Scientists examine bird flu infections to monitor for 'pandemic' mutations

Previous research has shown that the haemagglutinin on H5N1 favours a particular form of receptor known as a "2,3 receptor". These are abundant on cells of birds, but in humans are found mostly on cells of the lower respiratory tract (the lungs). Professor Feizi and colleagues have shown that mucus in the upper airway in humans also contains 2,3 receptors, but here the mucus acts as a defence mechanism to which the virus binds, blocking its progress and enabling the body to "sweep out" the virus. Both factors suggest that huge doses of the virus are required in order to infect humans, a theory supported by evidence that those who have become infected have spent large amounts of time in close proximity to infected fowl.

As with all viruses, H5N1 is continually mutating, and it is changes that allow the virus to attach to "2,6 receptors" in the human upper airway which may enable the virus to become more infectious to humans.

"If the bird flu virus evolves to favour the receptors in our nose and throat like normal flu, the results could be devastating," says Professor Feizi from the Division of Medicine at Imperial College London. "We could have a virus which is not only highly infectious but is easily transmissible by coughing and sneezing."

Dr Hay and Dr Gamblin will isolate haemagglutinin from samples of the virus taken from the patients in Vietnam, and Dr Matrosovich will grow cultures of human airway cells and isolate cell-membrane receptors and secreted mucus. Then, using a technique known as neoglycolipid (NGL) microarray analysis developed by Professor Feizi and her colleagues, the team at Imperial College will identify which of the various receptor structures the haemagglutinins bind most strongly to. Dr Gamblin's team will then use X-ray crystallography to probe, at the molecular level, how mutations might cause the bird virus to change into a human virus.

"If we can find out which mutations of haemagglutinin prefer which receptors, we may be able to identify quickly or even predict which mutations give the virus pandemic potential," says Professor Feizi.

Current antiviral treatments for influenza, such as Tamiflu, target neuraminidase (the "N" in H5N1), which is responsible for allowing the virus to jump off receptors on one cell and bind to those on another cell, and to replicate and spread once inside the body.

"Targeting the virus's ability to bind to the receptors – which until now has proved far more difficult – may provide an alternative, more effective way of preventing infection," says Professor Feizi. "We hope that our work will make this process simpler and faster."

1. Cumulative Number of Confirmed Human Cases of Avian Influenza A/(H5N1) Reported to WHO, 19 June 2008. http://www.who.int/csr/disease/avian_influenza/country/cases_table_2008_06_19/en/index.html