2018 marks the centenary of the worst infectious disease outbreak to have
affected modern man, the Spanish influenza pandemic. More than 50 million
people around the world died as a result of infection by that deadly pathogen.
Influenza pandemics arise every few decades from an alleoteric event of nature
that gives opportunity for an animal virus to adapt to man. Meanwhile, in the
interpandemic periods, seasonal influenza claims half a million lives every year
and poses challenges for vaccination that are only too often spelled out in
damning media headlines.

When I arrived at Robinson College in 1982 I had no intention to study a
biological subject. I begrudged that fact that the Natural Science tripos required
that I top up my Part 1a module choice with other subjects that tugged me from
my beloved chemistry and maths. I chose biochemistry and physiology, choices
that lumped me in with unruly medics who threw paper planes across the back
rows of the large lecture theatre on the New Museums site. However, these new
opportunities offered a more exciting and stimulating challenge than the O level
biology I had rejected three years previously and by Christmas I was hooked.

Immersed in the final year Part II Pharmacology, the laboratory based project
began, and the more days I spent in the lab, the more my heart realized this
was where I might thrive. I turned to the University career service, from where
each week a printed list of opportunities could be collected. Somewhere
hidden amongst the pages I found a PhD project that was collaboration
between Burroughs Wellcome and a unique research institute called the
Common Cold Unit. Thee idea was to study the virus that caused the common
cold, human rhinovirus, to decipher whether it would be possible to make a
vaccine to protect against it.

I have been a virologist ever since, enthralled by these tiny self-perpetuating
entities that are so small and simple that they can be created to order in the lab.
Postdoctoral training fellowships at the University of Reading and then at Mount
Sinai Medical Centre, New York honed my interest in small RNA viruses.

Now I head a small research team at Imperial College London that studies the
mechanisms by which influenza viruses evolve to continue to cause human
disease. We are ‘wet’ biologists working at the bench with contagious viruses that
we genetically manipulate to dissect how each feature of the genome determines
the outcome of infection. Over the past two decades we have contributed to
discoveries that reveal how avian strains of the virus, the notorious ‘bird flu’,
must mutate to transform into airborne transmissible human pathogens. The
explanation lies in the physiological and environmental differences between
humans and birds, the natural influenza virus hosts. All viruses are obligate
parasites, relying absolutely on factors inside the cells they infect to support their
replication. One such factor we recently discovered is a small nuclear protein
named ANP32A that is subtly different between mammals and birds; the factor
in birds being slightly longer than its mammalian counterpart. Avian influenza
viruses rely on co-opting this factor, but upon entering human cells are
mismatched with the shorter orthologue. In most cases of human exposure to
bird flus, this incompatibility between virus and host stops the infection short.
However, some avian viruses mutate to gain the ability to utilize the shorter
version of ANP32A offered within human cells, thus overcoming the host range
barrier. This results in uncontrolled infection in the exposed individual and
accounts for the high case fatality rates associated with human cases of H5N1
bird flu and perhaps also explains why the 1918 influenza virus was so deadly.

To fully transform into a pandemic virus, we and others have shown that
influenza must further mutate both to bind avidly to receptors that enable its
entry into cells lining the human nose and throat, and to stabilize the virus
particles so they survive in exhaled breath enabling airborne transmission. Avian
influenza viruses transmit through water or in air to animals in very close
proximity, so transmission properties of the bird viruses are quite different from
those required for contagiousness between humans. Understanding why some
strains of avian influenza virus can manage this evolutionary trick but others do
not will eventually allow us to better predict the human pandemic threat posed
by each new animal virus as it emerges. What is more, unravelling the virus’s
evolutionary strategies helps us to better understand how to design new antiviral
drugs and vaccines to counter those adapted viruses that go on to become
endemic in humans.

by Professor Wendy Barclay, Imperial College London

Bin Brook Easter 2018 ('Fighting flu' by Professor Wendy Barclay, page 9)

Imperial College London