Abstract
SARS-CoV-2 infection can cause fatal inflammatory lung pathology, including thrombosis and increased pulmonary vascular permeability leading to edema and hemorrhage. In addition to the lung, cytokine storm-induced inflammatory cascade also affects other organs. SARS-CoV-2 infection-related vascular inflammation is characterized by endotheliopathy in the lung and other organs. Whether SARS-CoV-2 causes endotheliopathy by directly infecting endothelial cells is not known and is the focus of the present study. We observed 1) the co-localization of SARS-CoV-2 with the endothelial cell marker CD31 in the lungs of SARS-CoV-2-infected mice expressing hACE2 in the lung by intranasal delivery of adenovirus 5-hACE2 (Ad5-hACE2 mice) and non-human primates at both the protein and RNA levels, and 2) SARS-CoV-2 proteins in endothelial cells by immunogold labeling and electron microscopic analysis. We also detected the co-localization of SARS-CoV-2 with CD31 in autopsied lung tissue obtained from patients who died from severe COVID-19. Comparative analysis of RNA sequencing data of the lungs of infected Ad5-hACE2 and Ad5-empty (control) mice revealed upregulated KRAS signaling pathway, a well-known pathway for cellular activation and dysfunction. Further, we showed that SARS-CoV-2 directly infects mature mouse aortic endothelial cells (AoECs) that were activated by performing an aortic sprouting assay prior to exposure to SARS-CoV-2. This was demonstrated by co-localization of SARS-CoV-2 and CD34 by immunostaining and detection of viral particles in electron microscopic studies. Moreover, the activated AoECs became positive for ACE-2 but not quiescent AoECs. Together, our results indicate that in addition to pneumocytes, SARS-CoV-2 also directly infects mature vascular endothelial cells in vivo and ex vivo, which may contribute to cardiovascular complications in SARS-CoV-2 infection, including multipleorgan failure.
Highlights
The confirmed case count of the global COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is in excess of a hundred million, with over two million deaths
We found that SARS-CoV-2-infected Ad5-Human ACE2 (hACE2) mice had greater levels of pulmonary vascular inflammation than the Ad5-empty mice, as evidenced by a significantly higher number of nucleated cells that infiltrated into the pulmonary tissue with a particular accumulation within and around the adventitial layer of venules and arterioles from day 3 to day 12 post-infection (Figures 1A, B)
RNAscope, and immune electron microscopic studies to detect the presence of SARS-CoV-2 in pulmonary endothelial cells of SARS-CoV-2-infected Ad-hACE2 mice at 3 days post-infection (DPI), when the viral load in the lung is at its highest (Han et al, 2021)
Summary
The confirmed case count of the global COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is in excess of a hundred million, with over two million deaths. It is possible that some of these mutations will render current vaccines less effective, starting a new arms race between the virus and host. The new variant B.1.1.7, in the UK has 17 amino acid mutations, eight of which are in the S gene, and appears to be better at spreading between people. The new variant B.1.351 is driving a resurgence of cases in South Africa and has raised concerns about the efficacy of current vaccines. Given the emergence of three deadly coronavirus infections (SARS, MERS, COVID-19) from 2003 to 2019, it is almost inevitable that new coronavirus pandemics will continue to emerge. A better understanding of the pathobiology of SARS-CoV-2 is essential for developing novel host- and/or virus-directed treatment strategies
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