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.


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
    Staller E, Sheppard CM, Neasham PJ, Mistry B, Peacock TP, Goldhill DH, Long JS, Barclay WSet al., 2019,

    ANP32 proteins are essential for influenza virus replication in human cells

    , Journal of Virology, ISSN: 0022-538X

    ANP32 proteins have been implicated in supporting influenza virus replication, but most of the work to date has focused on the ability of avian Anp32 proteins to overcome restriction of avian influenza polymerases in human cells. Using a CRISPR approach we show that human ANP32A and ANP32B are functionally redundant but essential host factors for mammalian-adapted influenza A virus (IAV) and influenza B virus (IBV) replication in human cells. When both proteins are absent from human cells, influenza polymerases are unable to replicate the viral genome, and infectious virus cannot propagate. Provision of exogenous ANP32A or –B recovers polymerase activity and virus growth. We demonstrate that this redundancy is absent in the murine Anp32 orthologues: murine Anp32A is incapable of recovering IAV polymerase activity, while murine Anp32B can. Intriguingly, IBV polymerase is able to use murine Anp32A. We show using a domain swap and point mutations that the LRR 5 region comprises an important functional domain for mammalian ANP32 proteins. Our approach has identified a pair of essential host factors for influenza virus replication and can be harnessed to inform future interventions.

  • Journal article
    Singanayagam A, Zambon M, Barclay W, 2019,

    Influenza virus with increased pH of HA activation has improved replication in cell culture but at the cost of infectivity in human airway epithelium.

    , J Virol

    Pandemic H1N1 (pH1N1) influenza virus emerged from swine in 2009 with adequate capability to infect and transmit between people. In subsequent years it has circulated as a seasonal virus and evolved further human-adapting mutations. Mutations in the haemagglutinin (HA) stalk that increase pH stability have been associated with human adaptation and airborne transmission of pH1N1 virus. Yet, our understanding of how pH stability impacts virus/host interactions is incomplete. Here, using recombinant viruses with point mutations that alter the pH stability of pH1N1 HA, we found distinct effects on virus phenotypes in different experimental models. Increased pH sensitivity enabled virus to uncoat in endosomes more efficiently, manifesting as increased replication rate in typical continuous cell cultures under single-cycle conditions. A more acid labile HA also conferred a small reduction in sensitivity to antiviral therapeutics that act at the pH-sensitive HA fusion step. Conversely, in primary human airway epithelium cultured at air-liquid interface, increased pH sensitivity attenuated multicycle viral replication, by compromising virus survival in the extracellular microenvironment. In a mouse model of influenza pathogenicity, there was an optimum HA activation pH and viruses with either more or less pH stable HA were less virulent. Opposing pressures inside and outside the host cell that determine pH stability may influence zoonotic potential. The distinct effects that changes in pH stability exert on viral phenotypes underscore the importance of using the most appropriate systems for assessing virus titre and fitness, which has implications for vaccine manufacture, antiviral drug development and pandemic risk assessment.ImportanceThe pH stability of the haemagglutinin surface protein varies between different influenza strains and subtypes and can affect the virus' ability to replicate and transmit. Here, we demonstrate a delicate balance the virus strikes within and

  • Journal article
    Long JS, Idoko-Akoh A, Mistry B, Goldhill D, Staller E, Schreyer J, Ross C, Goodbourn S, Shelton H, Skinner MA, Sang H, McGrew MJ, Barclay Wet al., 2019,

    Species specific differences in use of ANP32 proteins by influenza A virus

    , eLife, Vol: 8, ISSN: 2050-084X

    Influenza A viruses (IAV) are subject to species barriers that prevent frequent zoonotic transmission and pandemics. One of these barriers is the poor activity of avian IAV polymerases in human cells. Differences between avian and mammalian ANP32 proteins underlie this host range barrier. Human ANP32A and ANP32B homologues both support function of human-adapted influenza polymerase but do not support efficient activity of avian IAV polymerase which requires avian ANP32A. We show here that the gene currently designated as avian ANP32B is evolutionarily distinct from mammalian ANP32B, and that chicken ANP32B does not support IAV polymerase activity even of human-adapted viruses. Consequently, IAV relies solely on chicken ANP32A to support its replication in chicken cells. Amino acids 129I and 130N, accounted for the inactivity of chicken ANP32B. Transfer of these residues to chicken ANP32A abolished support of IAV polymerase. Understanding ANP32 function will help develop antiviral strategies and aid the design of influenza virus resilient genome edited chickens.

  • Journal article
    Lindsey BB, Singanayagam A, Tregoning JS, De Silva T, Barclay Wet al.,

    The impact of an updated pandemic H1N1 strain on shedding and immunogenicity to Russian-backbone live attenuated influenza vaccine among children in The Gambia: an open-label, observational, phase 4 study

    , Lancet Respiratory Medicine, ISSN: 2213-2600

    Background: Poor efficacy and effectiveness of thepandemic H1N1 (pH1N1) component inlive attenuated influenza vaccine (LAIV)has been demonstrated in several studies.The reasons for this are unclear, butmay be due toimpairedreplicative fitness of pH1N1 A/California/07/2009-like (Cal09) strains. The aim of this study was to establish whether an updated pH1N1 strain in the Russian-backbone trivalent LAIV resulted in greater shedding and immunogenicitycompared to Cal09.Methods: In an open-label, prospective,observational,phase 4study, we evaluated the impact of updating the pH1N1 component in the WHO prequalified Russian-backbone trivalent LAIV from Cal09in 2016-17(n=118) to an A/Michigan/45/2015-like strain (A/17/New York/15/5364, NY15) in 2017-18(n=126),on shedding and immunogenicity in Gambian children aged 2-4 years old.The study was nested within a randomised controlled trial investigating LAIV-microbiome interactions (ClinicalTrials.gov NCT02972957). Findings: Cal09 showed impairednasopharyngeal shedding(13.6%children shedding at day 2 post-LAIV)compared to H3N2(45.8%)and influenza B(80.5%), along with sub-optimal serum antibody(5.1%seroconversion)and T-cell responses(40.5% CD4+IFN-g+ and/or CD4+IL-2+responders). Following the switch to NY15, a significant increase in pH1N1 shedding(63.5%)was seen, along with improvements in seroconversion(19.1%)and influenza-specific CD4+ T-3cell responses(65.7%). The improvement in pH1N1 seroconversion with NY15 was even greater in children seronegative at baseline(37.5% vs. 7.6%). Persistent shedding today 7was independently associated with both seroconversionand CD4+ T cell responsein multivariable logistic regression. Interpretation:The pH1N1 component switch may have overcome problems in prior LAIV formulations.LAIV effectiveness against pH1N1 shouldtherefore improve in upcoming influenza seasons. Our dataalso highlightthe importance of evaluat

  • Journal article
    Lesch M, Luckner M, Meyer M, Weege F, Gravenstein I, Raftery M, Sieben C, Martin-Sancho L, Imai-Matsushima A, Welke R-W, Frise R, Barclay W, Schoenrich G, Herrmann A, Meyer TF, Karlas Aet al., 2019,

    RNAi-based small molecule repositioning reveals clinically approved urea-based kinase inhibitors as broadly active antivirals

    , PLOS PATHOGENS, Vol: 15, ISSN: 1553-7366
  • Journal article
    Dunning J, Blankley S, Hoang LT, Cox M, Graham CM, James PL, Bloom CI, Chaussabel D, Banchereau J, Brett SJ, Moffatt MF, O'Garra A, Openshaw PJM, Habibi MS, Johnston SL, Hansel TT, Levin M, Thwaites RS, Warner JO, Cookson WO, Gazzard BG, Hay A, McCauley J, Aylin P, Ashby D, Barclay WS, Elderfield RA, Nadel S, Herberg JA, Drumright LN, Garcia-Alvarez L, Holmes AH, Kon OM, Aston SJ, Gordon SB, Hussell T, Thompson C, Zambon MC, Baillie KJ, Hume DA, Simmonds P, Hayward A, Smyth RL, McNamara PS, Semple MG, Nguyen-Van-Tam JS, Ho L-P, McMichael AJ, Kellam P, Adamson WE, Carman WF, Griffiths MJet al., 2019,

    Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza (vol 19, pg 625, 2018)

    , NATURE IMMUNOLOGY, Vol: 20, Pages: 373-373, ISSN: 1529-2908
  • Journal article
    James J, Smith N, Ross C, Iqbal M, Goodbourn S, Digard P, Barclay WS, Shelton Het al., 2019,

    The cellular localization of avian influenza virus PB1-F2 protein alters the magnitude of IFN2 promoter and NFκB-dependent promoter antagonism in chicken cells.

    , J Gen Virol, Vol: 100, Pages: 414-430

    The accessory protein, PB1-F2, of influenza A virus (IAV) functions in a chicken host to prolong infectious virus shedding and thus the transmission window. Here we show that this delay in virus clearance by PB1-F2 in chickens is accompanied by reduced transcript levels of type 1 interferon (IFN)-induced genes and NFκB-activated pro-inflammation cytokines. In vitro, two avian influenza isolate-derived PB1-F2 proteins, H9N2 UDL01 and H5N1 5092, exhibited the same antagonism of the IFN and pro-inflammation induction pathways seen in vivo, but to different extents. The two PB1-F2 proteins had different cellular localization in chicken cells, with H5N1 5092 being predominantly mitochondrial-associated and H9N2 UDL being cytoplasmic but not mitochondrial-localized. We hypothesized that PB1-F2 localization might influence the functionality of the protein during infection and that the protein sequence could alter cellular localization. We demonstrated that the sequence of the C-terminus of PB1-F2 determined cytoplasmic localization in chicken cells and this was linked with protein instability. Mitochondrial localization of PB1-F2 resulted in reduced antagonism of an NFκB-dependent promoter. In parallel, mitochondrial localization of PB1-F2 increased the potency of chicken IFN 2 induction antagonism. We suggest that mitochondrial localization of PB1-F2 restricts interaction with cytoplasmic-located IKKβ, reducing NFκB-responsive promoter antagonism, but enhances antagonism of the IFN2 promoter through interaction with the mitochondrial adaptor MAVS. Our study highlights the differential mechanisms by which IAV PB1-F2 protein can dampen the avian host innate signalling response.

  • Journal article
    Barclay WS, 2019,

    Receptor for bat influenza virus uncovers potential risk to humans

    , Nature, Vol: 567, Pages: 35-36, ISSN: 0028-0836

    How bat influenza viruses infect cells has been unclear. The discovery that they bind to a cell receptor that is present in many different species raises concerns about their potential risk to humans.

  • Journal article
    Long JS, Mistry B, Haslam SM, Barclay WSet al., 2019,

    Host and viral determinants of influenza A virus species specificity (vol 17, pg 67, 2018)

    , NATURE REVIEWS MICROBIOLOGY, Vol: 17, Pages: 124-124, ISSN: 1740-1526
  • Journal article
    Goldhill DH, Langat P, Xie H, Galiano M, Miah S, Kellam P, Zambon M, Lackenby A, Barclay WSet al., 2019,

    Determining the Mutation Bias of Favipiravir in Influenza Virus Using Next-Generation Sequencing

    , JOURNAL OF VIROLOGY, Vol: 93, ISSN: 0022-538X

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