The membrane-bound form of angiotensin-converting enzyme 2 (ACE2) is essential for allowing infection with SARS-CoV-2, the virus that causes COVID-19, according to a study published in the review Cell.
There are two forms of ACE2 – a full-length form that can bind to the cell membrane of healthy host cells, and a shorter, soluble form that circulates in the blood in small amounts. While both forms contain the same genetic sequence used by the SARS-CoV-2 spike protein receptor binding domain, soluble ACE2 lacks the ability to anchor to the cell membrane.
The current findings demonstrate that the integral form is essential for SARS-CoV-2 infectivity while the soluble form does not promote infectivity, according to Daniel Batlle, MD, Earle, del Greco, Levin Professor of Nephrology/Hypertension and lead author of the study.
These findings are important for the COVID-19 field of promising therapies that involve ACE2 soluble proteins. They show that very low concentrations do not promote infectivity for SARS-CoV-2, whereas a high dose – which is the one targeted for the neutralization of SARS-CoV-2 – has the expected beneficial effect obtained in intercepting viral spikes such that they cannot reach membrane-bound ACE2.”
Daniel Batlle, MD, Earle, del Greco, Levin Professor of Nephrology/Hypertension and lead study author
Previous work by the Batlle lab and others demonstrated that when soluble ACE2 proteins were given in high doses to mice infected with SARS-CoV-2, viral replication was prevented and overall survival significantly improved.
However, other work has suggested that in a human kidney cell line, lower concentrations of soluble ACE2 may actually increase SARS-CoV-2 infectivity. This prompted a team of international researchers led by Batlle to carry out further research using low concentrations of soluble ACE2 proteins.
In the current study, the team assessed viral infectivity by measuring RNA levels in the same human kidney cell line infected with SARS-CoV-2, which was exposed to very low concentrations of Soluble ACE2. They also performed studies on human lung and kidney organoids infected with SARS-CoV-2.
Overall, they found that lower concentrations of soluble ACE2 did not increase SARS-CoV-2 infectivity in the kidney cell line or in lung and kidney organoids. Additionally, using a novel model of kidney organoids lacking ACE2, researchers found that SARS-CoV-2 infectivity is not possible in the absence of ACE2. This was the case for low and high concentrations of soluble ACE2 which had no impact on SARS-CoV-2 infection, demonstrating that membrane-bound ACE2 is the essential receptor for infection. by SARS-CoV-2, according to Batlle.
“Soluble ACE2 at low concentrations is found in normal people and patients with COVID-19 and cardiovascular disease at risk of complications from COVID-19, so it is reassuring to know that soluble ACE2 cannot not promote infectivity in humans,” Batlle said.
Jan Andrzej Wysocki, MD, PhD, assistant research professor of medicine in the Division of Nephrology and Hypertension, and Luise Hassler, researcher in the Division of Nephrology and Hypertension, were study co-authors.
Other co-authors include Vasuretha Chandar, MS, and Robert Schwartz, MD, PhD, from Cornell University; Vanessa Monteil, PhD, and Ali Mirazimi, MD, PhD, from the Karolinska Institute in Sweden; Elena Garreta, PhD, and Nuria Montserrat, PhD, from the Institute of Bioengineering of Catalonia in Spain; Michael Bader, PhD, of the Max Delbrück Center for Molecular Medicine in Berlin; and Josef Penninger, PhD, from the Department of Medical Genetics at the University of British Columbia in Vancouver, Canada.
This work was supported by a gift from the Joseph and Bessie Feinberg Foundation and National Institutes of Health grant R21AI166940-01.
Batlle, D. et al. (2022) Evidence in favor of essentiality of human cell membrane bound ACE2 and against soluble ACE2 for SARS-CoV-2 infectivity. Cell. doi.org/10.1016/j.cell.2022.05.004.