The current COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus gains entry to host cells via ACE2, which is expressed by type 2 alveolar epithelial cells in the lungs and by cells in other tissues, including the heart, kidney and blood vessels. Researchers now show that SARS-CoV-2 can infect human blood vessel and kidney organoids and that this infection can be inhibited by human recombinant soluble ACE2 (hrsACE2).
To assess whether hrsACE2 — a decoy protein that has already been tested in phase I and II clinical trials — can inhibit the interaction between SARS-CoV-2 and ACE2, Josef Penninger, Ali Mirazimi, Nuria Montserrat and colleagues administered the recombinant protein to SARS-CoV-2-infected Vero E6 cells. Treatment of cells with hrsACE2 inhibited SARS-CoV-2 infection in a dose-dependent manner and attenuated propagation of the virus.
Based on the hypothesis that the presence of ACE2 in extrapulmonary tissues might explain the multi-organ dysfunction caused by COVID-19, the researchers developed human capillary organoids from induced pluripotent stem cells, and kidney organoids from human embryonic stem cells. “Importantly, single-cell RNA sequencing of the kidney organoids showed that ACE2 is expressed in different cell populations, including tubular-like cells and podocyte-like cells,” says Montserrat. Following infection of the organoids with SARS-CoV-2 the researchers could detect viral RNA that increased in the days following infection, indicative of viral replication. Addition of hrsACE2, however, again reduced SARS-CoV-2 levels in a dose-dependent manner. “Our findings not only suggest that tissue organoids can be used to study the effects of SARS-CoV-2 on extrapulmonary tissues, but also suggest that rhsACE2 might block the virus from entering target cells,” says Penninger.
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Monteil, V. et al. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell https://doi.org/10.1016/j.cell.2020.04.004 (2020), pre-proof available at https://www.cell.com/pb-assets/products/coronavirus/CELL_CELL-D-20-00739.pdf
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Allison, S.J. SARS-CoV-2 infection of kidney organoids prevented with soluble human ACE2. Nat Rev Nephrol 16, 316 (2020). https://doi.org/10.1038/s41581-020-0291-8
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DOI: https://doi.org/10.1038/s41581-020-0291-8
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