vascular inflammation and promotes post-viral inflammation and CVD and the role of early inflammatory monocyte recruitment and infection in initiating these persistent immune changes and inflammation. Together, these studies will provide the mechanistic foundation for developing targeted interventions to mitigate CV complications triggered by viral agents.