More than three years after the sudden onset of the SARS-CoV-2 covid-19 pandemic, the world population has returned to pre-pandemic normality. Health authorities and infectious disease experts are now trying to guess which agent will be responsible for the next pandemic. It is not known when or where it will emerge, nor what type of micro-organism will surprise us, but all experts agree that sooner or later it will visit us with greater or lesser aggressiveness. Among the most likely candidates are still the viruses that cause avian influenza, belonging to the Influenza A genus. Their threat is not new; they have been causing sporadic infections in humans for almost three decades, but without ever becoming established and spreading efficiently in our species.  

For the past couple of years, a member of this group of avian viruses, called H5N1, has been causing innumerable highly virulent outbreaks in poultry and wild birds around the world, with very high mortality rates. But of added concern is that this virus has demonstrated the ability to severely infect several mammalian species, which is a first step towards crossing the species barrier and causing effective and virulent infections in humans.  

Numerous research groups are trying to unravel the factors involved in the adaptation of viruses to different animal species. In this article, the authors describe the identification of the protein BTN3A3 (Butyrophilin subfamily 3, member A3), which acts as a potent inhibitor of avian influenza viruses, but not of human influenza viruses. This protein is expressed in human respiratory tract cells and its inhibitory activity appears to have originated and evolved in primates. Specifically, the researchers show that the mechanism of action of BTN3A3 acts in the early stages of the virus cycle, inhibiting viral RNA replication. However, not all avian influenza viruses are sensitive to this inhibitory protein. For example, viruses of the H7 and H9 subtypes, as well as a high percentage of highly virulent H5N1 strains, are refractory to the inhibitory action of BTN3A3. Specifically, viruses isolated in the H5N1 outbreak that affected a ferret farm in Galicia in 2022 showed a mutation conferring resistance to BTN3A3 that the virus previously acquired in an avian host.  

In summary, this study provides a breakthrough in the understanding of the innate molecular mechanisms by which humans defend against avian influenza viruses. The authors postulate that this new resistance element could be of high epidemiological value in association with the ability of avian influenza viruses to transmit in humans.

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