An international study involving University of Nottingham researchers published in the journal Cell, has shown that during the recent West African ebola virus outbreak the virus was evolving and becoming better adapted to infecting human cells.
Jonathan Ball, Professor of Molecular Virology at the University of Nottingham, and one of the authors of the study said: “Whether or not ebola virus genetic changes that arose during the outbreak were affecting the virus’s ability to infect humans was a moot point, but I was fairly sure it must be happening – never before had this virus had such an opportunity to fine tune its ability for human transmission.”
The outbreak resulted in an unprecedented number of infections and deaths. To test their theory the researchers focussed on genetic changes that arose in the virus surface protein - which it uses to gain entry into a cell – to determine if these mutations improved the virus’ ability to infect. The team focussed on mutations that were being passed from one generation of viruses to the next, as these were more likely to be making the virus more fit. Once identified, the team needed to test how these mutant proteins behaved, to find out whether or not the mutations were affecting infectivity.
Commenting on the approach the researchers had to take, Dr Richard Urbanowicz, a research fellow in the School of Life Sciences, said “Working with ebola virus isn’t very easy – you need access to special high containment labs to handle the whole virus – and not many places have these. So instead we generated particles of a modified mouse virus related to HIV that had been tricked into coating itself with ebola virus surface protein. These pseudoviruses, as they are known, would then mimic how ebola virus gained entry into a cell, but importantly once inside the cell they would not replicate. This meant the studies could be performed without the need for ultra-high containment facilities.”
When the scientists infected human liver cells grown in a test tube with pseudoviruses containing different mutant surface proteins the data was clear – a number of genetic changes that occurred during the outbreak increased infectivity. The effects were not restricted to liver cells – similar trends were also seen for human cells derived from the lung.
“When I saw the first set of data the trend was so clear you didn’t really need to do any statistics to see the effect the changes were having – without doubt many of the genetic changes were increasing infectivity in human cells,” Dr Urbanowicz said.
One change in particular, a substitution of an amino acid that is involved in receptor binding, was particularly striking, not simply because it dramatically increased infectivity, but also because it was present in viruses that dominated the West African outbreak.
In an accompanying paper in the same issue of Cell, a team led by Professor Jeremy Luban from the Massachusetts Medical School show that this mutation increased infectivity in a wide range of human and non-human primate cells, highlighting how this particular mutation improved ebola virus infectivity.
The studies led at Nottingham threw up one more twist. Mutations that increased infectivity in human cells seemed to reduce the ability of the protein to mediate entry into cells obtained from fruit bat cells, which are thought to be the natural host for ebola virus.
The unprecedented number of human to human transmissions that occurred during the recent ebola outbreak gave the virus an opportunity to become adapted to humans and the study’s data suggests that this was an opportunity the virus didn’t miss.
It’s not known for sure whether these changes affected the virus’ ability to transmit during the outbreak or were associated with more severe disease – further studies will be needed to try to determine that - but Professor Ball does think that the study has wider implications: “I think our study reminds us that if you take a virus and allow it to infect a new host for a considerable amount of time, eventually it may acquire a set of mutations that will benefit it, for example increasing its ability to spread or changing the disease that it causes. In order to be prepared we need to know whether similar things are occurring in other outbreaks such as the ongoing Zika and MERS-coronavirus epidemics.”
The study involved a number of international collaborators including the NIHR Nottingham Digestive Diseases Biomedical Research Unit at The University of Nottingham; Institut Pasteur and CNRS in France; Institut Pasteur de Dakar in Senegal; Special Pathogens Program, National Microbiology Laboratory, Public Health Agency of Canada; Department of Medical Microbiology, Faculty of Medicine, University of Manitoba; Institute of Virology, University of Bonn Medical Center, Bonn, Germany; Marie Bashir Institute for Infectious Diseases and Biosecurity at The University of Sydney; Institut Pasteur, Département de Virologie, Unité de Virologie Structurale and CNRS UMR 3569 Virologie.
Funders for the research included the Medical Research Council and the Biotechnology and Biological Sciences Research Council (BBSRC).
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Notes to editors: The University of Nottingham has 43,000 students and is ‘the nearest Britain has to a truly global university, with a “distinct” approach to internationalisation, which rests on those full-scale campuses in China and Malaysia, as well as a large presence in its home city.’ (Times Good University Guide 2016). It is also one of the most popular universities in the UK among graduate employers and was named University of the Year for Graduate Employment in the 2017 The Times and The Sunday Times Good University Guide. It is ranked in the world’s top 75 by the QS World University Rankings 2015/16, and 8th in the UK for research power according to the Research Excellence Framework 2014. It has been voted the world’s greenest campus for four years running, according to Greenmetrics Ranking of World Universities.
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