Influenza Group
Wendy Barclay joined Imperial College in May 2007 to take up a Chair in Influenza Virology. She has worked in the field of molecular virology for more than 20 years, and has an established group of around 10 postdoctoral fellows and postgraduate students working with her to study many aspects of the replication of influenza viruses.
Particular interests in the Barclay lab are the interaction of the virus with the host cell and the way in which this can limit host range, for example to prevent avian influenza viruses crossing the species barrier to infect and transmit between humans. To study these problems the lab uses the technique of reverse genetics by which recombinant influenza viruses can be generated from cDNAs. In this way specific viral mutants can be created to test out hypotheses about regions of the viral genome that determine the features of the virus. Changing just one amino acid in one of the genes of an avian influenza virus can transform its ability to grow in human cells.
We have also used this technique to generate new vaccines against human and avian influenza strains. In the the lab we generate novel bird flu vaccine under high containment conditions, before safety testing allows it to be brought out for larger scale manufacture.
Much of the work involves analysis of mutant viruses in cell cultures. We are particularly excited about the use of a complex culture system of human or animal airway cells which we believe is a good representation of the target tissues for these respiratory pathogens. You can read more about our work in this system in Thompson et al. 2006. We are currently using what we have learned about the behaviour of different influenza viruses in this system to understand why some strains do not yet transmit between people. This could be key to predicting how or when a new pandemic, for example caused by H5N1 ‘bird flu’ might begin.
An important aspect of virus: host cell interaction is the balance between the host innate immune response, typified by induction of interferons, and the virus’ ability to counter that response. We have discovered that different strains of the influenza virus affect this balance in different ways and we suspect that this may determine why some strains of virus are more virulent than others. Read more in Hayman et al. 2006 and 2007.
Key recent publications:
1. A. Hayman, S. Comely, A. Lackenby, L.C.S. Hartgroves, S. Goodbourn, J.W. McCauley, and W.S. Barclay. 2007. NS1 proteins of avian influenza A viruses can act as antagonists of the human interferon-?/? response. Journal of Virology. 81: 2318-2327.
In this publication we address the possibility that the interferon response affects the host range of influenza virus. We demonstrate that avian influenza viruses can control the induction of the interferon response in human cells, but they may be more sensitive to the effects of the small response that does occur.
2. C.I. Thompson, W.S. Barclay, M.C. Zambon and R.J. Pickles. 2006. Infection of human airway epithelium by human and avian strains of influenza A virus. Journal of Virology. 80: 8060-8068.
In collaboration with a cell biologist, Professor Pickles, we provide virological expertise to characterize replication of influenza viruses in primary human airway cells. We note important differences between avian and human influenza virus infection of these cells that may contribute to the lack of transmission of avian viruses in people.
3. A Hayman, S Comely, A Lackenby, S. Murphy , J. McCauley, S Goodbourn and
W.S. Barclay. 2006. Variation in the ability of human influenza A viruses to induce and inhibit the IFN-? pathway. Virology. 347:52-64.
Here we show that not all influenza viruses are identical in the way in which they interact with the human innate immune system. Importantly we resolve a long standing debate about the mechanisms of control of interferon induction by demonstrating that two laboratory strains work in different ways.
4. R. Harvey, A.C.R. Martin, M. Zambon and W. S. Barclay. 2004. Restrictions to the adaptation of influenza A virus H5 haemagglutinin to the human host. Journal of Virology. 78: 502-507.
We address the issue of how easily a highly virulent avian influenza viruses could evolve to be able to transmit between people and conclude that two simultaneous mutations are required. This restriction may explain why H5N1 viruses have not yet caused a pandemic.
5. Y. Yongxiu, L.J. Mingay, J.W. McCauley and W.S. Barclay. 2001. Sequences in influenza A virus PB2 protein that determine productive infection for an avian influenza virus in mouse and human cell lines. Journal of Virology 75 5410-5415.
Avian influenza viruses do not replicate efficiently in human cells. Here we describe amino acid changes in a single gene that overcome that species barrier. This demonstrates how a highly virulent avian influenza strains like H5N1 might undergo zoonosis and cause a pandemic.
6. D. Jackson, A. Cadman, T. Zurcher and W.S. Barclay. 2002. A reverse genetics approach for recovery of recombinant influenza B viruses entirely from cDNA. Journal of Virology 76 :11744-11747.
Reverse genetics techniques allow the recovery of infectious virus from cDNAs thus enabling the generation of viruses engineered with any sequence to order. This revolutionizes the scope of our ability to understand how these viruses replicate and interact with the host cell.
Other recent papers from the Barclay lab:
A. Whiteley, D. Major, I. Legastellois, L. Campitelli, I. Donatelli, C.I. Thompson, M.C. Zambon, J.M. Wood and W.S. Barclay. 2007. Generation of candidate human influenza vaccine strains in cell culture- rehearsing the European response to an H7N1 pandemic threat. Influenza and other respiratory diseases. In press.
Owen R.E.; Yamada E., Thompson C.I., Phillipson L.J., Thompson C., Taylor E., Zambon M.C., Osborn H.M.I, Barclay W.S. and Borrow P. 2007. Alternations in receptor binding properties of recent human influenza H3N2 viruses are associated with reduced natural killer cell lysis of infected cells. J. Virol. Vol 81 11170-8.
Barclay WS, Jones IM, Osborn HM, Phillipson L, Ren J, Talevera GA, Thompson CI. 2007. Probing the receptor interactions of an H5 avian influenza virus using a baculovirus expression system and functionalised poly(acrylic acid) ligands.
Bioorg Med Chem. Jun 15;15(12):4038-47. Epub 2007 Apr 2.
Howard W, Hayman A, Lackenby A, Whiteley A, Londt B, Banks J, McCauley J, Barclay W. S. 2007 Development of a reverse genetics system enabling the rescue of recombinant avian influenza virus A/Turkey/England/50-92/91 (H5N1).
Avian DisMar;51(1 Suppl):393-5.
D. Jackson ,W.S. Barclay , and T. Zurcher. 2005. Characterization of recombinant influenza B viruses with key neuraminidase inhibitor resistance mutations. Journal of Antimicrobial Chemotherapy. 55(2):162-9.
D. Jackson, T. Zurcher and W.S. Barclay. 2004. Reverse genetics studies of the influenza B virus BM2 gene indicate a role for the protein in viral entry. Virology. 322:278-285.
C.I. Thompson, W.S. Barclay and M.C. Zambon. 2004. Changes in In Vitro Sensitivity of Influenza A H3N2 viruses to a Neuraminidase Inhibitor Drug during Evolution in the Human Host. Journal of Antimicrobial Chemotherapy. 53: 759-765.
A. Whiteley, M. Trikic and W.S. Barclay. 2004. Attenuating mutations in the influenza virus genome which may increase the safety of vaccine production. Proceeding of Options for Control of Influenza V. Elsevier International Congress Series.
C.J. Elleman and W.S. Barclay. 2004. The influenza A virus matrix protein controls virus morphology. Virology. 321: 144-153.
W.S. Barclay and M.C. Zambon. 2004. Pandemic risks from bird flu. British Medical Journal 318.
M.Zambon and W.S. Barclay. 2002. Unravelling the mysteries of influenza. The Lancet. 360 1801-1802.
