‘Accidental’ breakthrough helps develop new ways to prevent flu

By Stephen Beech

New ways to prevent flu are being developed following an "accidental" lab breakthrough.

Scientists investigating how influenza viruses replicate within cells "accidentally" discovered that different viruses use distinct strategies to initially infiltrate cells.

The team also found that it is possible to target specific molecules to prevent the viruses from entering new cells, thereby stopping their replication.

American researchers say their discovery provides "fundamental insights" into how seasonal influenza viruses infect people — and highlights a path for developing better medications to prevent infections in the future.

Principal investigator Dr. Emily Bruce said: "The hope is that fundamental, curiosity-based research like this helps to pave the way for novel strategies to treat and prevent influenza infections."

Several different flu strains can cause illness, with H1N1 and H3N2 influenza A viruses being the most common.

But current flu tests don't differentiate between the two viruses, and clinical treatments are the same for both.

While flu vaccines can help prevent infection, and antiviral drugs can shorten the illness and prevent complications in high-risk individuals, Bruce says there is a "dire" need for better medications to prevent flu viruses from replicating and infiltrating new cells in the human body.

Bruce and her colleagues at the University of Vermont's Larner College of Medicine examined H1N1 and H3N2 viruses isolated from the nasal passages of people who tested positive for the flu in 2022.

The study, published in the Journal of Virology, initially aimed to learn how viral proteins move within cells and enable viruses to replicate themselves, which is what causes people to become ill.

Bruce said: "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.

"We were looking at how influenza virus RNA segments are transported within cells to the right place at the right time to make new virus particles."

During the investigation, Bruce's team unexpectedly discovered a cellular pathway that blocked the viruses from entering lung cells.

The data revealed that H3N2, but not H1N1 viruses, failed to enter human lung cells when a particular protein called Rab11B was depleted.

Using reverse genetics, the team mapped this Rab11B-dependent defect and found a new and H3N2-specific role for Rab11B during viral entry into a lung cell.

The fortuitous discovery suggests that H1N1 and H3N2 viruses enter lung cells via different routes, and it can inform therapeutic targets to prevent viral entry.

Bruce said: "Viruses are like pirates from different countries hijacking someone's ship.

"Different viruses, like different types of pirates, use different methods to get onboard."

She added: "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.

"H1N1 and H3N2 need different proteins to get in, and if you get rid of the right protein, a specific virus can't get in."

Bruce says the discovery can help scientists think about new ways to prevent distinct flu viruses from entering cells.

She said the team will next seek to determine whether Rab11B-dependency is a fundamental property of H3N2 that no one realized previously, or whether it is new to currently circulating H3N2.