Rationale: While respiratory failure is a frequent and clinically significant outcome of COVID-19, cardiac complications are a common feature in hospitalized COVID-19 patients and are associated with worse patient outcomes . The cause of cardiac injury in COVID-19 patients is not yet known . Case reports of COVID-19 autopsy heart samples have demonstrated abnormal inflammatory infiltration of macrophages in heart tissues.
Objective: Generate an immuno-cardiac co-culture platform to model macrophage-mediated hyper-inflammation in COVID-19 hearts and screen for drugs that can block the macrophage-mediated inflammation . Methods and
Results: We systematically compared autopsy samples from non-COVID-19 donors and COVID-19 patients using RNA-seq and immunohistochemistry . We observed strikingly increased expression levels of CCL2 as well as macrophage infiltration in heart tissues of COVID-19 patients . We generated an immuno-cardiac co-culture platform containing human pluripotent stem cell (hPSC) -derived cardiomyocytes (CMs) and macrophages . We found that macrophages induce increased reactive oxygen species (ROS) and apoptosis in CMs by secreting IL-6 and TNF- & #945; after SARS-CoV-2 exposure . Using this immuno-cardiac co-culture platform, we performed a high content screen and identified ranolazine and tofacitinib as compounds that protect CMs from macrophage-induced cardiotoxicity .
Conclusions: We established an immuno-host co-culture system to study macrophage-induced host cell damage following SARS-CoV-2 infection and identified FDA-approved drug candidates that alleviate the macrophage-mediated hyper-inflammation and cellular injury.