COVID-19, cardiovascular SARS-CoV-2 receptors, the influence of age and susceptibility of endothelial cells to infection

By Blerina Ahmetaj-Shala

In a paper just accepted for publication in JACC Basic to Translation Science, we have used publicly available transcriptomic data to investigate the expression of key putative SARS-CoV-2 entry and processing genes in a panel of human tissues and cells.

Vascular and cardiovascular inflammation and thrombosis occur in patients with severe coronavirus disease 2019 (COVID-19). Advancing age is the most significant risk factor for severe COVID-19. Our team, which included members from NHLI and Biomedical Research Centre, aimed to map gene expression across our target tissues and cells and determine how age, as the single most dominant risk factor for severe COVID-19, affects expression of SARS-CoV-2 entry and processing genes in human cardiorenal and other tissues. We focused on cardiorenal tissues, including aorta, coronary artery, heart (atria and left ventricle), whole blood, and the kidney and for comparison the colon, spleen, and lung. For cells, we focused on endothelial cells and, for comparison, airway (nasal and bronchial) epithelium and leukocytes (peripheral blood mononuclear cells). Using the GTex (tissues) and NCBI/Array Express (cells) databases, we found that 1) cardiovascular tissues and endothelial cells express putative genes for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection, including ACE2 and BSG; 2) The ACE2 and BSG pathways somewhat polarize to lung/epithelium and vessel/endothelium, respectively; 3) expression of host genes is relatively stable with age; and 4) notable exceptions are ACE2, which decreases with age in some tissues, and BSG, which increases with age in endothelial cells, suggesting that BSG expression in the vasculature may explain the heightened risk for severe disease with age. There is controversy in the field regarding the functional relevance of BSG as a receptor for SARS-CoV-2, nonetheless, since BSG is utilised by other pathogens and functions in a range of cardiovascular diseases and fibrosis, our observations may have relevance to our understanding of the diseases associated with ageing.

In collaboration with Prof Wendy Barclay at the Department of Infectious Diseases, we have now further expanded this work and examined the permissivity of primary endothelial cells to infection by SARS-CoV-2 or by pseudoviruses expressing SARS-CoV-2 spike protein. We made the surprising discovery that endothelial cells are not susceptible to infection with SARS-CoV-2 in vitro and that this is best explained by low levels of ACE2 expression. These findings clarify that the vascular and thrombotic syndrome seen in severe COVID-19 is may be independent of direct endothelial cell infection with SARS-CoV-2 and as such, likely to be mediated by factors released by adjacent infected cells (e.g. epithelial cells), circulating systemic inflammatory mediators and/or SARS-CoV-2 virus without conventional binding, cell entry and virus replication. Our work also suggests that where viremia occurs in COVID-19, SARS-CoV-2 passes through the endothelium facilitated by loss of barrier function, as a result of local inflammation at the site of infection. This work is published in bioxriv (https://www.biorxiv.org/content/10.1101/2020.11.08.372581v1) and is currently under review in a leading cardiovascular journal.

References

Ahmetaj-Shala, B., Vaja, R., Atanur, S. S., George, P. M., Kirkby, N. S., & Mitchell, J. A. (2020). Cardiorenal tissues express SARS-CoV-2 entry genes and basigin (BSG/CD147) increases with age in endothelial cells. JACC. Basic to Translational Science, 10.1016/j.jacbts.2020.09.010. Advance online publication. https://doi.org/10.1016/j.jacbts.2020.09.010