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A study published in Science looks at a mutation in bovine influenza (H5N1) hemagglutinin (HA) which could switch binding specificity to human receptors.
Prof Ian Brown, Dr Thomas Peacock and Prof Munir Iqbal, Influenza Research Leads at The Pirbright Institute, said:
“This new study reaffirms the importance of closely tracking and monitoring H5 viruses that can transmit between animal populations to look for changes that might alter their binding affinities from avian to human cells. The study builds on existing knowledge but in the context of the virus from dairy cattle where key mutations were introduced into a ‘wild type’ virus detected in a single human case. The mutated ‘laboratory’ non infectious viral protein carrying single or double amino acid changes at key sites in the haemagglutinin viral glycoprotein, switched host cell binding from avian to human. It must be stressed that the introduced mutations have not been detected to date in the H5 virus as it naturally transmits between cattle and spills over to avian and mammalian hosts, underlining the importance of work in both UK and overseas research groups that is actively addressing naturally occurring mutations in the virus. As the authors acknowledge the switch in binding preference is one of several barriers the virus must overcome before it can acquire strong affinity to infect humans and spread between.”
Prof Ed Hutchinson, Professor of Molecular and Cellular Virology, Medical Research Council-University of Glasgow Centre for Virus Research, said:
“Over the last year, the highly pathogenic H5N1 ‘bird flu’ influenza virus has gained the ability to infect cattle and has spread widely among dairy herds in the USA. This has provided far more opportunities for the virus to ‘spillover’ and infect humans. These spillover infections of H5N1 can have unpredictable effects. Many have been mild, but some have been associated with severe disease. Importantly, so far H5N1 infections have caused isolated cases, and the virus has not gained the ability to spread efficiently from human to human and create a pandemic.
“There are multiple barriers to H5N1 adapting to spread efficiently among humans. The most important is probably the ability of the virus to bind to new cells by grabbing onto sugars on the cell surface with ‘spikes’ of a protein called HA. These sugars are different shapes in different animals. Birds make different sugars from humans. The sugars in cows look more bird-like than human-like, which means that an influenza virus adapted to birds (or cows) would have to evolve and change the way HA binds to sugars to spread efficiently among humans.
“In this paper, the authors (leading experts in studying the structure of the HA protein) show that just a single mutation in an HA from an H5N1 influenza, isolated from a human case of cow flu, can be sufficient to change it so that it binds to the sugars needed to enter human cells.
“This finding is important because it shows that, in principle, a single mutation might be enough for an H5N1 virus to become better at spreading effectively among humans. This is concerning because influenza viruses can acquire mutations and evolve very rapidly. For example, recent studies of the influenza viruses in a Canadian teenager, who has been severely ill for a prolonged period with H5N1 bird flu, implied that the virus had begun to evolve to ‘explore’ ways of binding more effectively to the cells in their body during the course of an infection. As yet, H5N1 viruses with these changes are not circulating. However, the current study shows that it is in principle possible for H5N1 to take a simple step to evolve into a form more suitable to spread among humans.
“It is very important to note that this mutation is not the only barrier to emergence. As the authors note the virus needs to overcome multiple barriers to become an effective disease of humans, including changing other properties of the HA protein that are needed for aerosol transmission. We do not yet know whether H5N1 influenza viruses will evolve to become a disease of humans. This study only worked only with purified proteins and did not generate any potentially dangerous viruses, so we also do not know for sure if this mutation has any hidden costs for the virus which might make it harder to acquire. However, the work does identify one way in which H5N1 has the potential to become more dangerous for us. It highlights the need for the current outbreak in cattle in the USA to be taken extremely seriously and for every effort to be made to monitor the evolution of this virus and intervene where possible to limit its opportunities to try out its options of evolving further in humans.”
Professor David Heymann at the London School of Hygiene & Tropical Medicine (LSHTM) said:
“It is always important to look for genetic changes that could indicate a possible increase in transmissibility or virulence, as has been done here by the authors. However, even when a mutation is found, it is still impossible to predict how this may change the behaviour of the organism in humans.
“In addition to surveillance of the virus for emerging mutations, there must be concurrent surveillance to detect cases and continued study of the epidemiology of these infections, the patterns in which they occur and why. This combination is vital to fully understand the behaviour of the virus.
“By understanding the natural history of these infections and making sure that, when confirmed infection occurs, there is an investigation of contacts and others who are in the community, we can begin to piece together helpful characteristics such as asymptomatic cases, and risk factors of infection, including where and how they occur. It’s this broad understanding of a virus that will then help determine the best possible control activities and management of those infected.
“While any new mutations or transmission of a virus can be concerning, it’s important to remember that it also increases our understanding of it, which in turn improves surveillance and vaccine development.”
Prof Tom Solomon FMedSci, Director of The Pandemic Institute, Liverpool, said:
“This is a really important paper. Avian flu has been around for nearly two decades now, and recently spread from birds into cattle in the USA. When humans do occasionally become infected by the virus it is not able to then pass easily from human to human. It does not have the right protein on its surface (called the haemagglutinin protein) to easily infect human lungs. However, this new paper shows which genetic changes would be necessary to alter this protein making human infection more likely. It also shows the protein structure which allows it to interact with human tissue and cause human infections. The scientific community will continue to monitor changes in the virus’ genetics as it evolves further to help us prepare for any future pandemics.”
‘A single mutation in bovine influenza H5N1 hemagglutinin switches specificity to human receptors’ by Ting-Hui Lin et al. was published in Science at 19:00 UK time on Thursday 5 December.
DOI: 10.1126/science.adt0180
Declared interests
Prof Ian Brown, Dr Thomas Peacock and Prof Munir Iqbal: IB, TP and MI all receive research funding to study avian influenza in multiple hosts. IB is a member of the UK scientific committee ‘New and Emerging Respiratory Threats Assessment Group’. IB and TP participate in UKHSA led fora that assess the risk to human health from avian influenza viruses. MI receives industry funding for vaccinology and diagnostics.
Ed Hutchinson: He Professor of Molecular and Cellular Virology at the MRC-University of Glasgow Centre for Virus Research. He has received honoraria for work in a steering group of the Centre for Open Science (Open Practices in Influenza Research; 2021-2022) and on an advisory board for Seqirus (2022). He has unpaid positions on the board of the European Scientific Working group on Influenza and other respiratory viruses (ESWI) and as a scientific adviser to PinPoint Medical. Work in his group is funded by the UK Medical Research Council and by Flu-TrailMAP-OneHealth, an H5N1 rapid response consortium. He was not involved in the current study.
Prof Tom Solomon: TS is Director of The Pandemic Institute which has received funding from CSL Seqirus, and AstraZeneca
For all other experts, no reply to our request for DOIs was received.