Bird flu viruses dodge the human body’s fever defense

Fever is one of the body’s oldest antiviral tactics: turn up the heat to make life hard for invading pathogens. But new research led by the University of Cambridge shows why that strategy falters against avian influenza.

The team pinpointed a viral gene that sets how tolerant a flu virus is to heat and found that many bird-origin viruses can keep replicating at temperatures that shut down human flu.

The work helps explain past pandemic dynamics and highlights a practical test for spotting more dangerous strains before they spread.

Bird flu survival hinges on heat

Seasonal human influenza A viruses prefer the cooler airways of the upper respiratory tract, roughly 91°F (33°C). They struggle as temperatures climb toward 98.6°F (37°C) deeper in the lungs, and even more during fever.

Avian influenza viruses flip that script. In their natural hosts – ducks, gulls, and other birds – they often infect the gut, where temperatures run 104–108°F (40–42°C). In people, they’re more prone to the warmer lower respiratory tract.

That fundamental difference hinted for years that fever might curb human flu better than bird flu, but the mechanism wasn’t clear.

Testing fever’s real power

To probe cause and effect, the researchers used a human-origin lab strain (PR8) in mouse models.

Mice don’t reliably spike fevers with the flu, so the team mimicked fever by housing animals at higher ambient temperatures to elevate core temperature in a controlled way.

The result was stark: a modest 3.6°F (2°C) rise transformed lethal PR8 infections into mild disease. In other words, human-like flu replication is heat-sensitive in vivo.

By contrast, avian-like viruses kept going at fever-range temperatures, suggesting that many bird strains can shrug off the body’s thermal defense.

Tracking bird flu’s hidden moves

The key difference was traced to PB1, one of the polymerase genes that copy the virus’s genome inside infected cells. Swapping in an avian-like PB1 made viruses far more temperature-resilient. Swapping it out reduced resilience.

That matters for evolution: when human and avian strains co-infect an intermediary host (pigs are a classic example), they can exchange gene segments, a process known as reassortment.

Historical forensic genetics shows that in 1957 and 1968, human pandemic strains acquired an avian PB1. That shift likely helped them replicate efficiently in the warmer parts of the airway despite fever.

“The ability of viruses to swap genes is a continued source of threat for emerging flu viruses,” said the Matt Turnbull of the University of Glasgow, the study’s lead author.

Researchers also pointed out how crucial it is to monitor bird flu strains to help us prepare for potential outbreaks. Testing potential spillover viruses for fever resistance may help identify more virulent strains.

Tracking today’s bird flu threat

Although bird-to-human transmission remains uncommon, the severity of many documented cases keeps public health agencies on alert.

That concern has grown with the ongoing spread of H5N1 in wild birds and its sporadic appearances in mammalian hosts.

“Thankfully, humans don’t tend to get infected by bird flu viruses very frequently, but we still see dozens of human cases a year,” said the study’s senior author Sam Wilson.

“Bird flu fatality rates in humans have traditionally been worryingly high, such as in historic H5N1 infections that caused more than 40 percent mortality.”

“Understanding what makes bird flu viruses cause serious illness in humans is crucial for surveillance and pandemic preparedness efforts.”

A practical implication is to add a fever-resilience check to the lab toolkit: screen candidate spillover viruses for replication at febrile temperatures and flag those that keep growing.

Rethinking bird flu fever suppression

The findings also brush up against a perennial clinical question: should we routinely suppress fever with antipyretics like ibuprofen or aspirin during influenza?

The team emphasizes that more work is needed before changing guidelines, but they note existing clinical evidence that lowering fever may not always help patients. In fact, it might even increase viral shedding and transmission in some contexts.

If fever differentially suppresses human-like strains but not avian-like ones, blanket fever suppression could, in theory, remove a key layer of innate control for the former without affecting the latter.

Genetics behind heat survival

Taken together, the study links a specific viral gene (PB1) to a host-level defense (fever), clarifying why human flu burns out at higher temperatures while many avian-origin strains keep replicating.

The research also offers a coherent explanation for historical reassortment events that coincided with severe pandemics.

The immediate next steps fall into translational work. That includes adding temperature-sensitivity assays to surveillance, mapping PB1 variants in birds and pigs, and examining whether the polymerase’s heat tolerance could be a treatment target.

Thus, fever is still a powerful antiviral, just not a universal one. And in a world where avian and human influenzas continue to cross paths, the thermal “rules” of replication are part of the risk calculus.

The study is published in the journal Science.

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