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Updated: Oct 14, 2025
Monitoring Changes in Human Umbilical Vein Endothelial Cells upon Viral Infection Using Impedance-Based Real-Time Cell Analysis
Published on: May 5, 2023
Endothelial cells are not productively infected by SARS-CoV-2
Lilian Schimmel1, Keng Yih Chew2, Claudia J Stocks1,3
1Institute for Molecular Bioscience, Division of Cell and Developmental Biology The University of Queensland Brisbane QLD Australia.
Insights
COVID-19 complications may arise from endothelial cell inflammation, not direct viral infection. SARS-CoV-2 infection of endothelial cells is unlikely, but they respond to nearby infections by releasing inflammatory cytokines.
Area of Science:
- Vascular biology
- Infectious diseases
- Cellular pathology
Background:
- Thrombotic and microvascular complications are common in fatal COVID-19 cases.
- The role of direct SARS-CoV-2 endothelial infection versus inflammation in these complications is debated.
Purpose of the Study:
- To investigate whether SARS-CoV-2 directly infects endothelial cells or if inflammation drives complications.
Main Methods:
- Analysis of autopsy samples from COVID-19 patients.
- Experiments using primary human endothelial cells.
- In vitro modeling of pulmonary epithelial-endothelial cell barriers.
Main Results:
- Endothelial cells express low ACE2 and TMPRSS2, limiting SARS-CoV-2 infection.
- Infection only occurs with ACE2 overexpression or high viral loads.
- Endothelial cells sense adjacent epithelial infection, increasing ICAM-1 and releasing cytokines.
Conclusions:
- Endothelial cells are unlikely to be infected by SARS-CoV-2 in vivo.
- Endothelial cells contribute to COVID-19 pathogenesis through inflammatory responses to infection.
Objectives:
Thrombotic and microvascular complications are frequently seen in deceased COVID-19 patients. However, whether this is caused by direct viral infection of the endothelium or inflammation-induced endothelial activation remains highly contentious.
Methods:
Here, we use patient autopsy samples, primary human endothelial cells and an in vitro model of the pulmonary epithelial-endothelial cell barrier.
Results:
We show that primary human endothelial cells express very low levels of the SARS-CoV-2 receptor ACE2 and the protease TMPRSS2, which blocks their capacity for productive viral infection, and limits their capacity to produce infectious virus. Accordingly, endothelial cells can only be infected when they overexpress ACE2, or are exposed to very high concentrations of SARS-CoV-2. We also show that SARS-CoV-2 does not infect endothelial cells in 3D vessels under flow conditions. We further demonstrate that in a co-culture model endothelial cells are not infected with SARS-CoV-2. Endothelial cells do however sense and respond to infection in the adjacent epithelial cells, increasing ICAM-1 expression and releasing pro-inflammatory cytokines.
Conclusions:
Taken together, these data suggest that in vivo, endothelial cells are unlikely to be infected with SARS-CoV-2 and that infection may only occur if the adjacent pulmonary epithelium is denuded (basolateral infection) or a high viral load is present in the blood (apical infection). In such a scenario, whilst SARS-CoV-2 infection of the endothelium can occur, it does not contribute to viral amplification. However, endothelial cells may still play a key role in SARS-CoV-2 pathogenesis by sensing adjacent infection and mounting a pro-inflammatory response to SARS-CoV-2.
