Fever-Proof Bird Flu Variant Could Fuel the Next Pandemic

Bird flu viruses present a significant risk to humans because they can continue replicating at temperatures higher than a typical fever. Fever is one of the body's main tools for slowing or stopping viral infections, yet research led by the universities of Cambridge and Glasgow shows that avian flu strains can keep multiplying even when the body reaches temperatures that normally hinder viruses.

In a study published in Science, the researchers identified a gene that strongly influences how sensitive a flu virus is to heat. During the major pandemics of 1957 and 1968, this gene moved into human flu viruses, and the resulting strains were able to spread efficiently.

Why Temperature Matters for Flu Viruses

Human flu viruses infect millions of people annually, with influenza A being the most common seasonal strain. These viruses replicate most effectively in the upper respiratory tract, where temperatures are around 33 °C. They replicate less efficiently deeper in the lungs, where temperatures rise to about 37 °C.

If left uncontrolled, viruses spread through the body and may cause severe illness. Fever is one of the body's protective responses and can raise core temperature to as high as 41 °C. Until recently, however, it remained unclear exactly how fever limits viral growth, or why some viruses can continue thriving despite it.

Avian Flu Thrives in Hotter Environments

Avian influenza viruses behave differently from human flu strains. They often grow in the lower respiratory tract, and in their usual hosts, including ducks and seagulls, they frequently infect the gut. These environments can reach temperatures of 40 to 42 °C.

Past laboratory studies using cultured cells showed that avian flu viruses tend to withstand temperatures similar to those seen during fever in humans. The new research turns to in vivo models, using mice infected with influenza viruses, to better understand how fever protects the body and why this protection may not be enough against bird flu.

Simulating Fever in Mice

The international team led by scientists in Cambridge and Glasgow created fever-like conditions in mice to observe how different flu strains responded. Their experiments used a laboratory-adapted human-origin influenza virus known as PR8, which is not a danger to humans.

Mice do not usually develop fever in response to influenza A viruses, so the team mimicked fever by raising the temperature of the environment where the mice lived (elevating the body temperature of the mice).

Human Flu Stops at High Heat, Avian Flu Does Not

The findings showed that increasing body temperature to fever levels effectively stopped human-origin flu viruses from replicating. This same temperature increase did not stop avian flu viruses. For human flu strains, raising the temperature by just 2 °C was enough to turn what would have been a lethal infection into a mild one.

A Key Gene Behind Bird Flu's Heat Resistance

The study also found that the PB1 gene, which supports viral genome replication inside infected cells, plays a major role in determining temperature sensitivity. Viruses with an avian-like PB1 gene tolerated fever-associated temperatures and caused severe illness in mice. This matters because human and bird flu viruses can exchange genes when they infect the same host, such as pigs, at the same time.

Dr. Matt Turnbull, first author of the study from the Medical Research Council Centre for Virus Research at the University of Glasgow, said: "The ability of viruses to swap genes is a continued source of threat for emerging flu viruses. We've seen it happen before during previous pandemics, such as in 1957 and 1968, where a human virus swapped its PB1 gene with that from an avian strain. This may help explain why these pandemics caused serious illness in people.

"It's crucial that we monitor bird flu strains to help us prepare for potential outbreaks. Testing potential spillover viruses for how resistant they are likely to be to fever may help us identify more virulent strains."

High Fatality Rates Highlight the Danger

Senior author Professor Sam Wilson, from the Cambridge Institute of Therapeutic Immunology and Infectious Disease at the University of Cambridge, said: "Thankfully, humans don't tend to get infected by bird flu viruses very frequently, but we still see dozens of human cases a year. Bird flu fatality rates in humans have traditionally been worryingly high, such as in historic H5N1 infections that caused more than 40% mortality.

"Understanding what makes bird flu viruses cause serious illness in humans is crucial for surveillance and pandemic preparedness efforts. This is especially important because of the pandemic threat posed by avian H5N1 viruses."

Implications for Treatment

Reference: "Avian-origin influenza A viruses tolerate elevated pyrexic temperatures in mammals" by Matthew L. Turnbull, Yingxue Wang, Simon Clare, Gauthier Lieber, Stephanie L. Williams, Marko Noerenberg, Akira J. T. Alexander, Sara Clohisey Hendry, Douglas G. Stewart, Joseph Hughes, Simon Swingler, Spyros Lytras, Emma L. Davies, Katherine Harcourt, Katherine Smollett, Rute M. Pinto, Hui-Min Lee, Eleanor R. Gaunt, Colin Loney, Johanna S. Jung, Paul A. Lyons, Darrell R. Kapczynski, Edward Hutchinson, Ana da Silva Filipe, Jeffery K. Taubenberger, Suzannah J. Rihn, J. Kenneth Baillie, Ervin Fodor, Alfredo Castello, Kenneth G. C. Smith, Paul Digard and Sam J. Wilson, 27 November 2025, Science.
DOI: 10.1126/science.adq4691

The research was funded primarily by the Medical Research Council, with additional funding from the Wellcome Trust, Biotechnology and Biological Sciences Research Council, European Research Council, European Union Horizon 2020, UK Department for Environment, Food & Rural Affairs, and US Department of Agriculture.