Single Bird‑Flu Gene Enables Resistance to Human Fever, Study Shows

Researchers have identified a single viral gene that allows some avian influenza strains to withstand elevated body temperatures and continue replicating despite the human fever response. The discovery helps explain why certain bird flu viruses, including H5N1, can cause unusually severe disease in people.

Scientists at the University of Cambridge and the University of Glasgow found that the viral gene known as PB1 gives avian influenza viruses the ability to tolerate higher temperatures than seasonal human flu viruses. Many human-adapted influenza strains are optimized for the cooler environment of the upper respiratory tract and struggle to replicate at fever temperatures around 40°C, a natural defense the body uses during infection.

By contrast, avian influenza viruses such as H5N1 are adapted to the warmer internal temperatures of birds. In waterfowl — the natural hosts for many avian strains — H5N1 commonly replicates in the gut at temperatures of about 40–42°C, which helps explain the gene's heat tolerance.

How the researchers tested PB1

The team engineered two experimental influenza strains: one carrying PB1 from a bird-derived virus and the other carrying PB1 from a human-adapted strain. They tested both viruses in cell cultures and in mice. At normal body temperatures both viruses produced severe illness, but when mice were warmed to simulate a fever, the human-adapted virus showed a marked inability to replicate while the bird-PB1 strain continued to replicate effectively.

“This elegant study builds on the very simple observation that different animals have different body temperatures, and shows how this may impact the way that viruses replicate in new hosts as they cross species barriers,”

said Professor Wendy Barclay, Chair of the MRC Infections and Immunity Board.

The findings, published in Science, may help explain H5N1's high lethality in humans: since the late 1990s about 1,000 human infections have been reported worldwide, with a mortality rate of roughly 50%. The researchers note that avian-derived PB1 was also present in the influenza strains responsible for the 1957 and 1968 pandemics.

Implications for surveillance and preparedness

Study authors warn that the main concern is reassortment — the process by which a person infected simultaneously with an avian and a human flu virus can host viruses that swap gene segments. If a human-transmissible virus acquires an avian-derived PB1 gene, it might retain efficient spread between people while becoming more resistant to fever-mediated suppression.

“Understanding what makes bird flu viruses cause serious illness in humans is crucial for surveillance and pandemic preparedness,” said Professor Sam Wilson, a co-author. Dr Matt Turnbull, the study's first author, added that monitoring bird flu strains for fever resistance could help identify more virulent threats and guide public health responses.

These results underscore the importance of continued surveillance of avian influenza, research into viral factors that affect host adaptation, and preparedness planning that considers how gene exchange between animal and human influenza viruses could alter virulence and transmissibility.