Unravelling consequences of SARS-CoV-2 mediated inflammatory immune responses in heart and vasculature

The 2019 coronavirus disease pandemic (COVID-19) is a global public health challenge, with rapid spread, high reproductive rates, and an approximate mortality rate between 1.0-2.3%. Due to the lack of specific treatment, therapy has so far been limited to symptom relief. Although acute respiratory distress syndrome (ARDS) is the central feature of disease severity, non-pulmonary organ damage has emerged as an important predictor of mortality. Severe cases admitted to hospital for COVID-19 are significantly affected by cardiovascular disease (CVD) and kidney failure as well as symptoms of the central nervous system (CNS), all of which correlate with a poor outcome. However, the underlying mechanisms of non-pulmonary tissue damage in COVID-19 and associated coagulopathies are poorly understood. CoVasc combines the complementary expertise in vascular inflammation/atherosclerosis (Döring, Van der Vorst), neuroimmunology/brain barrier function (Engelhardt), coagulation/complement activation/thrombo-inflammation (Rieben, Sorvillo), heart development and function (Mercader), and electrophysiology and vascular coronary function of the heart (Odening, Longnus, Kleinbongard) with expertise in virology and specifically SARS-CoV-2 (Dijkman, Leib) and know how in BSL3 research (Leib, Summermatter), also with respect to animal models (Benarafa), to unravel the consequences of SARS-Cov-2 mediated inflammatory responses in the cardiovascular system. There is lack of certainty about which cell types are prone to be infected and how the route of infection or cell type being infected determines disease manifestation. One established entry point of SARS-CoV-2 into cells is angiotensin converting enzyme 2 (ACE2), expressed in several cell types including endothelial cells, pericytes and cardiomyocytes. Within CoVasc we propose to combine our complementary expertise in cardiovascular biology to study SARC-CoV-2 infection employing primary and iPSC-derived in vitro models of human microvascular and macrovascular endothelium, as well as pericytes and, in vivo in animal models, namely zebrafish and mouse. As CD147 was identified as an alternative ligand for SARS-CoV-2 and is highly expressed on the endothelial and epithelial brain barriers, it will also be included in our analysis. We will study if disease progression is dependent on the cell type infected and combined analysis of animal models will allow us to study long-term outcome of infection, which is currently completely unknown. Beyond providing the knowledge which vascular cell types can be infected by SARS-CoV-2 and the receptors involved, CoVasc holds the promise of providing insight into yet unknown downstream signaling events triggered by SARS-CoV-2 and involved in the observed coagulopathies or neurological symptoms. CoVasc may thus set the stage for characterization of COVID-19 clinical phenotypes, and, therefore, for discovering entirely novel avenues for therapeutic intervention targeting the vasculature and or the brain barriers for the treatment of COVID-19.