Scientists say strains of bird flu should be screened for mutations that increase the risk of them being resistant to a particular gene after Glasgow researchers discovered it plays a key role in preventing "spillover" events.
The spread of avian influenza viruses from birds to humans poses one of the biggest threats for a new global pandemic.
Being able to predict at an early stage the strains which are most likely to cross the species barrier is considered a vital tool in being able to react to newly emerging infectious diseases.
READ MORE: No 'silver bullet' to mitigate effect of bird flu, says NatureScotland report
Now scientists at Glasgow University's Centre for Virus Research (CVR) have pinpointed for the first time a gene which plays a "potent" role in inhibiting the transmission of avian influenza A viruses (IAVs) into humans.
At least 99.9% of humans carry a variant of BTN3A3 which appears to have evolved in our primate ancestors around 40 million years ago.
Genes play a crucial role in coding for the body's immune response.
The BTN3A3 gene is expressed in the human airways, where it creates an antiviral barrier against avian IAVs.
However, some forms of avian influenza have developed mutations which allow them to escape these protections.
An analysis of around 29,000 samples of bird flu strains found that the frequency of BTN3A3-resistant genotypes peaked at 49.5 to 62% between 2012 and 2019, which "correlates with peaks of avian-to-human IAV zoonotic cases within the same time period".
Around half of isolates from the currently circulating H5N1 strain - which has caused 12 known bird-to-human infections since 2020 - were found to be BTN3A3-resistant.
READ MORE: Nicola Sturgeon to be quizzed on pandemic response by UK Covid inquiry
It is not the only gene involved in blocking bird-to-human spillover events, but it is the first time scientists have realised its significance.
Professor Massimo Palmarini, director of CVR, said: “We know that most emerging viruses with human pandemic potential come from animals.
"It is therefore critical to understand which genetic barriers might block an animal virus from replicating in human cells, thereby preventing infection.
“Of course, viruses are constantly changing and can potentially overcome some of these barriers by mutating over time.
"This is why virus genetic surveillance will be crucial to help us better understand and control the spread of viruses with zoonotic and pandemic potential.”
Prof Palmarini added that there are around "five or six" genes currently known to play a role in blocking bird-to-human transmission, with work ongoing to unravel the rest.
He said: "I think in my lifetime we will come to a point where we will pretty much be able to identify any barrier to this virus, and we will get to the point where we will be able to assess from the genetic sequence of the virus all of the risks of what it is that this virus can do.
"We're not quite there yet, but this is a piece of the puzzle that will contribute to get there."
READ MORE: Genomic sequencing and the future of infection control
Avian flu, also commonly referred to as bird flu, primarily spreads among wild birds such as ducks and gulls and can also infect farmed and domestic birds such as chickens, turkeys and quails.
Since 2022 there has been a rise in bird flu cases around the world in both domestic and wild birds.
More recently it has been crossing into mammals, such as sea lions, and in rare cases - usually involving farm workers - infecting humans.
There is currently no evidence of human-to-human transmission, however, which would signal a major potential threat.
Previous flu pandemics, such as the 1918 Spanish flu which caused more than 25 million deaths worldwide and the 2009 swine flu pandemic, were caused by influenza viruses that were resistant to BTN3A3.
Dr Rute Maria Pinto, an expert in immunity at the CVR and first author on the study, said: “Identifying BTN3A3 resistant variants when they first emerge in birds might help prevent human infections.
"Control measures against emerging avian flu viruses can be tailored specifically against those that are BTN3A3-resistant, in addition to other genetic traits known to be important for zoonotic transmission.”
Dr Stephen Oakeshott, head of infections and immunity at the Medical Research Council, which funds the CVR, said the research "illustrates an important piece of the very complex puzzle underpinning viral transmission between species".
He added: “This type of mechanistic scientific insight, coupled with genetic surveillance, can offer a window into future disease risks to inform public health planning.”
The findings are published in the journal, Nature.
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