Membrane-bound form of the angiotensin-converting enzyme 2 (ACE2) is essential to enable infection with SARS-CoV-2, the virus that causes COVID-19, according to a study published in the journal 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. Although both forms contain the same genetic sequence used by the SARS-CoV-2 spike protein receptor binding domain, soluble ACE2 does not have the ability to anchor to the cell membrane.
Current findings show that the long-lasting 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 involving soluble ACE2 proteins. They show that very low concentrations do not favor SARS-CoV-2 infectivity, while a high dose, which is intended to neutralize SARS-CoV-2, has the expected beneficial effect that is achieved by intercepting viral peaks so that they cannot reach the membrane-bound ACE2 “.
Daniel Batlle, MD, Earle, del Greco, Levin Professor of Nephrology / Hypertension and lead author of the study
Previous work by Batlle Lab and others has shown that when high-dose soluble ACE2 proteins were administered to SARS-CoV-2-infected mice, viral replication was prevented and overall survival was markedly improved.
However, other work has suggested that in a human kidney cell line, lower concentrations of soluble ACE2 may increase SARS-CoV-2 infectivity. This led to a team of international researchers led by Batlle conducting further research using low concentrations of soluble ACE2 proteins.
In the current study, the team evaluated 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.
In general, they found that lower concentrations of soluble ACE2 did not improve SARS-CoV-2 infectivity in the kidney cell line or in the lung and kidney organoids. In addition, using a new model of renal organoids that lacked ACE2, the researchers found that SARS-CoV-2 infectivity is not possible in the absence of ACE2. This was the case for the low and high concentrations of soluble ACE2 that had no impact on SARS-CoV-2 infection, demonstrating that membrane-bound ACE2 is the essential receptor for SARS infection. -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 promote infectivity in humans, “Batlle said.
Jan Andrzej Wysocki, MD, PhD, Assistant Professor of Medical Research in the Division of Nephrology and Hypertension, and Luise Hassler, Researcher in the Division of Nephrology and Hypertension, co-authored the study.
Other co-authors include Vasuretha Chandar, MS, and Robert Schwartz, MD, PhD, of 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, Max Delbrück Center for Molecular Medicine in Berlin; and Josef Penninger, PhD, of 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 a grant from the National Institutes of Health R21AI166940-01.
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Magazine reference:
Batlle, D., et al. (2022) Evidence for the essentiality of ACE2 bound to the human cell membrane and against soluble ACE2 for SARS-CoV-2 infectivity. Cell. doi.org/10.1016/j.cell.2022.05.004.