Science & Technology

NIH scientists identify mechanisms that may increase the infectivity of COVID variants

A creative representation of SARS-COV-2 virus particles with spiked proteins scattered on the surface. The image is not proportional to the actual size. Credits: National Institute of Infectious Diseases, NIH

Enzymatic processes alter the function of peplomer proteins.

Scientists at the National Institutes of Health have discovered that intracellular processes can limit infectivity. SARS-CoV-2Mutations in the, and alpha and delta variants can overcome this effect and increase the ability of the virus to spread.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.

Several more infectious variants of SARS-CoV-2, the causative virus, since the coronavirus pandemic began in early 2020 COVID-19 (New Coronavirus Infection), Appeared. The original or wild-type virus was followed by the alpha mutant that became widespread in the United States in early 2021, followed by the delta mutant, the most prevalent strain in circulation today. Mutants have acquired mutations that infect people and help them spread 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 fuse with their neighbors more often than cells with wild-type spikes. Cells with wild-type spikes also fuse less frequently 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.

The team analyzed to see if this process could happen to people as well. RNA Cellular expression from healthy volunteers. 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.

Reference: “Flynn cleavage of SARS-CoV-2 spikes is regulated by O-glycosylation” Lipping Zhang, Matthew Mann, Zulfeqhar A. Syed, Hayley M. Reynolds, E. Tian, ​​Nadine L. Samara, Darryl C. Zeldin, Lawrence A. Tabak and Kenny G. Tenhagen, November 3, 2021 Minutes of the National Academy of Sciences..
DOI: 10.1073 / pnas.2109905118

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.

NIH scientists identify mechanisms that may increase the infectivity of COVID variants NIH scientists identify mechanisms that may increase the infectivity of COVID variants

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