Publications

Search or filter publications

Search publications Search

Filter by type:

Filter by publication type

• Book
• Book chapter
• Conference paper
• Journal article
• Patent
• Report
• Software

Filter by year:

Filter from 202120202019201820172016201520142013201220112010200920082007200620052004200320022001 to Filter to 202120202019201820172016201520142013201220112010200920082007200620052004200320022001

---

Search results

• Journal article
  Goldhill DH, te Velthuis AJW, Fletcher RA, Langat P, Zambon M, Lackenby A, Barclay WSet al., 2018,

  The mechanism of resistance to favipiravir in influenza

  , Proceedings of the National Academy of Sciences of the United States of America, Vol: 115, Pages: 11613-11618, ISSN: 0027-8424

  Favipiravir is a broad-spectrum antiviral that has shown promise in treatment of influenza virus infections. While emergence of resistance has been observed for many antiinfluenza drugs, to date, clinical trials and laboratory studies of favipiravir have not yielded resistant viruses. Here we show evolution of resistance to favipiravir in the pandemic H1N1 influenza A virus in a laboratory setting. We found that two mutations were required for robust resistance to favipiravir. We demonstrate that a K229R mutation in motif F of the PB1 subunit of the influenza virus RNA-dependent RNA polymerase (RdRP) confers resistance to favipiravir in vitro and in cell culture. This mutation has a cost to viral fitness, but fitness can be restored by a P653L mutation in the PA subunit of the polymerase. K229R also conferred favipiravir resistance to RNA polymerases of other influenza A virus strains, and its location within a highly conserved structural feature of the RdRP suggests that other RNA viruses might also acquire resistance through mutations in motif F. The mutations identified here could be used to screen influenza virus-infected patients treated with favipiravir for the emergence of resistance.

  • Abstract
  • Publisher Web Link
  • Author Web Link
  • Open Access Link
  • Cite
• Journal article
  Barclay W, Openshaw P, 2018,

  The 1918 Influenza Pandemic: one hundred years of progress, but where now?

  , Lancet Respiratory Medicine, Vol: 6, ISSN: 2213-2600
  • Author Web Link
  • Open Access Link
  • Cite
• Journal article
  Te Velthuis AJW, Long JS, Barclay WS, 2018,

  Assays to Measure the Activity of Influenza Virus Polymerase.

  , Methods Mol Biol, Vol: 1836, Pages: 343-374

  Influenza viruses use an RNA-dependent RNA polymerase (RdRp) to transcribe and replicate their segmented negative-stranded RNA genomes. The influenza A virus RdRp consists of a heterotrimeric complex of the proteins PB1, PB2, and PA. The RdRp is associated with the incoming influenza A viral RNA (vRNA) genome bound by the viral nucleoprotein (NP), in complexes called viral ribonucleoproteins, vRNPs. During the viral replication cycle, the RdRp snatches capped primers from nascent host mRNAs to carry out primary viral transcription. Viral mRNA translation produces new copies of the RdRp subunits and NP, which are required to stabilize and encapsidate complementary copies of the genome (cRNAs), forming cRNPs. These cRNPs then use the cRNAs to make new vRNAs, which are encapsidated into new vRNPs. Secondary transcription by new vRNPs results in further viral mRNAs and an increase of the viral protein load in the cell. The activities of the RdRp (mRNA, cRNA, and vRNA synthesis) in the influenza virus replication cycle can be measured on several levels, ranging from assessment of the accumulation of RNA products in virus-infected cells, through in situ reconstitution of the RdRp from cloned cDNAs, to in vitro biochemical assays that allow the dissection of individual functions of the RdRp enzyme. Here we describe these assays and point out the advantages and drawbacks of each.

  • Abstract
  • Author Web Link
  • Cite
• Journal article
  Dunning J, Blankley S, Hoang LT, Cox M, Graham CM, James PL, Bloom CI, Chaussabel D, Banchereau J, Brett SJ, Moffatt MF, OGarra A, Openshaw PJMet al., 2018,

  Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza

  , Nature Immunology, Vol: 19, Pages: 625-635, ISSN: 1529-2916

  Transcriptional profiles and host-response biomarkers are used increasingly to investigate the severity, subtype and pathogenesis of disease. We now describe whole-blood mRNA signatures and concentrations of local and systemic immunological mediators in 131 adults hospitalized with influenza, from whom extensive clinical and investigational data were obtained by MOSAIC investigators. Signatures reflective of interferon-related antiviral pathways were common up to day 4 of symptoms in patients who did not require mechanical ventilator support; in those who needed mechanical ventilation, an inflammatory, activated-neutrophil and cell-stress or death (‘bacterial’) pattern was seen, even early in disease. Identifiable bacterial co-infection was not necessary for this ‘bacterial’ signature but was able to enhance its development while attenuating the early ‘viral’ signature. Our findings emphasize the importance of timing and severity in the interpretation of host responses to acute viral infection and identify specific patterns of immune-system activation that might enable the development of novel diagnostic and therapeutic tools for severe influenza.

  • Abstract
  • Publisher Web Link
  • Author Web Link
  • Open Access Link
  • Cite
• Journal article
  Belser JA, Barclay W, Barr I, Fouchier RAM, Matsuyama R, Nishiura H, Peiris M, Russell CJ, Subbarao K, Zhu H, Yen H-Let al., 2018,

  Ferrets as Models for Influenza Virus Transmission Studies and Pandemic Risk Assessments

  , EMERGING INFECTIOUS DISEASES, Vol: 24, Pages: 965-971, ISSN: 1080-6040
  • Author Web Link
  • Cite
• Journal article
  Groves HT, McDonald JU, Langat P, Kinnear E, Kellam P, McCauley J, Ellis J, Thompson C, Elderfield R, Parker L, Barclay W, Tregoning JSet al., 2018,

  Mouse Models of Influenza Infection with Circulating Strains to Test Seasonal Vaccine Efficacy

  , Frontiers in Immunology, Vol: 9, ISSN: 1664-3224

  Influenza virus infection is a significant cause of morbidity and mortality worldwide. The surface antigens of influenza virus change over time blunting both naturally acquired and vaccine induced adaptive immune protection. Viral antigenic drift is a major contributing factor to both the spread and disease burden of influenza. The aim of this study was to develop better infection models using clinically relevant, influenza strains to test vaccine induced protection. CB6F1 mice were infected with a range of influenza viruses and disease, inflammation, cell influx, and viral load were characterized after infection. Infection with circulating H1N1 and representative influenza B viruses induced a dose-dependent disease response; however, a recent seasonal H3N2 virus did not cause any disease in mice, even at high titers. Viral infection led to recoverable virus, detectable both by plaque assay and RNA quantification after infection, and increased upper airway inflammation on day 7 after infection comprised largely of CD8 T cells. Having established seasonal infection models, mice were immunized with seasonal inactivated vaccine and responses were compared to matched and mismatched challenge strains. While the H1N1 subtype strain recommended for vaccine use has remained constant in the seven seasons between 2010 and 2016, the circulating strain of H1N1 influenza (2009 pandemic subtype) has drifted both genetically and antigenically since 2009. To investigate the effect of this observed drift on vaccine induced protection, mice were immunized with antigens from A/California/7/2009 (H1N1) and challenged with H1N1 subtype viruses recovered from 2009, 2010, or 2015. Vaccination with A/California/7/2009 antigens protected against infection with either the 2009 or 2010 strains, but was less effective against the 2015 strain. This observed reduction in protection suggests that mouse models of influenza virus vaccination and infection can be used as an additional tool to predic

  • Abstract
  • Open Access Link
  • Cite
• Journal article
  Li H, Bradley KC, Long JS, Frise R, Ashcroft JW, Hartgroves LC, Shelton H, Makris S, Johansson C, Cao B, Barclay WSet al., 2018,

  Internal genes of a highly pathogenic H5N1 influenza virus determine high viral replication in myeloid cells and severe outcome of infection in mice.

  , PLoS Pathogens, Vol: 14, ISSN: 1553-7366

  The highly pathogenic avian influenza (HPAI) H5N1 influenza virus has been a public health concern for more than a decade because of its frequent zoonoses and the high case fatality rate associated with human infections. Severe disease following H5N1 influenza infection is often associated with dysregulated host innate immune response also known as cytokine storm but the virological and cellular basis of these responses has not been clearly described. We rescued a series of 6:2 reassortant viruses that combined a PR8 HA/NA pairing with the internal gene segments from human adapted H1N1, H3N2, or avian H5N1 viruses and found that mice infected with the virus with H5N1 internal genes suffered severe weight loss associated with increased lung cytokines but not high viral load. This phenotype did not map to the NS gene segment, and NS1 protein of H5N1 virus functioned as a type I IFN antagonist as efficient as NS1 of H1N1 or H3N2 viruses. Instead we discovered that the internal genes of H5N1 virus supported a much higher level of replication of viral RNAs in myeloid cells in vitro but not in epithelial cells and that this was associated with high induction of type I IFN in myeloid cells. We also found that in vivo during H5N1 recombinant virus infection cells of haematopoetic origin were infected and produced type I IFN and proinflammatory cytokines. Taken together our data infer that human and avian influenza viruses are differently controlled by host factors in alternative cell types; internal gene segments of avian H5N1 virus uniquely drove high viral replication in myeloid cells, which triggered an excessive cytokine production, resulting in severe immunopathology.

  • Abstract
  • Open Access Link
  • Cite
• Journal article
  Singanayagam A, Zambon M, Lalvani A, Barclay Wet al., 2017,

  Can defective interfering RNAs affect the live attenuated influenza vaccine? Reply

  , Lancet Infectious Diseases, Vol: 17, Pages: 1235-1236, ISSN: 1473-3099
  • Open Access Link
  • Cite
• Journal article
  Singanayagam A, Zambon M, Lalvani A, Barclay Wet al., 2017,

  Urgent challenges in implementing live attenuated influenza vaccine.

  , Lancet Infectious Diseases, Vol: 18, Pages: e25-e32, ISSN: 1473-3099

  Conflicting reports have emerged about the effectiveness of the live attenuated influenza vaccine. The live attenuated influenza vaccine appears to protect particularly poorly against currently circulating H1N1 viruses that are derived from the 2009 pandemic H1N1 viruses. During the 2015-16 influenza season, when pandemic H1N1 was the predominant virus, studies from the USA reported a complete lack of effectiveness of the live vaccine in children. This finding led to a crucial decision in the USA to recommend that the live vaccine not be used in 2016-17 and to switch to the inactivated influenza vaccine. Other countries, including the UK, Canada, and Finland, however, have continued to recommend the use of the live vaccine. This policy divergence and uncertainty has far reaching implications for the entire global community, given the importance of the production capabilities of the live attenuated influenza vaccine for pandemic preparedness. In this Personal View, we discuss possible explanations for the observed reduced effectiveness of the live attenuated influenza vaccine and highlight the underpinning scientific questions. Further research to understand the reasons for these observations is essential to enable informed public health policy and commercial decisions about vaccine production and development in coming years.

  • Abstract
  • Open Access Link
  • Cite
• Journal article
  Peacock TP, Benton DJ, James J, Sadeyen J-R, Chang P, Sealy JE, Bryant JE, Martin SR, Shelton H, Barclay WS, Iqbal Met al., 2017,

  Immune Escape Variants of H9N2 Influenza Viruses Containing Deletions at the Hemagglutinin Receptor Binding Site Retain Fitness In Vivo and Display Enhanced Zoonotic Characteristics

  , Journal of Virology, Vol: 91, ISSN: 1098-5514

  H9N2 avian influenza viruses are enzootic in poultry across Asia and North Africa, where they pose a threat to human health as both zoonotic agents and potential pandemic candidates. Poultry vaccination against H9N2 viruses has been employed in many regions; however, vaccine effectiveness is frequently compromised due to antigenic drift arising from amino acid substitutions in the major influenza virus antigen hemagglutinin (HA). Using selection with HA-specific monoclonal antibodies, we previously identified H9N2 antibody escape mutants that contained deletions of amino acids in the 220 loop of the HA receptor binding sites (RBSs). Here we analyzed the impact of these deletions on virus zoonotic infection characteristics and fitness. We demonstrated that mutant viruses with RBS deletions are able to escape polyclonal antiserum binding and are able to infect and be transmitted between chickens. We showed that the deletion mutants have increased binding to human-like receptors and greater replication in primary human airway cells; however, the mutant HAs also displayed reduced pH and thermal stability. In summary, we infer that variant influenza viruses with deletions in the 220 loop could arise in the field due to immune selection pressure; however, due to reduced HA stability, we conclude that these viruses are unlikely to be transmitted from human to human by the airborne route, a prerequisite for pandemic emergence. Our findings underscore the complex interplay between antigenic drift and viral fitness for avian influenza viruses as well as the challenges of predicting which viral variants may pose the greatest threats for zoonotic and pandemic emergence.

  • Abstract
  • Author Web Link
  • Open Access Link
  • Cite

This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.