Scientists have discovered that a gene present in humans – and found in the lungs and upper respiratory tract, where flu viruses replicate – is a powerful barrier that prevents most avian flu viruses moving from birds to people.
The BTN3A3 gene’s antiviral abilities are a new discovery, reports The Guardian, uncovered after a six-year study led by the MRC-University of Glasgow Centre for Virus Research.
Although relatively rare, some avian flu virus strains have occasionally spilled over into humans, two of the most recent H5N1 cases being reported in UK poultry farm workers in May this year.
Human cases of H5N1 bird flu were first found in Hong Kong in 1997.
Globally since 2003, 873 human H5N1 infections have been reported to the World Health Organisation. Of those, 458 people died.
The study found that some bird and swine flu viruses have a genetic mutation that allows them to escape the blocking effects of the BTN3A3 gene and infect people.
By tracking the history of human influenza pandemics and linking resistance to the gene with key virus types, the researchers concluded that all human influenza pandemics, including the 1918 Spanish flu and the 2009 swine flu pandemics, were a result of BTN3A3-resistant strains.
The findings suggest that resistance to the gene could help determine whether flu strains have human pandemic potential or not. That may lead to testing of wild birds, poultry and other animals susceptible to flu viruses such as pigs, for BTN3A3-resistant viruses.
“The antiviral functions of the (BTN3A3) gene appeared 40m years ago in primates,” said Professor Massimo Palmarini who led the study, and is director of Glasgow’s virology research centre.
“Understanding the barriers that block avian flu in humans means better targeted solutions and better control measures to prevent the spillovers.”
He said that if a gene-resistant virus were identified, “we can direct preventative measures to those viruses, sooner, to prevent the spillover (into humans)”.
Dr Rute Maria Pinto, the study’s lead author, said: “We are all fairly proud of the outcome. This gene had been identified before, and other functions were attributed to it, but we found that it is antiviral against avian flu. No one had found that before.”
She said the discovery was expected to have immediate practical applications. “Now, when we find cases of bird flu, we can basically swab sick birds, carcasses or faeces and find out whether the virus can overcome the BTN3A3 gene, simply by looking at its sequence and determining if this virus is more or less likely to jump into humans.
“If the virus can, in fact, overcome BTN3A3, then stricter measurements should be put in place to prevent spillovers.”
The study was also able to retrospectively identify increases in gene-resistant viruses ahead of previous human spillovers.
Before the H7N9 bird flu virus outbreak, which first infected humans in China in 2013, the study found “an increased frequency of the BTN3A3-resistant genotype (in birds) in 2011-2012”. To date there have been almost 1 570 cases of H7N9 and at least 616 deaths.
“What these observations provide is a snapshot of what the frequency of the BTN3A3 resistant gene was at different periods of times in the birds,” Palmarini said.
“Because birds haven’t got BTN3A3, there is no evolutionary pressure to keep, or not, those traits.”
He said certain mutations “might make the virus more or less fitter in the birds” but this had not yet been studied.
Similarly, before the 2009 H1N1 swine flu pandemic, the study found H1N1 gene resistance in pigs occurring between 2002 and 2006. The swine flu pandemic is estimated to have killed between 150 000 and 575 400 people during the first year the virus circulated in humans.
Study details
BTN3A3 evasion promotes the zoonotic potential of influenza A viruses
Rute Maria Pinto, Siddharth Bakshi, Massimo Palmarini et al.
Published in Nature on 28 June 2023
Abstract
Spillover events of avian influenza A viruses (IAVs) to humans could represent the first step in a future pandemic1. Several factors that limit the transmission and replication of avian IAVs in mammals have been identified. There are several gaps in our understanding to predict which virus lineages are more likely to cross the species barrier and cause disease in humans1. Here, we identified human BTN3A3 (butyrophilin subfamily 3 member A3)2 as a potent inhibitor of avian IAVs but not human IAVs. We determined that BTN3A3 is expressed in human airways and its antiviral activity evolved in primates. We show that BTN3A3 restriction acts primarily at the early stages of the virus life cycle by inhibiting avian IAV RNA replication. We identified residue 313 in the viral nucleoprotein (NP) as the genetic determinant of BTN3A3 sensitivity (313F or, rarely, 313L in avian viruses) or evasion (313Y or 313V in human viruses). However, avian IAV serotypes, such as H7 and H9, that spilled over into humans also evade BTN3A3 restriction. In these cases, BTN3A3 evasion is due to substitutions (N, H or Q) in NP residue 52 that is adjacent to residue 313 in the NP structure3. Thus, sensitivity or resistance to BTN3A3 is another factor to consider in the risk assessment of the zoonotic potential of avian influenza viruses.
Nature article – BTN3A3 evasion promotes the zoonotic potential of influenza A viruses (Open access)
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