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Marshall Swearingen, MSU News Service

As more contagious and potentially lethal versions of the pandemic-causing coronavirus make headlines, Montana State University scientists have some good news: A local variant appears to undermine, not enhance, the pathogen's ability to overcome the human immune system.

As part of a global effort to monitor for mutations of the virus that could cause it to spread more easily or inflict more severe disease, the MSU team used cutting-edge technologies to identify and analyze a variant that circulated in Bozeman during the early months of the pandemic before apparently dying out. The results of the study were published online this month in the journal Cell Reports.

It would be alarming to discover a mutation that makes the coronavirus more pathogenic, "but it's also interesting to see that that's not always the case," said Artem Nemudryi, the lead author of the paper and a postdoctoral researcher in the Department of Microbiology and Cell Biology in MSU's College of Agriculture. "Some mutations strengthen the virus, and some weaken it, and learning why gives us a better understanding of how the virus works."

As any virus replicates, it's common for biochemical errors to result in mutations of one or two nucleotides, the building blocks of the virus's genetic code. Most of these errors result in genetic defects that limit the virus' ability to replicate and cause the altered versions of the virus to naturally disappear unnoticed.

However, in rare cases the errors improve viral fitness. For instance, the coronavirus variants that alarmed health officials after being detected in the U.K. and South Africa are more contagious and may resist antibodies because of alterations in their protein spikes, which are structures that bind to human cells.

Through a partnership with Bozeman Health Deaconess Hospital, researchers in the lab of Blake Wiedenheft, associate professor of microbiology, analyzed 55 samples from patients who tested positive for the disease during April-July 2020. Using a relatively new and powerful technology called nanopore sequencing, they recorded the entire genome of each virus sample, sometimes processing as many as 24 samples per day, which was "really fast," said study co-first author Anna Nemudraia, postdoctoral researcher in the Wiedenheft lab.

Among those samples, five had the same mutation: a deletion of the same 115 nucleotides in the virus's 30,000-nucleotide genome -a significant change that signaled a variant. Further analysis linked the mutation to a change in a single viral protein, which is a complex molecule that performs some biological function.

Scientists worldwide have sequenced the genomes of roughly 1.5 million coronavirus samples and share their results in a global database to help track mutations. By comparing their results against the database, the MSU researchers found that similar mutations in the protein, called ORF7a, had been observed elsewhere. Unlike the spike protein, which has an easily identifiable function, however, scientists haven't yet determined the function of ORF7a, although it appears to play some role in suppressing the human immune response.

"We know these genes aren't essential for viral replication but may be very important for how the virus evades the immune response," Nemudraia said.

That correlated with what the MSU researchers observed. In collaboration with members of Regents Professor Mark Jutila's lab, the team was able to show that the variant replicated at a much slower rate than the standard coronavirus, which is why the variant apparently died out within a relatively short time in Bozeman.

"It appears that this variant is basically incompetent at overcoming the immune system," Nemudryi said.

If the researchers had observed an apparently more pathogenic variant, they would have reported their findings immediately to health officials, Nemudryi added. And the Wiedenheft lab continues to monitor for new variants, having now sequenced the genomes of more than 160 coronavirus samples isolated from patients in Bozeman.

From the early days of the pandemic, MSU's research enterprise sought to help the community in the fight against the coronavirus. The Wiedenheft lab was a pioneer in measuring coronavirus in municipal wastewater as a way to warn of local outbreaks. Multiple MSU labs repurposed genetic analysis tools called qPCR machines to help Bozeman Health, and then the Montana Department of Public Health and Human Services, expand COVID-19 testing capacity. Helping to identify new variants of the virus was another way his lab could help out, said Wiedenheft, whose research normally focuses on the complex interactions between viruses and bacteria.

"I'm really grateful for the responsiveness of people in the lab," Wiedenheft said. "They've been willing to drop everything and work long days to make meaningful contributions to help with the pandemic." Nemudryi and Nemudraia, who led the work on monitoring for variants, "are highly talented researchers who were able to take an idea and turn it into reality within a couple days."

Other co-authors on the paper include Wiedenheft lab members Helen Lee, research assistant, and graduate students Calvin Cicha, Joseph Nichols and Tanner Wiegand; Department of Microbiology and Cell Biology faculty Diane Bimczok, associate professor; Jodi Hedges, assistant research professor; Mark Jutila, Regents Professor; Deann Snyder, research associate; and Karl Vanderwood of Gallatin City-County Health Department.