Emily Bruce's lab at the University of Vermont was hunting for how flu viruses shuffle their genetic cargo inside cells when they stumbled onto something far more promising: a molecular gatekeeper that blocks one of the most common flu strains from entering human lung cells in the first place.
The finding, published in The Journal of Virology, emerged from research examining H1N1 and H3N2 influenza A viruses—the two strains responsible for most seasonal flu infections. What began as a curiosity-driven investigation into viral replication has illuminated a fundamentally new understanding of how these viruses penetrate cells, offering a pathway toward treatments that could prevent infection before it takes hold.
"You don't get sick when a virus is in one cell. You get sick because a virus replicates itself and goes into many more cells," explains Bruce, an assistant professor of microbiology and molecular genetics at the Larner College of Medicine. Her team was examining viruses isolated from nasal passages of people who tested positive for influenza in 2022, tracing how viral RNA segments navigate within cells to construct new virus particles. It was during this meticulous work that they discovered something unexpected: a cellular protein called Rab11B that prevented H3N2 viruses from entering lung cells—but only H3N2, not H1N1.
Using reverse genetics, the researchers mapped this difference and uncovered a discovery that reshapes how scientists think about seasonal flu: the two most common flu viruses don't use the same route to invade cells. H1N1 and H3N2 require different proteins to gain entry, meaning they are fundamentally distinct in how they hijack human cells.
"Viruses are like pirates from different countries hijacking someone's ship," Bruce says. "Different viruses, like different types of pirates, use different methods to get onboard. We had previously thought that all flu viruses used the same way to get into a cell, but we discovered that this is not true."
This distinction matters enormously in the landscape of flu prevention and treatment. Current diagnostic tests cannot differentiate between H1N1 and H3N2, and clinical treatments remain the same for both. While seasonal vaccines can reduce infection risk and antiviral drugs can shorten illness in high-risk populations, neither approach directly stops the virus from entering new cells. The urgent need for better preventive medications—one that could block a virus before it establishes infection—remains largely unmet.
The accidental discovery suggests a new strategy: if scientists can target Rab11B or block its function in H3N2-specific ways, they might prevent that virus from entering cells entirely. The next phase of research will determine whether Rab11B-dependency is a fundamental property of H3N2 viruses that researchers simply hadn't recognized before, or whether it reflects changes in currently circulating strains. Understanding the precise molecular mechanism of how Rab11B facilitates H3N2 entry will be crucial to developing such therapies.
For Bruce, this serendipitous finding validates the importance of fundamental, hypothesis-free research. "The hope is that fundamental, curiosity-based research like this helps to pave the way for novel strategies to treat and prevent influenza infections," she says. In a world where flu viruses continue to circulate and evolve, knowing that these pirates use different methods to board the ship opens new possibilities for keeping them off entirely.