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.
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 articleElderfield RA, Koutsakos M, Frise R, et al., 2016,
NB protein does not affect Influenza B virus replication in vitro and is not required for replication in or transmission between ferrets., Journal of General Virology, Vol: 97, Pages: 593-601, ISSN: 1465-2099
The influenza B virus encodes a unique protein, NB, a membrane protein whose function in the replication cycle is not, as yet, understood. We engineered a recombinant influenza B virus lacking NB expression with no concomitant difference in expression or activity of viral neuraminidase protein, an important caveat since NA is encoded on the same segment and initiated from a start codon just 4 nucleotides downstream of NB. Replication of the virus lacking NB was not different to wild type virus with full length NB in clonal immortalized or complex primary cell cultures. In the mouse model, virus lacking NB induced slightly lower IFN levels in infected lungs but this did not affect virus titres or weight loss. In ferrets infected with a mixture of viruses that did or did not express NB, there was no fitness advantage for the virus that retained NB. Moreover, virus lacking NB protein was transmitted following respiratory droplet exposure of sentinel animals. These data suggest no role for NB in supporting replication or transmission in vivo in this animal model. The role of NB and the nature of selection to retain it in all natural influenza B viruses remain unclear.
Journal articlePeacock T, Reddy K, James J, et al., 2016,
Antigenic mapping of an H9N2 avian influenza virus reveals two discrete antigenic sites and a novel mechanism of immune escape, Scientific Reports, Vol: 6, ISSN: 2045-2322
H9N2 avian influenza virus is a major cause of poultry production loss across Asia leading to the wide useof vaccines. Efficacy of vaccines is often compromised due to the rapid emergence of antigenic variants.To improve the effectiveness of vaccines in the field, a better understanding of the antigenic epitopesof the major antigen, hemagglutinin, is required. To address this, a panel of nine monoclonal antibodieswere generated against a contemporary Pakistani H9N2 isolate, which represents a major Asian H9N2viral lineage. Antibodies were characterized in detail and used to select a total of 26 unique ‘escape’mutants with substitutions across nine different amino acid residues in hemagglutinin including seventhat have not been described as antigenic determinants for H9N2 viruses before. Competition assaysand structural mapping revealed two novel, discrete antigenic sites “H9-A” and “H9-B”. Additionally,a second subset of escape mutants contained amino acid deletions within the hemagglutinin receptorbinding site. This constitutes a novel method of escape for group 1 hemagglutinins and could representan alternative means for H9N2 viruses to overcome vaccine induced immunity. These results will guidesurveillance efforts for arising antigenic variants as well as evidence based vaccine seed selection andvaccine design.
Journal articleLong J, Efstathios SG, Moncorge O, et al., 2016,
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 articleKoutsakos M, Thi HN, Barclay WS, et al., 2015,
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 articleMatos-Patron A, Byrd-Leotis L, Steinhauer DA, et al., 2015,
Journal articleLiu M, Lam MK-H, Zhang Q, et al., 2015,
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 articleElderfield RA, Parker L, Stilwell P, et al., 2015,
Journal articleLong 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 articleLong J, Wright E, Molesti E, et 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 paperAlmond MH, Bakhsoliani E, Edwards MR, et 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
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