Influenza Gene Interactions May Help Researchers Accurately Predict Dominant Strains


Understanding the relationship between viral protein activity and rapid gene mutations could help researchers save more lives by creating a more effective flu vaccine.

Researchers identified the role of 2 proteins in viral evolution, neuraminidase (NA), and hemagglutinin (HA) to predict which strains of the flu should be targeted in a vaccine, in a study published in Cell Host & Microbe. Understanding interactions between HA, genes in proteins such as NA, and gene mutations can predict how HA will evolve, thus helping to more accurately predict future strains, according to the study.

“It’s a super high-stakes guessing game,” said Chris Brooke, associate professor of microbiology, University of Illinois Urbana-Champaign, in a press release. “We're basically sitting here trying to guess what variants might pop up next.”

The NA and HA proteins promote viral infection and spread. Researchers found that the 2 proteins were compensatory, meaning that a decrease in one would cause reduced activity in the other to achieve balance.

Each year in the United States, millions of people are infected with influenza and it costs billions more in direct medical costs. It is difficult to vaccinate against influenza because the virus mutates rapidly, creating multiple strains at once. Experts create vaccines based on predictions about which strains will be most prevalent.

“I think that emphasizes just how critical it is to better understand the fundamental rules that govern the evolution of viruses and how they escape from our immune systems,” Brooke said in the press release.

Brooke and colleagues compared a wildtype strain of influenza with 2 almost-identical strains, apart from the almost-identical strains having a mutation to reduce NA activity. The team used deep mutational scanning to create variations of the 3 strains that were HA mutated, then measured their HA activity and fitness.

When HA was faced with changes, the 2 viral strains with reduced NA activity showed a higher mutational tolerance. Brooke explained that NA and HA have different functions—NA breaks into cells, and HA escapes the cell. Consequently, when mutated NA was paired with mutated HA, neither had observably worse fitness. This basically means that the less influenza that could break into cells, the less chance there was of it escaping and spreading to new cells.

“The textbook view of mutations is that they are mostly deleterious,” said Tongyu Liu, a graduate student in Brooke’s lab and lead author on the paper in a press release.

“But here in our experiment, we demonstrated that the interaction between HA and NA could reshape the fitness effect of mutations, from mostly deleterious to primarily neutral.”

An additional study examined how immune cells target and attack HA to get rid of infection, finding that HA is reliant on NA to evade attacks from the immune cell. This study shows supportive evidence that NA affects HA activity and influenza strength, according to the investigators.

“It's really important to understand the rules that govern the evolution of the virus so that we can better predict the specific pathways it'll take,” Brooke said in the press release.


University of Illinois at Urbana-Champaign. Researchers explore gene interactions in influenza to help improve accuracy of flu vaccines. EurekAlert! October 18, 2022. Accessed on October 19, 2022.

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