Study shows cell membrane-bound enzyme is essential for COVID-19 infection

The membrane-bound form of angiotensin-converting enzyme 2 (ACE2) is essential in enabling 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. While both forms contain the same genetic sequence used by the receptor-binding domain of the SARS-CoV-2 spike protein, soluble ACE2 lacks the ability to anchor to the cell membrane.

The current results show that the whole form is essential for SARS-CoV-2 infectivity, while the soluble form does not promote infectivity, according to Dr. Daniel Batlle, The Earle, del Greco, Levin Professor of Nephrology/Hypertension and study lead author.

“These results are important to the COVID-19 field of promising therapies that involve soluble ACE2 proteins,” Batlle said. “They show that very low concentrations do not promote infectivity for SARS-CoV-2, while a high dose – aimed at neutralizing SARS-CoV-2 – has the expected positive effect, which is achieved by scavenging the viral spikes such as e.g that they cannot reach the membrane-bound ACE2.”

Previous work from the Batlle lab and others has shown that when soluble ACE2 proteins were administered at high doses to mice infected with SARS-CoV-2, viral replication was prevented and overall survival was significantly improved.

However, other work suggests that in a human kidney cell line, lower levels of soluble ACE2 may actually increase the infectivity of SARS-CoV-2. This prompted a team of international researchers led by Batlle to conduct further research using low levels 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 and exposed to very low levels of soluble ACE2. They also conducted studies on human lung and kidney organoids infected with SARS-CoV-2.

Overall, they found that lower levels of soluble ACE2 did not enhance SARS-CoV-2 infectivity in the kidney cell line or in the lung and kidney organoids. In addition, using a new model of kidney organoids lacking ACE2, the researchers discovered that SARS-CoV-2 infectivity is not possible without ACE2. This was true for both low and high concentrations of soluble ACE2, which had no effect on SARS-CoV-2 infection, showing that membrane-bound ACE2 is the essential receptor for SARS-CoV-2 infection, according to Batlle.

“Soluble ACE2 at low levels is found in normal humans and patients with COVID-19 and cardiovascular disease at risk for COVID-19 complications, so it is reassuring to know that soluble ACE2 cannot promote human infectivity.” ‘ Batlle said.