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Now, researchers at Washington University School of Medicine in St. Louis have found that a single mutation gives SARS-CoV-2 the ability to enter cells through another route – one that does not require the ACE2. The possibility of using an alternative route of entry opens up the possibility of escaping COVID-19 antibodies or vaccines, but researchers have found no evidence of such an escape. However, the discovery shows that the virus can change unexpectedly and find new ways to cause infection. The study is published in the journal Cell Reports.
“This mutation occurred at one of the places that change a lot as the virus circulates in the human population,” said co-lead author Sebla Kutluay, PhD, assistant professor of molecular microbiology.
“Most of the time, alternative receptors and attachment factors just enhance ACE2-dependent entry. But in this case, we found an alternative way to infect a key human lung cell that the virus has found. acquired this ability through a mutation that we know happens. This is something we absolutely need to know more about, ”said Kutluay.
The discovery was fortuitous. Last year, Kutluay and co-lead author M. Ben Major, PhD, Alan A. and Edith L. Wolff Distinguished Professor of Cell Biology and Physiology, planned to study the molecular changes that occur in the inside cells infected with SARS-CoV-2.
Most researchers study SARS-CoV-2 in primate kidney cells because the virus grows well there, but Kutluay and Major felt it was important to do the study in the lungs or others. cells similar to those that are naturally infected. To find more relevant cells capable of growing SARS-CoV-2, Kutluay and Major examined a panel of 10 lung and head and neck cell lines.
“The only one that could have been infected was the one I had included as a negative control,” Major said. “It was a human lung cancer cell line with no detectable ACE2. So it was a crazy surprise,” he said.
Kutluay, Major and colleagues, including co-lead authors and postdoctoral fellows Maritza Puray-Chavez, PhD, and Kyle LaPak, PhD, as well as co-authors Dennis Goldfarb, PhD, assistant professor of cell biology and physiology and medicine, and Steven L. Brody, MD, Professor Dorothy R. and Hubert C. Moog of lung disease in medicine and a professor of radiology found that the virus they were using for the experiments had detected a mutation.
The virus was originally obtained from a person in Washington state infected with COVID-19, but as it grew over time in the lab, it acquired a mutation that led to a change in a single amino acid at position 484 in the virus. peak protein. SARS-CoV-2 uses a spike to attach to ACE2, and position 484 is a hot spot for mutations.
A variety of mutations at the same position have been found in viral variants from humans and mice, and in viruses grown in the laboratory. Some of the mutations found in virus samples taken from people are identical to those Kutluay and Major found in their variant. The alpha and beta variants of concern have mutations at position 484, although these mutations are different.
“This position changes over time in the human population and in the laboratory. Based on our data and that of others, it is possible that the virus is under selective pressure to enter cells without using the virus. ‘ACE2. In many ways, it’s frightening to think of the world’s population fighting a virus that is diversifying the mechanisms by which it can infect cells, ”Major said.
To determine whether the possibility of using an alternative route of entry allowed the virus to escape COVID-19 antibodies or vaccines, the researchers looked at panels of antibodies and blood serum with antibodies from people who have been vaccinated for COVID-19 or recovered from COVID-19 infection. There was some variation, but in general the antibodies and blood sera were effective against the virus carrying the mutation.
It is not yet clear whether the alternative route kicks in under real conditions when people are infected with SARS-CoV-2. Before researchers can begin to answer this question, they must find the alternate receptor the virus uses to enter cells.
“It is possible that the virus uses ACE2 until it runs out of cells with ACE2, then it switches to using this alternate route, it could have relevance in the body, but without knowing the receptor, we can’t say what the relevance is going to be, “Kutluay said. The Major added,” That’s where we’re going right now. What is the receiver? If it’s not ACE2, what is it? “