A study published on November 28 in Science reports the discovery of a gene that strongly influences how sensitive a virus is to heat. During the major flu pandemics of 1957 and 1968, this gene moved from bird flu viruses into circulating human flu strains, which helped those strains thrive.

Seasonal human flu viruses infect millions of people each year. These common influenza A viruses usually multiply most effectively in the cooler upper airways, where temperatures average about 33°C. They do not spread as efficiently in the warmer lower respiratory tract, which is typically closer to 37°C.

How Fever Limits Infection and Why Bird Flu Can Resist It

Viruses spread through the body when left unchecked, sometimes leading to severe illness. Fever is one of the body's natural responses and can raise core temperature to as high as 41°C. Until recently, the exact way fever slows down viruses, and why some can withstand such heat, had not been fully understood.

Avian influenza viruses operate differently from human strains. They tend to multiply in the lower respiratory tract, and in their usual hosts, such as ducks and seagulls, they often infect the gut. Temperatures in these environments can reach 40-42°C.

Earlier work in cultured cells suggested that bird flu viruses are more tolerant of fever-level temperatures than human flu viruses. The new study uses in vivo experiments with mice infected with influenza viruses to shed light on how fever provides protection and why this protection may not be enough against avian strains.

Experiments Show Why Fever Slows Human Flu but Not Avian Flu

In the new research, scientists from Cambridge and Glasgow recreated fever conditions in mice to observe how the virus responded. They used a laboratory-adapted human-origin influenza strain known as PR8, which is not a risk to people.

Mice do not usually develop a fever when infected with influenza A viruses, so the researchers simulated one by increasing the temperature of the environment where the mice were kept (elevating the body temperature of the mice).

The results showed that raising body temperature to fever levels was highly effective at preventing human-origin flu viruses from replicating. However, similar temperature increases did not stop avian influenza viruses. A rise of just 2C was enough to turn what would normally be a deadly human-origin influenza infection into a mild one.

The PB1 Gene Helps Bird Flu Withstand Fever

The team also found that the PB1 gene, which is essential for copying the viral genome inside infected cells, plays a central role in temperature resistance. Viruses containing an avian-like PB1 gene were able to tolerate the high temperatures associated with fever and caused serious disease in mice. This discovery is notable because bird and human flu viruses can exchange genetic material when they infect the same host, such as pigs.

Dr. Matt Turnbull, the study's first author 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 Make Bird Flu a Persistent Global Threat

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 Fever Treatment and Future Research

According to the researchers, the findings may eventually affect treatment recommendations, although more studies will be necessary before any changes are made. Fever is often treated with antipyretic medications, including ibuprofen and aspirin. Some clinical evidence suggests that lowering fever might not always help patients and may even support the spread of influenza A viruses in humans.

The research received primary funding from the Medical Research Council, with additional support 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.