Endothelial cells elicit a pro-inflammatory response to SARS-CoV-2 without productive viral infection

• DOI: 10.1101/2021.02.14.431177
• Publication Date: 2021-02-17T08:00:36Z
• Authors: Lilian Schimmel; Keng Yih Chew; Claudia Stocks; Teodor Yordanov; Patricia Essebier; Arutha Kulasinghe; James Monkman; Anna Flavia Ribei...; Caroline Cooper; Lucia de Noronha; Anne K. Lagendijk; Kate Schroder; Larisa I. Labzin; Emma J. Gordon; Kirsty R. Short
• Keywords: 0301 basic medicine; 03 medical and health sciences; 3. Good health

ABSTRACTObjectivesThrombotic 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.MethodsHere, we use patient autopsy samples, primary human endothelial cells and anin vitromodel of the pulmonary epithelial-endothelial cell barrier to show that primary human endothelial cells express very low levels the SARS-CoV-2 receptor ACE2 and the protease TMPRSS2.ResultsAccordingly, endothelial cells can only be infected when SARS-CoV-2 is present at very high concentrations. However, this is not a productive infection (i.e. no infectious virus is produced) and viral entry induces an inflammatory response. 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. They do however sense and respond to infection in the adjacent epithelial cells, increasing ICAM-1 expression and releasing pro-inflammatory cytokines.ConclusionsTaken together, these data suggest thatin vivo, endothelial cells are unlikely to be infected with SARS-CoV-2 and that infection is only likely to 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 are still likely to play a key role in SARS-CoV-2 pathogenesis by sensing adjacent infection and mounting a pro-inflammatory response to SARS-CoV-2.