A Virus Resistant To Fever: The Evolution Of Avian Influenza And The Risk Of a New Pandemic

Fever is not just a sign of illness, but a natural defense mechanism of the body against infections. This study showed that a small increase in body temperature can hinder the multiplication of the influenza virus and protect against serious illness. However, influenza viruses originating from birds are able to resist this defense because they are adapted to higher temperatures. This helps explain why some influenza strains are more dangerous and highlights the importance of monitoring avian viruses that could cause future pandemics.

Influenza is an infectious disease caused by viruses that circulate continuously between humans and animals, especially birds. Among these viruses, the so-called type A influenza viruses are the most concerning, as they have a great capacity for genetic mutation and crossing the species barrier. Birds are the main natural reservoir of these viruses, and in them, infection usually occurs in the digestive system without causing significant damage.

An important detail is that birds naturally maintain a very high body temperature, generally between forty and forty-two degrees Celsius. Humans, on the other hand, have a lower body temperature, around thirty-seven degrees, and even when they have a fever, it rarely exceeds thirty-nine degrees. This temperature difference between species has profound implications for how influenza viruses adapt and behave.

Influenza viruses that circulate in humans over the years, called seasonal viruses, are adapted to multiply best in the cooler parts of the body, such as the nose and throat, where the temperature is around thirty-three degrees. Therefore, in most healthy people, these viruses cause mild to moderate symptoms.

In contrast, avian influenza viruses are adapted to much higher temperatures and can replicate efficiently in environments that would be hostile to human viruses. This detail helps explain why avian influenza virus infections in humans tend to be more severe.

When the human body detects an infection, one of the oldest and most universal responses is an increase in body temperature, known as fever. Fever is not just an unpleasant symptom, but a defense strategy that arose throughout evolution.

By raising body temperature, the organism creates a less favorable environment for the multiplication of many microorganisms, while simultaneously accelerating immune system processes. However, for a long time, it was unclear whether fever directly combats viruses, hindering their replication, or whether its effect is only indirect, by stimulating the immune response.

To clarify this question, researchers decided to investigate whether the increase in body temperature, by itself, would be able to prevent the multiplication of the influenza virus within the organism. The hypothesis was that influenza viruses adapted to humans would be sensitive to fever, while viruses of avian origin, accustomed to higher temperatures, might resist this natural defense.

To test this idea in a controlled manner, scientists created versions of the virus that were virtually identical to each other, differing only in their ability to multiply at high temperatures. This was possible because the genetic material of the influenza virus is divided into segments, which can be exchanged or modified.

The researchers focused on an essential viral protein responsible for copying its genetic material within infected cells. This protein functions as part of a viral replication "machine." It was discovered that versions of this protein originating from avian viruses allowed the virus to continue multiplying even at high temperatures.

Interestingly, historical analyses have shown that the major pandemic influenza viruses, responsible for the pandemics of 1918, 1957, and 1968, contained precisely this version of the avian-origin protein. These viruses caused much more severe illnesses than the seasonal viruses that circulated after them, suggesting a direct link between resistance to high temperatures and greater severity of infection.

To study the effect of fever on a living organism, scientists used a human influenza virus adapted in the laboratory, which does not cause serious illness in people but causes severe infection in mice. This virus behaves similarly to common human viruses, multiplying poorly at temperatures close to forty degrees Celsius.

From this, the researchers created a modified version, altering only two small components of the replication protein, so that the virus would behave like an avian virus in relation to temperature.

In the experiments, mice infected with either version of the virus developed severe illness when kept under normal conditions. However, when the researchers raised the ambient temperature to induce an increase in the animals' body temperature, simulating a moderate fever similar to that of humans, the results changed drastically.

Mice infected with the common human virus became much less ill and were largely protected. In contrast, mice infected with the modified temperature-resistant virus continued to develop severe illness, even with elevated body temperature.

These results directly showed that increased body temperature, by itself, can act as a powerful antiviral defense. A relatively small increase, of about two degrees Celsius, was enough to transform a potentially serious infection into a mild illness. However, this protection fails when the virus is able to multiply efficiently at high temperatures, as occurs with avian-borne viruses.

These findings help explain why avian influenza viruses and certain pandemic viruses cause more severe illness in humans. They carry adaptations that allow them to bypass one of the body's oldest defenses: fever.

This also raises an important alert for epidemiological surveillance. If a fever-resistant avian virus acquires the ability to easily transmit between humans, it could pose a high pandemic risk.

Avian influenza doesn't feel the heat. When mammals are infected with influenza viruses, they often raise their body temperature as an immune response. The resulting fever can protect against serious illness, but this defense is overcome by avian influenza viruses that have evolved to replicate at the higher body temperature of birds.

Furthermore, the study contributes to the debate on the use of fever-reducing medications. While these medications alleviate discomfort, they can, in some cases, eliminate an important natural defense against certain viruses. Understanding when fever is beneficial and when it is not can help guide more accurate clinical decisions in the future.

READ MORE:

Avian-origin influenza A viruses tolerate elevated pyrexic temperatures in mammals

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

Science. Vol 390, Issue 6776, 27 November 2025. 

DOI: 10.1126/science.adq4691

Abstract:

Host body temperature can define a virus’s replicative profile, influenza A viruses (IAVs) adapted to 40° to 42°C in birds are less temperature sensitive in vitro compared with human isolates adapted to 33° to 37°C. In this work, we show that avian-origin PB1 polymerase subunits enable IAV replication at elevated temperatures, including avian-origin PB1s from the 1918, 1957, and 1968 pandemic viruses. Using a model system to ensure biosafety, we show that a small increase in body temperature protects against severe disease in mice and that this protection is overcome by a febrile temperature-resistant PB1. These findings indicate that although elevated temperature itself can be a potent antiviral defense, it may not be effective against all influenza strains. These data inform both the clinical use of antipyretics and IAV surveillance efforts.