Notable Recent Publications

These are some recent publications which give a flavour of the research from the Barclay lab. For a complete list of publications, please see below.

Species difference in ANP32A underlies influenza A virus polymerase host restriction. Nature (2016).
Jason S. Long, Efstathios S. Giotis, Olivier Moncorgé, Rebecca Frise, Bhakti Mistry, Joe James, Mireille Morisson, Munir Iqbal, Alain Vignal, Michael A. Skinner & Wendy S. Barclay

This paper identified a key factor that explained why the polymerases from avian influenza viruses are restricted in humans.  For more, please see the associated New and Views.

See our latest ANP32 papers here: eLIFE, Journal of Virology, Journal of Virology.

The mechanism of resistance to favipiravir in influenza. PNAS (2018).
Daniel H. GoldhillAartjan J. W. te VelthuisRobert A. FletcherPinky LangatMaria ZambonAngie Lackenby & Wendy S. Barclay

This paper showed how influenza could evolve resistance to favipiravir, an antiviral that may be used to treat influenza. The residue that mutated to give resistance was highly conserved suggesting that the mechanism of resistance may be applicable to other RNA viruses.

Internal genes of a highly pathogenic H5N1 influenza virus determine high viral replication in myeloid cells and severe outcome of infection in mice. Plos Path. (2018).
Hui Li*, Konrad C. Bradley*, Jason S. Long, Rebecca Frise, Jonathan W. Ashcroft, Lorian C. Hartgroves, Holly Shelton, Spyridon Makris, Cecilia Johansson, Bin Cao & Wendy S. Barclay

Why do avian influenza viruses like H5N1 cause such severe disease in humans? This paper demonstrated that H5N1 viruses replicate better than human viruses in myeloid cells from mice leading to a cytokine storm and more severe disease.

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  • Journal article
    Long J, Efstathios SG, Moncorge O, Frise R, Mistry B, James J, Morrison M, Iqbal M, Vignal A, Skinner MA, Barclay WSet al., 2016,

    Species difference in ANP32A underlies influenza A virus polymerase host restriction

    , Nature, Vol: 529, Pages: 101-104, ISSN: 1476-4687

    Influenza pandemics occur unpredictably when zoonotic influenza viruses with novel antigenicity acquire the ability to transmit amongst humans1. Host range breaches are limited by incompatibilities between avian virus components and the human host. Barriers include receptor preference, virion stability and poor activity of the avian virus RNA-dependent RNA polymerase in human cells2. Mutants of the heterotrimeric viral polymerase components, particularly PB2 protein, are selected during mammalian adaptation, but their mode of action is unknown3, 4, 5, 6. We show that a species-specific difference in host protein ANP32A accounts for the suboptimal function of avian virus polymerase in mammalian cells. Avian ANP32A possesses an additional 33 amino acids between the leucine-rich repeats and carboxy-terminal low-complexity acidic region domains. In mammalian cells, avian ANP32A rescued the suboptimal function of avian virus polymerase to levels similar to mammalian-adapted polymerase. Deletion of the avian-specific sequence from chicken ANP32A abrogated this activity, whereas its insertion into human ANP32A, or closely related ANP32B, supported avian virus polymerase function. Substitutions, such as PB2(E627K), were rapidly selected upon infection of humans with avian H5N1 or H7N9 influenza viruses, adapting the viral polymerase for the shorter mammalian ANP32A. Thus ANP32A represents an essential host partner co-opted to support influenza virus replication and is a candidate host target for novel antivirals.

  • Journal article
    Koutsakos M, Thi HN, Barclay WS, Kedzierska Ket al., 2015,

    Knowns and unknowns of influenza B viruses

    , Future Microbiology, Vol: 11, Pages: 119-135, ISSN: 1746-0913

    Influenza B viruses (IBVs) circulate annually along with influenza A (IAV) strains during seasonal epidemics. IBV can dominate influenza seasons and cause severe disease, particularly in children and adolescents. Research has revealed interesting aspects of IBV and highlighted the importance of these viruses in clinical settings. Yet, many important questions remain unanswered. In this review, the clinical relevance of IBV is emphasized, unique features in epidemiology, host range and virology are highlighted and gaps in knowledge pinpointed. Multiple aspects of IBV epidemiology, evolution, virology and immunology are discussed. Future research into IBV is needed to understand how we can prevent severe disease in high-risk groups, especially children and elderly.

  • Journal article
    Matos-Patron A, Byrd-Leotis L, Steinhauer DA, Barclay WS, Ayora-Talavera Get al., 2015,

    Amino acid substitution D222N from fatal influenza infection affects receptor-binding properties of the influenza A(H1N1)pdm09 virus

    , VIROLOGY, Vol: 484, Pages: 15-21, ISSN: 0042-6822
  • Journal article
    Liu M, Lam MK-H, Zhang Q, Elderfield R, Barclay WS, Shaw P-Cet al., 2015,

    The Functional Study of the N-Terminal Region of Influenza B Virus Nucleoprotein

    , PLOS One, Vol: 10, ISSN: 1932-6203

    Influenza nucleoprotein (NP) is a major component of the ribonucleoprotein (vRNP) in influenzavirus, which functions for the transcription and replication of viral genome. Comparedto the nucleoprotein of influenza A (ANP), the N-terminal region of influenza B nucleoprotein(BNP) is much extended. By virus reconstitution, we found that the first 38 residues areessential for viral growth. We further illustrated the function of BNP by mini-genome reconstitution,fluorescence microscopy, electron microscopy, light scattering and gel shift.Results show that the N terminus is involved in the formation of both higher homo-oligomersof BNP and BNP-RNA complex.

  • Journal article
    Elderfield RA, Parker L, Stilwell P, Roberts KL, Schepelmann S, Barclay WSet al., 2015,

    Ferret airway epithelial cell cultures support efficient replication of influenza B virus but not mumps virus

    , JOURNAL OF GENERAL VIROLOGY, Vol: 96, Pages: 2092-2098, ISSN: 0022-1317
  • Journal article
    Long JS, Benfield CT, Barclay WS, 2015,

    One-way trip: Influenza virus' adaptation to gallinaceous poultry may limit its pandemic potential (vol 37, pg 204, 2015)

    , BIOESSAYS, Vol: 37, Pages: 463-463, ISSN: 0265-9247
  • Journal article
    Long J, Wright E, Molesti E, Temperton N, Barclay Wet al., 2015,

    Antiviral therapies against Ebola and other emerging viral diseases using existing medicines that block virus entry.

    , F1000 Research, Vol: 4, Pages: 30-30, ISSN: 2046-1402

    Emerging viral diseases pose a threat to the global population as intervention strategies are mainly limited to basic containment due to the lack of efficacious and approved vaccines and antiviral drugs. The former was the only available intervention when the current unprecedented Ebolavirus (EBOV) outbreak in West Africa began. Prior to this, the development of EBOV vaccines and anti-viral therapies required time and resources that were not available. Therefore, focus has turned to re-purposing of existing, licenced medicines that may limit the morbidity and mortality rates of EBOV and could be used immediately. Here we test three such medicines and measure their ability to inhibit pseudotype viruses (PVs) of two EBOV species, Marburg virus (MARV) and avian influenza H5 (FLU-H5). We confirm the ability of chloroquine (CQ) to inhibit viral entry in a pH specific manner. The commonly used proton pump inhibitors, Omeprazole and Esomeprazole were also able to inhibit entry of all PVs tested but at higher drug concentrations than may be achieved in vivo. We propose CQ as a priority candidate to consider for treatment of EBOV.

  • Conference paper
    Almond MH, Bakhsoliani E, Edwards MR, Barclay WS, Johnston SLet al., 2015,

    Obesity Is Associated With Decreased Expression Of Suppressor Of Cytokine Signalling 3 In Human Alveolar Macrophages

    , International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
  • Journal article
    Long JS, Benfield CT, Barclay WS, 2014,

    One-way trip: Influenza virus' adaptation to gallinaceous poultry may limit its pandemic potential

    , Bioessays, Vol: 37, Pages: 204-212, ISSN: 1521-1878

    We hypothesise that some influenza virus adaptations to poultry may explain why the barrier for human-to-human transmission is not easily overcome once the virus has crossed from wild birds to chickens. Since the cluster of human infections with H5N1 influenza in Hong Kong in 1997, chickens have been recognized as the major source of avian influenza virus infection in humans. Although often severe, these infections have been limited in their subsequent human-to-human transmission, and the feared H5N1 pandemic has not yet occurred. Here we examine virus adaptations selected for during replication in chickens and other gallinaceous poultry. These include altered receptor binding and increased pH of fusion of the haemagglutinin as well as stalk deletions of the neuraminidase protein. This knowledge could aid the delivery of vaccines and increase our ability to prioritize research efforts on those viruses from the diverse array of avian influenza viruses that have greatest human pandemic potential.

  • Journal article
    Elderfield RA, Watson SJ, Godlee A, Adamson WE, Thompson CI, Dunning J, Fernandez-Alonso M, Blumenkrantz D, Hussell T, MOSAIC Investigators, Zambon M, Openshaw P, Kellam P, Barclay WSet al., 2014,

    Accumulation of human-adapting mutations during circulation of A(H1N1)pdm09 influenza virus in humans in the United Kingdom.

    , Journal of virology, Vol: 88, Pages: 13269-13283, ISSN: 0022-538X

    <h4>Unlabelled</h4>The influenza pandemic that emerged in 2009 provided an unprecedented opportunity to study adaptation of a virus recently acquired from an animal source during human transmission. In the United Kingdom, the novel virus spread in three temporally distinct waves between 2009 and 2011. Phylogenetic analysis of complete viral genomes showed that mutations accumulated over time. Second- and third-wave viruses replicated more rapidly in human airway epithelial (HAE) cells than did the first-wave virus. In infected mice, weight loss varied between viral isolates from the same wave but showed no distinct pattern with wave and did not correlate with viral load in the mouse lungs or severity of disease in the human donor. However, second- and third-wave viruses induced less alpha interferon in the infected mouse lungs. NS1 protein, an interferon antagonist, had accumulated several mutations in second- and third-wave viruses. Recombinant viruses with the third-wave NS gene induced less interferon in human cells, but this alone did not account for increased virus fitness in HAE cells. Mutations in HA and NA genes in third-wave viruses caused increased binding to α-2,6-sialic acid and enhanced infectivity in human mucus. A recombinant virus with these two segments replicated more efficiently in HAE cells. A mutation in PA (N321K) enhanced polymerase activity of third-wave viruses and also provided a replicative advantage in HAE cells. Therefore, multiple mutations allowed incremental changes in viral fitness, which together may have contributed to the apparent increase in severity of A(H1N1)pdm09 influenza virus during successive waves.<h4>Importance</h4>Although most people infected with the 2009 pandemic influenza virus had mild or unapparent symptoms, some suffered severe and devastating disease. The reasons for this variability were unknown, but the numbers of severe cases increased during successive waves of human infection i

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