Human cardiac stromal cells exposed to SARS-CoV-2 evolve into hyper-inflammatory/pro-fibrotic phenotype and produce infective viral particles depending on the levels of ACE2 receptor expression

Patients with severe respiratory syndrome caused by SARS-CoV-2 undergo cardiac complications due to hyper-inflammatory conditions. Although the presence of the virus has been detected in the myocardium of infected patients, and infection of cardiac cells may involve ACE2 receptor, the underlying molecular/cellular mechanisms are still uncharacterized. We analyzed expression of ACE2 receptor in primary human cardiac stromal cells using proteomic and transcriptomic methods before exposing them to SARS-CoV-2 in vitro. Using conventional and high sensitivity PCR methods, we measured virus production in the cellular supernatants and monitored the intracellular viral bioprocessing. We performed high-resolution imaging to show the sites of intracellular viral production. We finally used Q-RT-PCR assays to detect genes linked to innate immunity and fibrotic pathways coherently regulated in cells exposed to virus. Our findings indicate that human cardiac stromal cells have a susceptibility to SARS-CoV-2 infection and produce variable viral yields depending on the extent of cellular ACE2 receptor expression. Interestingly, these cells also evolved toward hyper-inflammatory/pro-fibrotic phenotypes independently of ACE2 levels, suggesting a dual cardiac damage mechanism that could account for the elevated numbers of cardiac complications in severe COVID-19 cases.