Rational treatment strategies for SARS-CoV-2 derived from human iPSC models

ABSTRACT: SARS-CoV-2 infects the respiratory tract, primarily causing pulmonary disease and cardiac complications described in many COVID-19 cases. To elucidate the molecular mechanisms of SARS-CoV-2 infection in the lung and heart, we conducted paired experiments in human stem cell-derived lung alveolar type II (AT2) epithelial cell and cardiac cultures, that were productively infected with SARS-CoV-2. SARS-CoV-2 variants of concern infected heart and lung cells with comparable efficiency. With CRISPR-Cas9 mediated knock-out of ACE2, we demonstrated that angiotensin converting enzyme 2 (ACE2) was essential for SARS-CoV-2 infection of both cell types. Further processing of the spike protein in lung cells required TMPRSS2 while infection of cardiac cells was achieved through the endosomal pathway and Cathepsin L. Host responses were significantly different, with a strong interferon response following infection in cardiac cells but not in lung AT2 cells. Transcriptome profiling and phosphoproteomics demonstrated that response to SARS-CoV-2 depended strongly on the cell type. We evaluated antiviral drugs that are approved for treatment of COVID-19, drugs that showed antiviral activity in vitro but were not found to be effective in clinical trials or are still under investigation and drugs targeting molecules identified in our molecular datasets in both cell types. 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 drug combinations for effective treatment of a virus that affects multiple organ systems.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Heart, Lung, Stem Cell

DISEASE(S): Covid-19

SUBMITTER: Sean Humphrey  

LAB HEAD: Sean Humphrey

PROVIDER: PXD037615 | Pride | 2023-05-08

REPOSITORIES: Pride