NIH scientists identify mechanisms that can affect the infectivity of SARS-CoV-2 mutants

news release

Friday, November 5, 2021

Enzymatic processes alter the function of peplomer proteins.

Scientists at the National Institutes of Health have said that intracellular processes may limit the infectivity of SARS-CoV-2, and mutations in alpha and delta mutants overcome this effect and increase the ability of the virus to spread. I discovered that there is a possibility.Survey results published online Minutes of the National Academy of Sciences.. The study was led by Dr. Kelly Tenhagen, Principal Researcher at the National Institute of Dental and Facial Research (NIDCR) at NIH.

Since the coronavirus pandemic began in early 2020, several more infectious variants of SARS-CoV-2, the virus that causes COVID-19, have emerged. The original or wild-type virus was followed by the alpha mutant, which became widespread in the United States in early 2021, followed by the delta mutant, a strain that is prevalent today. Mutants have acquired mutations that help spread and infect people more easily. Many of the mutations affect the peplomer that the virus uses to invade cells. Scientists are trying to understand how these changes change the functioning of the virus.

“Through the pandemic, NIDCR researchers have applied their expertise in oral health science to answer important questions about COVID-19,” said NIDCR directors Rena D’Souza, DDS, Ph.D. Says. “This study provides fresh insights into the greater infectivity of alpha and delta mutants and provides a framework for the development of future therapies.”

The outer surface of SARS-CoV-2 is decorated with spike proteins that the virus uses to attach and invade cells. However, before this happens, the peplomer must be activated by a series of cleavages or cleavages by the host protein, starting with the furin enzyme. In alpha and delta variants, mutations to peplomers appear to promote furin cleavage, which is thought to be more effective for the virus to invade cells.

Studies have shown that protein cleavage can be reduced by adding a bulky sugar molecule (a process performed by an enzyme called GALNT) next to the cleavage site. Ten Hagen’s team wondered if this would happen to the SARS-CoV-2 peplomer, and if so, whether it would alter the function of the protein.

Scientists have investigated the effect of GALNT activity on peaplomers in Drosophila and mammalian cells. Experiments have shown that one enzyme, GALNT1, adds sugar to wild-type peplomer, and this activity reduces furin cleavage. In contrast, mutations to peplomers, like mutations in alpha and delta mutants, reduce GALNT1 activity and increase furin cleavage. This suggested that GALNT1 activity may partially suppress furin cleavage in wild-type viruses, and alpha and delta mutations overcome this effect and prevent furin cleavage from being checked.

Further experiments supported this idea. Researchers have expressed wild-type or mutant spikes in dish-grown cells. They observed a tendency for cells to fuse with their neighbors. This is an action that can promote the spread of the virus during infection. Scientists have found that cells expressing mutated peplomers are more likely to fuse with adjacent cells than wild-type cells. Cells with wild-type spikes also have less fusion in the presence of GALNT1, suggesting that their activity may limit the function of the spike protein.

“Our findings show that alpha and delta mutations can overcome the suppressive effects of GALNT1 activity and increase the ability of the virus to enter cells,” said Ten Hagen.

To see if this process also occurs in humans, the team analyzed RNA expression in healthy volunteer cells. Researchers have found that GALNT1 is widely expressed in lower and upper respiratory tract cells that are susceptible to SARS-CoV-2 infection. This indicates that this enzyme can affect human infectious diseases. Scientists have theorized that individual differences in GALNT1 expression may affect the spread of the virus.

“This study suggests that GALNT1 activity may regulate viral infectivity and provides insight into how mutations in alpha and delta mutants affect this,” he said. Tenhagen said. This knowledge may be useful in future efforts to develop new interventions.

This study was supported by the NIDCR department of In-Wall Studies. There was also support from the on-campus program of the National Institute of Environmental Health Sciences.

This press release describes the results of basic research. Basic research deepens our understanding of human behavior and biology. This is the basis for promoting new and better ways to prevent, diagnose and treat illness. Science is an unpredictable and gradual process. Advances in each study are often based on past discoveries in unexpected ways. Most clinical progress is impossible without knowledge of basic basic research. For more information on basic research, please visit the following website. https://www.nih.gov/news-events/basic-research-digital-media-kit..

About the National Institute of Dental and Craniofacial Research: NIDCR Is one of the leading domestic funders of research on oral, dental and craniofacial health.

About the National Institutes of Health (NIH):NIH, a US medical research institute, has 27 laboratories and centers and is a component of the US Department of Health and Human Services. NIH is a leading federal agency that conducts and supports basic, clinical, and translational medical research, investigating the causes, treatments, and treatments for both common and rare diseases. For more information on NIH and its programs, please visit: www.nih.gov..

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