Related Experiment Video
Updated: Jul 26, 2025
Generation of 3D Whole Lung Organoids from Induced Pluripotent Stem Cells for Modeling Lung Developmental Biology and Disease
Published on: April 12, 2021
Parallel use of human stem cell lung and heart models provide insights for SARS-CoV-2 treatment
Rajeev Rudraraju1, Matthew J Gartner1, Jessica A Neil1
1The Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, VIC, Australia.
Abstract:
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 SARS-CoV-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 drug combinations for effective treatment of a virus that affects multiple organ systems.
Insights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects lungs and hearts. ACE2 is crucial, but lung and heart cells use different pathways, impacting antiviral drug development for COVID-19.
Area of Science:
- Molecular biology
- Virology
- Cardiology
- Pulmonology
- Drug discovery
Background:
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), leading to severe pulmonary and cardiac complications.
- Understanding the molecular mechanisms of SARS-CoV-2 infection in different organ systems is critical for developing effective treatments.
Purpose of the Study:
- To elucidate the molecular mechanisms of SARS-CoV-2 infection in human lung alveolar type II (AT2) epithelial cells and cardiac cells.
- To investigate the role of angiotensin-converting enzyme 2 (ACE2) and associated pathways in SARS-CoV-2 entry into lung and cardiac cells.
- To identify potential antiviral compounds and evaluate their efficacy and toxicity in relevant cell types.
Main Methods:
- Paired experiments using human stem cell-derived lung AT2 and cardiac cell cultures infected with SARS-CoV-2.
- CRISPR-Cas9-mediated knockout of ACE2 to determine its essentiality for infection.
- Transcriptome profiling and phosphoproteomics to analyze host responses.
- Evaluation of antiviral compounds for efficacy and toxicity.
Main Results:
- ACE2 is essential for SARS-CoV-2 infection in both lung AT2 and cardiac cells.
- Lung cells require TMPRSS2 for viral entry, while cardiac cells utilize the endosomal pathway.
- Host responses, including transcriptome and phosphoproteome profiles, differ significantly between lung and cardiac cells.
- Several antiviral compounds demonstrated distinct efficacy and toxicity profiles in the evaluated cell types.
Conclusions:
- The distinct cellular mechanisms of SARS-CoV-2 infection in lung and cardiac cells necessitate cell-type-specific therapeutic strategies.
- Evaluating antiviral drugs in multiple relevant cell types is crucial for accurate assessment of efficacy and toxicity.
- The findings provide insights for developing rational drug combinations to treat multi-organ involvement in COVID-19.
