Avian influenza viruses can resist fever

The article analyses how certain variants of the avian influenza virus respond to heat, and demonstrates in a robust and well-designed manner that some changes in the virus can confer greater resistance to high temperatures. The study, which is easy to follow despite its technical complexity, has its own limitations: the authors point out that only one of the possible configurations that could influence the virus's sensitivity to temperature has been evaluated, that experimentally induced fever does not completely reproduce the natural immune response, and that it is not possible to know exactly the actual temperature at which the virus replicates in animals with simulated fever.

Even so, the work provides relevant information on the role of fever in the evolution and control of respiratory infections and offers clues that could help to better understand phenomena such as the observed loss of seasonality of this virus, as it is stable in higher temperature contexts.

Although the results come from cell cultures and mouse models, and therefore cannot be directly extrapolated to other species, including humans, the study opens up a promising avenue by identifying the importance of the role of virus proteins other than those targeted by antibodies, which could influence the development of the infection. It is, in short, a solid first step towards future research.

Influenza viruses are adapted to very different temperatures depending on their host: human strains replicate best in the upper respiratory tract, which is around 33–37°C, while avian strains thrive in the respiratory and digestive systems of birds, where the temperature reaches 40–42°C. Although this difference was known, it had not been studied in depth at the molecular level. The new published work shows—through the use of chimeric viruses and experiments in cells and in a “simulated fever” model in mice—that temperature alone can slow down seasonal flu, but not viruses that have adapted some of their genes, such as the PB1 segment, which allows them to adapt depending on the context, better at higher temperatures, such as those found in birds or the temperature we have when we have a fever.

This finding of PB1-associated adaptation helps explain why fever is an effective defence against common strains adapted to humans and why certain avian viruses can circumvent that barrier and resist, which is interesting as an additional mechanism that could explain the adaptation to species jumping and the increased virulence of avian viruses that have been sources of pandemics, such as the influenza viruses of 1918, 1957 and 1968.

As aspects that remain to be clarified in the future (limitations), the “simulated fever” model used in in vivo experiments in mice does not reproduce the actual temperatures of the human respiratory tract or the respiratory and digestive systems of birds, which are lower; even so, the phenotype remains, suggesting that it does not depend solely on absolute temperature, but on cellular mechanisms adapted to specific temperature ranges that modulate viral activity. Among these, the role of ANP32 proteins stands out, whose variation between species conditions the thermal sensitivity of the viral polymerase and explains why adaptation is not uniform in different animals.

Fever can act as an antiviral defence against seasonal strains that are sensitive to temperature. The indiscriminate use of antipyretics could promote replication. This effect does not apply to avian or pandemic viruses with thermoresistant PB1. Caution is recommended in the management of fever, monitoring of thermal sensitivity as a risk marker, and explaining to patients that moderate fever is part of the defence mechanism.

The current risk of avian influenza to the general population remains low, although there is a global H5N1 panzootic spreading to mammals that requires surveillance. There is no sustained human-to-human transmission. The study explains how some avian viruses could resist the thermal barrier of fever thanks to thermoresistant PB1, which is relevant for preparedness, not alarmism.

This avian influenza study focusses on the influence of the host's body temperature, in this case using mice as a model, on the proliferative capacity of influenza A viruses of avian or mammalian origin. Influenza viruses multiply most effectively in the animal species to which they have adapted during their biological cycle. However, their replicative efficiency is reduced to a greater or lesser extent in other species, depending on various factors, including the cellular and tissue tropism of the virus, the presence of appropriate viral receptors, and other anatomical or physiological factors, such as the host's body temperature, which facilitate or condition the fitness of the virus.

This differential adaptation is clearly evident between avian and mammalian influenza viruses, which does not prevent an avian strain from successfully infecting a mammal, including humans, and vice versa, under certain conditions. This host promiscuity is a hallmark of Influenza A viruses and has a disturbing example in the current highly pathogenic H5N1 subtype strain circulating among wild birds worldwide, which has been able to infect various mammalian species and threatens to cause a pandemic at any time.

The authors of the study, from laboratories in Great Britain, the US, Japan and Australia, demonstrate that the PB1 protein, involved in viral replication in avian viruses, is adapted to the temperatures typical of birds, 40o-42o, and therefore is not significantly affected by human physiological temperatures (33°C in the upper respiratory tract and 37°C in the lower respiratory tract), even in a feverish state (40°C). In addition, researchers have found that this is also true for the PB1 proteins of avian viruses that caused the pandemics of 1918, 1957 and 1968.

One consequence of these findings is the loss of the defensive function of increased body temperature (fever), which mammals, including humans, use to curb infections from pathogens, including influenza viruses. The authors warn of the clinical and epidemiological implications that this particular feature of avian influenza viruses may have in terms of potential transmission to humans.