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.
