Parallel use of human stem cell lung and heart models provide insights for SARS-CoV-2 treatment

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily infects the respiratory tract, but pulmonary and cardiac complications occur in severe coronavirus disease 2019 (COVID-19). To elucidate molecular mechanisms in the lung and heart, we conducted paired experiments in human stem cell-derived lung alveolar type II (AT2) epithelial cell and cardiac cultures infected with SARS-CoV-2. With CRISPR-Cas9-mediated knockout of ACE2, we demonstrated that angiotensin-converting enzyme 2 (ACE2) was essential for SARSCoV-2 infection of both cell types but that further processing in lung cells required TMPRSS2, while cardiac cells required the endosomal pathway. Host responses were significantly different; transcriptome profiling and phosphoproteomics responses depended strongly on the cell type. We identified several antiviral compounds with distinct antiviral and toxicity profiles in lung AT2 and cardiac cells, highlighting the importance of using several relevant cell types for evaluation of antiviral drugs. Our data provide new insights into rational Q2 drug combinations for effective treatment of a virus that affects multiple organ systems. Comparative gene expression profiling of SARS-CoV-2 infected lung AT2 cells and cardiac cultures was performed by inoculating cultures with 10^4 TCID50 of SARS-CoV-2 (VIC01 isolate). Supernatant samples were harvested at 0-, 1- and 3-days post-infection for RNA extraction and RNA sequencing.