Scientists said they had uncovered an important genetic clue to understanding how some avian influenza virus strains were able to spill over into humans whilst others were not.
A study published in Nature, identified the human gene BTN3A3 (butyrophilin subfamily 3 member A3) as a potent inhibitor of avian but not human influenza A viruses (IAVs).
A team of researchers, led by the MRC-University of Glasgow Centre for Virus Research, said they were able to show that some avian influenza viruses had a genetic mutation that allowed them to evade the blocking effect of the BTN3A3 gene.
Investigators set out to address "several gaps" in knowledge that allowed scientists to predict which virus lineages were more likely to cross the species barrier and cause disease in humans.
They determined that BTN3A3, which is expressed in the upper and lower respiratory tracts, acts primarily at the early stages of the virus life cycle by inhibiting avian 'flu RNA replication.
Resistance to Genetic Blocking Mechanism
Seasonal human influenza viruses were found to be resistant to BTN3A3 and thus able to evade the blocking mechanism. The researchers found that some avian influenza viruses, such as H7N9, which since 2013 had infected more than 1500 people with 40% case fatality rates, possessed a genetic mutation that allowed them also to defeat the gene's blocking effect.
The scientists were also able to show that there had been an increase in the number of BTN3A3-resistant strains circulating in poultry around the same time as spill over events into human populations.
Pandemic Preparedness
Professor Massimo Palmarini, director of the MRC-University of Glasgow Centre for Virus Research, and the corresponding study author, explained during a briefing hosted by the Science Media Centre that the problem with spill over events was then "when a human is infected, there's also the possibility, then this is transmitted to other humans".
The team concluded that resistance to the BTN3A3 gene could be a key factor in whether a particular strain of avian 'flu had human pandemic potential. By tracking the history of influenza pandemics in humans, the researchers were also able to link BTN3A3 resistance with endemic IAVs, including those that emerged during the 1918 global 'flu pandemic, and the H1N1 'swine flu' pandemic of 2009.
The authors stressed that there were "many barriers preventing zoonotic cross-species transmission of animal IAV, and BTN3A3 has to be considered one of many, rather than the sole determinant of the zoonotic potential of IAV". Nevertheless, Professor Palmarini predicted: "As we go further with our knowledge, there will be a point where from the genetic sequence of a virus, we will be able to characterise all the risks of what it is that this virus can do. We are not quite there yet, and this is a piece of the puzzle that will contribute to get there."
Dr Rute Maria Pinto, the study's first author, 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."
The work was funded primarily by the Medical Research Council (MRC), and in part by the Wellcome Trust, BBSRC, NSERC (Canada), EU Horizon2020, and Medical Research Scotland. Professor Massimo Palmarini declared membership of the Standing Committee on Pandemic Preparedness of the Scottish Government.
