Flu virus breakthrough without studying infectious material

24 April 2013

Influenza virus imaged by electron cryotomography.

Image: Influenza virus imaged by electron cryotomography.©  Calder, LJ; Wasilewski, S; Berriman, JA and Rosenthal, PB. Structural organization of a filamentous influenza A virus. Proc Natl Acad Sci USA. 2010;107(23):10685-90.

The strength with which flu viruses bind to host cells can be simply predicted without the need to generate and work with infectious material, according to new research from the MRC's National Institute for Medical Research (NIMR; now part of the Francis Crick Institute). 

The team has developed a way to calculate how strongly a particular virus binds to host cells based on the binding strength of a single interaction by one of its cell surface proteins. 

Steve Gamblin of NIMR explained: "It has been one of our long-term interests to understand the species specificity of flu viruses. Biologically, the natural reservoir of flu is wild fowl - their cells carry a binding molecule that is related to the one found in human airways but its chemistry is a bit different. To switch from birds to humans, the virus needs to adapt its binding protein so that it prefers human-type receptors." 

Flu viruses are categorised into types A, B and C. Type A viruses are categorised depending on two proteins on their surface - called haemagglutinin (H) and neuraminidase (N). There are many different combinations of H and N, such as H5N1 avian influenza - commonly known as bird flu.  

The haemagglutinin is responsible for the virus binding to host cells through multiple interactions with a cell receptor. Individual binding sites on haemagglutinin bind host cell receptors weakly, but multiple interactions can result in a very high binding strength (high avidity) when the virus binds to cells carrying preferred receptors - this is what determines its affinity for a particular host species. 

In 2011, international researchers controversially developed a mutated strain of H5N1 avian influenza that was able to transmit directly between ferrets. Because ferrets are used as a model to study human flu and have very similar receptors for the virus, it is assumed that this mutant strain could also pass between humans. In contrast, the H5N1 strain currently circulating in the wild has only infected humans via contact with birds and cannot transmit directly between people. 

In the current study, the NIMR researchers studied the haemagglutinin from the mutant H5N1 strain bound to its receptors (but not the virus itself) and compared it with the haemagglutinin from naturally occurring H5N1 that primarily infects birds. They found that the mutant strain had acquired a small increase in affinity for the human receptor, but a significant decrease in affinity for the bird receptor - resulting in a 200-fold preference for binding human cells over bird cells. 

The team showed that the mutant haemagglutinin had acquired the ability to bind to human receptors in the same way as seen for previous pandemic viruses, such as the 1918 (Spanish flu) and 2009 (swine flu) viruses. This binding mode is considerably different to how naturally occurring avian H5N1 binds human receptors. 

Dr Gamblin concluded: "Our work has two major implications. Firstly, we can now get a good idea of how well a virus will bind to human cells without having to make or work with infectious material. 

"Secondly, we have visualised how ferret-transmissible bird flu has acquired the ability to bind human receptors like other pandemic viruses."    

The paper, Receptor binding by a ferret-transmissible H5 avian influenza virus, is published in the Nature. 

  • Influenza, commonly known as flu, is a viral infection that can cause serious complications and even death in some people, particularly those with certain underlying health problems. 
  • Flu viruses infect a variety of species, including humans, birds, pigs and horses. When a new virus crosses from a non-human species to humans, the absence of immunity in the human population enables it to spread quickly and cause a pandemic. This happened in 2009 with a flu virus called H1N1 from pigs - the pandemic was consequently named swine flu by the media. It very quickly spread around the globe.  A vaccine to control the disease was quickly developed and is now included in seasonal flu vaccines worldwide. 
  • There has been concern for several years about a strain of avian flu called H5N1 that causes severe illness and high death rates in birds and humans - but so far it cannot transmit directly between humans and is only caught through contact with birds.