When you suffer a severe case of flu (influenza), your temperature soars. That is the body mounting an immune response to block the virus from replicating. Unlike seasonal influenza viruses that infect humans, avian influenza viruses are not prevented from causing severe disease even by fever. That is because the "thermometer" of avian influenza viruses is already set to a higher temperature.
An international team led by Sam Wilson of the University of Cambridge said in Science on the 28th that "we confirmed in animal experiments that the human fever immune response is useless against avian influenza viruses that have already adapted to birds' high body temperatures." Scientists said the study could help prepare for a pandemic by revealing why avian influenza viruses are so deadly in humans.
◇ Avian-type replication genes function even at high temperatures
The team tested how the human fever immune response affects type A influenza viruses that infect humans and birds, respectively. They injected laboratory-cultured PR8 influenza viruses into mice. This strain is not dangerous to humans, and its genes involved in viral replication were modified to resemble those of either human or avian influenza viruses.
Influenza viruses have evolved to suit their hosts. A prime example is temperature adaptation. The upper respiratory tract, from the mouth and nose to the larynx, is 33 C in humans, and the lower respiratory tract, from the bronchi to the lungs, is 37 C. Avian influenza viruses replicate in birds' lower respiratory tracts and intestines, where body temperatures reach 40–42 C.
Unlike humans, mice do not develop fever when infected with influenza viruses. The researchers instead raised the room temperature to see how the viruses respond to a fever-like state. In the experiments, mice infected with influenza viruses carrying human-type genes died at normal temperatures but survived at 41 C, which simulates a fever response. Because the virus could not replicate at high temperatures, a lethal infection turned into a mild illness. In contrast, mice injected with viruses carrying avian-type genes died at both normal and high temperatures.
The team also found that the PB1 polymerase protein, which plays a key role in viral genome replication, acts as a kind of thermometer. Influenza viruses with avian-type PB1 genes replicated normally even at high temperatures and caused fatal disease in mice. Viruses with human-type PB1 genes had a lower temperature threshold and could not replicate their genes at high temperatures.
Avian influenza viruses spread to chickens or ducks via migratory birds. Since last year, however, cases of dairy cattle being infected with highly pathogenic H5N1 avian influenza virus in 18 U.S. states have put health authorities worldwide on high alert. Livestock as well as wild mammals, and even people who had contact with dairy cows, have been infected, and there have been deaths. Last month in Korea, H5N1 avian influenza was detected in poultry and migratory birds.
The H5N1 avian influenza virus is named for the hemagglutinin (HA) and neuraminidase (NA) proteins on its surface being type 5 and type 1, respectively. HA acts as the key that lets the virus attach to human respiratory cells, and NA allows it to punch out of the cell after replication. H5N1 avian influenza has now become a constant threat rather than a seasonal disease. It is detected on every continent except Antarctica.
◇ If genes exchange in pigs, a pandemic is a concern
Fortunately, the H5N1 avian influenza virus has not spread from person to person and has not triggered a pandemic. Even so, on the same day, the Pasteur Institute in France warned that "if avian influenza viruses spreading among wild birds, poultry and mammals mutate to enable human-to-human transmission, they could cause a pandemic more severe than COVID-19."
Humans carry antibodies against H1 or H3 influenza viruses that cause seasonal flu, but not against the H5 avian influenza virus. The Pasteur Institute said, "Unlike COVID-19, which targeted people with weak immunity, avian influenza viruses can cause death even in healthy people."
Mutant viruses that scientists fear have already inflicted deadly harm on humanity. The 1918 H1N1 Spanish flu, the 1957 H2N2 Asian flu and the 1968 H3N2 Hong Kong flu claimed millions to tens of millions of lives. In the Science paper, the team warned that "in the past three influenza pandemics, variants emerged in which avian-type PB1 genes were introduced."
In other words, an influenza virus could emerge against which the human fever immune response is useless. That possibility is real because viruses can exchange genes with one another. The team explained, "If human and avian influenza viruses infect a host such as a pig at the same time, they can exchange genes and produce deadly variants."
Matt Turnbull of the University of Glasgow, the first author of the paper, said, "To prepare for a pandemic, we need to track and monitor avian influenza viruses," adding, "Testing how resistant a virus is to heat could help identify more virulent strains."
References
Science (2025), DOI: https://doi.org/10.1126/science.adq4691