A team of researchers from the Larner College of Medicine at the University of Vermont has made a discovery that challenges a long-held assumption about influenza: not all flu viruses enter human cells in the same way.
The finding, detailed in The Journal of Virology, reveals that H1N1 and H3N2, two of the most prevalent influenza A virus strains, utilize distinct cellular pathways to infect lung tissue. This difference has the potential to reshape strategies for developing antiviral medications.
Researchers have determined that different proteins are required for these viruses to gain entry. If a necessary protein is removed, a specific virus will be blocked from infecting a cell.
The study’s lead author, Emily Bruce, and her colleagues were not initially searching for this specific revelation. Their primary objective was to investigate how influenza virus RNA segments move within infected cells to assemble new viral particles. The discovery about entry pathways emerged unexpectedly as a deviation from their main line of inquiry.
“We were investigating how flu virus RNA segments are transported to the precise location and at the right time within cells to make new viral particles,” Bruce explained. During their investigation, the team identified a cellular mechanism that prevented viruses from entering lung cells.
The key to this identification was a protein known as Rab11B. By tracing a defect associated with this protein, the scientists realized that H1N1 and H3N2 viruses employ different routes for cellular invasion.
Bruce likened the viruses to “pirates from different countries boarding a ship. Each virus, like each band of pirates, uses different methods to get on board.”
Influenza continues to pose a significant global health threat. The World Health Organization estimates that between 10% and 20% of the world’s population contracts the flu annually, and the virus is directly responsible for 250,000 to 500,000 deaths from respiratory infections each year. The development of novel treatment methods is therefore urgently needed.
“There is a critical need for more effective drugs that can prevent flu viruses from replicating and from entering new human cells,” Bruce stated.
There are three types of influenza viruses, designated A, B, and C. Types A and B are responsible for seasonal epidemics of greatest public health concern, while infections in animals—particularly swine and birds—add another layer of risk.
Type A causes the most severe outbreaks. Type B typically results in more localized epidemics. Type C causes only mild illness with few symptoms and is rarely detected.
Within influenza A, H1N1 and H3N2 are the predominant strains.
Working with viruses isolated from the nasal passages of patients identified with the flu in 2022, the Vermont-based team employed reverse genetics to examine the behavior of H1N1 and H3N2 viruses within cells. Their findings indicated a departure from the established understanding.
“We used to think that all influenza viruses used the same entry pathway into the cell, but we found that is not the case,” Bruce said. “H1N1 and H3N2 viruses require different proteins to enter, and if you remove the required protein, that specific virus cannot get into the cell.”
The study reports that the two strains “enter the cell through different pathways that are independent of sialic acid levels.” The authors position this work as foundational for an expanding class of viruses associated with Rab11.
“Our data provide fundamental insights for a growing class of Rab11-dependent viruses,” the article’s introduction states.
The practical implication is clear. If each strain relies on its own molecular keys to unlock a cell, then these keys become targets for drug development. Block them, and replication will cease.
“We are hopeful that curiosity-driven research like this will help pave the way for novel strategies for treating and preventing influenza,” Bruce commented.
This potential has clinical relevance. Current diagnostic tests do not differentiate between H1N1 and H3N2, leading physicians to treat both strains with the same antiviral medications.
The development of strain-specific drugs in the future will necessitate both more precise diagnostics and a revision of treatment protocols.
The results from the Vermont-based research emerge at a time when scientists globally are striving to develop treatments that move beyond the outdated approach of neuraminidase inhibitors.
By identifying a structural divergence between the two most commonly circulating winter flu strains, the study points to a biological aspect that drug developers have yet to fully exploit.
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