An Immuno-Cardiac Model for Macrophage-Mediated Inflammation in COVID-19 Hearts.

Yang, Liuliu; Han, Yuling; Jaffre, Fabrice; Nilsson-Payant, Benjamin E; Bram, Yaron; Wang, Pengfei; Zhu, Jiajun; Zhang, Tuo; Redmond, David; Houghton, Sean; Uhl, Skyler; Borczuk, Alain; Huang, Yaoxing; Richardson, Chanel; Chandar, Vasuretha; Acklin, Joshua A; Lim, Jean K; Xiang, Jenny; Ho, David D; tenOever, Benjamin R; Schwartz, Robert E; Evans, Todd; Chen, Zhengming; Chen, Shuibing

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-α 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.