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.