The Pirbright Institute publication directory contains details of selected publications written by our researchers.

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Sadigh Y, Nair V (2017)

A review on PML nuclear bodies and their interaction with herpesviruses

Annals of Virology and Research 3 (1), 1027


PML nuclear bodies (PNBs) are proteinaceous structures which predominantly reside inside the nuclei of mammalian cells. Their antiviral effects on a wide range of DNA and RNA viruses are shown. Viruses have evolved a diverse range of mechanisms to overcome the antiviral effect of PNBs. In particular, herpesviruses enter into an association with PNBs to control such antiviral effects. An outcome of this association is switching between the two life cycles of the virus. In this manuscript, we have reviewed our current knowledge on the biology of PNBs and the interplay between them and herpesviruses with an emphasis on the factors that affect the life cycle of the virus.

Rohaim M A, El Naggar R F, Helal A M, Hussein H A, Munir M (2017)

Reverse spillover of avian viral vaccine strains from domesticated poultry to wild birds

Vaccine 35 (28), 3523-3527


Transmission of viruses from the commercial poultry to wild birds is an emerging paradigm of livestock–wildlife interface. Here, we report the identification and isolation of vaccine strains of avian paramyxovirus serotype 1 (APMV1) and avian coronaviruses (ACoV) from different wild bird species across eight Egyptian governorates between January 2014 and December 2015. Surveillance of avian respiratory viruses in free-ranging wild birds (n = 297) identified three species that harboured or excreted APMV1 and ACoVs. Genetic characterization and phylogenetic analysis of recovered viruses revealed a close association with the most widely utilized vaccine strains in the country. These results highlight the potential spillover of vaccine-viruses probably due to extensive use of live-attenuated vaccines in the commercial poultry, and close interaction between domesticated and wild bird populations. Further exploring the full spectrum of vaccine-derived viral vaccine strains in wild birds might help to assess the emergence of future wild-birds origin viruses.

Mwangi W N, Vasoya D, Kgosana L B, Watson M, Nair V (2017)

Differentially expressed genes during spontaneous lytic switch of Marek's disease virus in lymphoblastoid cell lines determined by global gene expression profiling

Journal of General Virology 98 (4), 779-790


Marek’s disease virus (MDV), an alphaherpesvirus of poultry, causes Marek’s disease and is characterized by visceral CD4+TCR??+ T-cell lymphomas in susceptible hosts. Immortal cell lines harbouring the viral genome have been generated from ex vivo cultures of MD tumours. As readily available sources of large numbers of cells, MDV-transformed lymphoblastoid cell lines (LCLs) are extremely valuable for studies of virus–host interaction. While the viral genome in most cells is held in a latent state, minor populations of cells display spontaneous reactivation identifiable by the expression of lytic viral genes. Spontaneous reactivation in these cells presents an opportunity to investigate the biological processes involved in the virus reactivation. For detailed characterization of the molecular events associated with reactivation, we used two lymphoblastoid cell lines derived from lymphomas induced by pRB1B-UL47eGFP, a recombinant MDV engineered to express enhanced green fluorescent protein (EGFP) fused with the UL47. We used fluorescence-activated cell sorting to purify the low-frequency EGFP-positive cells with a spontaneously activating viral genome from the majority EGFP-negative cells and analysed their gene expression profiles by RNA-seq using Illumina HiSeq2500. Ingenuity pathway analysis on more than 2000 differentially expressed genes between the lytically infected (EGFP-positive) and latently infected (EGFP-negative) cell populations identified the biological pathways involved in the reactivation. Virus-reactivating cells exhibited differential expression of a significant number of viral genes, with hierarchical differences in expression levels. Downregulation of a number of host genes including those directly involved in T-cell activation, such as CD3, CD28, ICOS and phospholipase C, was also noticed in the LCL undergoing lytic switch.

Mills M K, Michel K, Pfannenstiel R S, Ruder M G, Veronesi E, Nayduch D (2017)

Culicoides-virus interactions: infection barriers and possible factors underlying vector competence

Current Opinion in Insect Science 22, 7-15


In the United States, Culicoides midges vector arboviruses of economic importance such as bluetongue virus and epizootic hemorrhagic disease virus. A limited number of studies have demonstrated the complexities of midge–virus interactions, including dynamic changes in virus titer and prevalence over the infection time course. These dynamics are, in part, dictated by mesenteron infection and escape barriers. This review summarizes the overarching trends in viral titer and prevalence throughout the course of infection. Essential barriers to infection and dissemination in the midge are highlighted, along with heritable and extrinsic factors that likely contribute to these barriers. Next generation molecular tools and techniques, now available for Culicoides midges, give researchers the opportunity to test how these factors contribute to vector competence.

Gordon S J G, Bolwell C, Rogers C W, Musuka G, Kelly P, Guthrie A, Mellor P S, Hamblin C (2017)

The sero-prevalence and sero-incidence of African horse sickness and equine encephalosis in selected horse and donkey populations in Zimbabwe

Onderstepoort Journal of Veterinary Research 84 (1), e1-e5


Sentinel herds and samples submitted by private equine practitioners were used to determine the sero-prevalence and sero-incidence of African horse sickness virus (AHSV) and equine encephalosis virus (EEV) in horse and donkey populations in the Highveld region of Zimbabwe. The sero-prevalence and sero-incidence of antibodies against these viruses were determined using the competitive enzyme-linked immunosorbent assay (ELISA) for the detection of serum antibodies. In donkeys, the median sero-prevalence of AHSV antibodies, across the three rainy seasons under study, was 75% (inter quartile range [IQR] 67-83), with a seasonal median sero-incidence of 45% (IQR 40-63). In horses, the median sero-prevalence of EEV antibodies was 63% (IQR 21-73), with a median seasonal sero-incidence of 10.5% (IQR 10-14), while in donkeys the median sero-prevalence of EEV antibodies was 80% (IQR 67-90), with a median seasonal sero-incidence of 50% (IQR 40-60). This study highlighted the significant levels of exposure of donkeys to AHSV and horses and donkeys to EEV in Zimbabwe despite equine encephalosis remaining unreported by Zimbabwean veterinarians to date. Most seroconversions in sentinel herd animals to AHSV and EEV occurred towards the end of the rainy season in March, April and May corresponding to the time of the year when the Culicoides vectors are in high abundance. In order to determine the clinical significance of these infections, blood and spleen samples, submitted by private equine veterinary practitioners over a 5-year period, from horses showing characteristic clinical signs of African horse sickness were tested for the presence of viral antigen using the antigen capture ELISA. The median sero-prevalence of AHSV antigen in horses recorded from these samples was 38% (IQR 33-88). The predominant AHSV antigen from these samples was serotype 7 (33%) followed by serotype 2 (26%) and serotypes 4 and 8 (16% each). African horse sickness virus serotypes 3 and 9, identified in this study, had not been previously reported in Zimbabwe.

Dunn J R, Reddy S M, Niikura M, Nair V, Fulton J E, Cheng H H (2017)

Evaluation and identification of Marek's disease virus BAC clones as standardized reagents for research

Avian Diseases 61 (1), 107-114


Marek's disease virus (MDV) is an alphaherpesvirus that causes Marek's disease (MD), a lymphoproliferative disease in chickens. Understanding of MDV gene function advanced significantly following the cloning of the MDV genome as either a series of overlapping cosmids or as a bacterial artificial chromosome (BAC), both of which could produce viable MDV. The objectives of this study were to compare multiple virulent MDV BAC clones using the Avian Disease and Oncology Laboratory's pathotyping assay, and to demonstrate the use of these clones as standardized reagents for a modified pathotyping assay by other laboratories. To date, MDV BAC clones have been produced for at least 10 MDV strains from all three serotypes including several virulent serotype 1 strains. We determined that MDV BAC clones exist for each virulent pathotype, despite the fact that these clones are not always equal in virulence to their corresponding parental strains. One clone from each pathotype was further evaluated in commercial specific-pathogen-free (SPF) chickens and found suitable for use in assays such as best-fit pathotyping, although results were variable based on the source of the SPF birds. The benefits of using BAC clones, which include easy shipping, ability to more easily manipulate, and long-term ability to use at a low passage level, are likely to result in the use of BAC clones as standard reagents for MD research. The use of the defined set of clones should allow side-by-side comparison, allowing researchers to better interpret results produced in different laboratories using different MDV field strains. Furthermore, a modified best-fit pathotyping assay has been proposed using these clones and reduced bird numbers.

Clarke B, Mahapatra M, Friedgut O, Bumbarov V, Parida S (2017)

Persistence of lineage IV peste-des-petits ruminants virus within Israel since 1993: an evolutionary perspective

PLOS ONE 12 (5), e0177028


Peste-des-petits ruminants (PPR) is one of the most important infectious diseases of domesticated small ruminants. From the initial identification in 1942 in West Africa, PPR virus (PPRV) has spread throughout much of the developing world. PPRV is now considered endemic throughout Africa, with the notable exception of South Africa, the Middle-East and Israel, as well as South-, East-, and Central Asia. Despite this widespread dispersal, the evolution and transmission of PPRV in endemic populations is not well understood. This understanding will be critical in the planning of rational measures to eradicate PPRV by the planned time as defined by the FAO and OIE. To further advance the understanding of the evolution of PPRV the full genome sequence of 18 viruses isolated from Israel from consecutive years between 1997–2014 were generated. This data set is unique and crucial for the understanding of the evolution of PPRV, as it represents the first set of full-length sequence data available from consecutive years from a single geographic location. Analysis of these full genome sequences shows 96.2–99.9% nucleotide conservation across the Israel isolates and further demonstrates the strong purifying selection pressures on PPRV within Israel and globally. Four amino acid substitutions indicative of putative positive selection were additionally identified within the Israel isolates. The mean substitution rate per site per year was estimated to be 9.22 x 10?4 (95% HPD 6.206 x 10?4–1.26 x 10?3). Using Bayesian and phylogenetic analyses we further demonstrate that the PPRV isolates from Israel belongs to linage IV and form a single strong regional cluster within all other lineage IV viruses circulating worldwide implying a single incursion into Israel.

Bassano I, Ong S H, Lawless N, Whitehead T, Fife M, Kellam P (2017)

Accurate characterization of the IFITM locus using MiSeq and PacBio sequencing shows genetic variation in Galliformes

BMC Genomics 18 (1), 419


Interferon inducible transmembrane (IFITM) proteins are effectors of the immune system widely characterized for their role in restricting infection by diverse enveloped and non-enveloped viruses. The chicken IFITM (chIFITM) genes are clustered on chromosome 5 and to date four genes have been annotated, namely chIFITM1, chIFITM3, chIFITM5 and chIFITM10. However, due to poor assembly of this locus in the Gallus Gallus v4 genome, accurate characterization has so far proven problematic. Recently, a new chicken reference genome assembly Gallus Gallus v5 was generated using Sanger, 454, Illumina and PacBio sequencing technologies identifying considerable differences in the chIFITM locus over the previous genome releases.

Peacock T P, Benton D J, James J, Sadeyen J-R, Chang P, Sealy J E, Bryant J E, Martin S R, Shelton H, Barclay W S, Iqbal M (2017)

Immune escape variants of H9N2 influenza viruses containing deletions at the haemagglutinin receptor binding site retain fitness in vivo and display enhanced zoonotic characteristics

Journal of Virology 91 (14), e00218-17


H9N2 avian influenza viruses are enzootic in poultry across Asia and North Africa where they pose a threat to human health, both as zoonotic agents and as 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 antigen, haemagglutinin (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 (RBS). Here, we analysed the impact of these deletions on virus zoonotic infection characteristics and fitness. We demonstrated that the mutant viruses with RBS deletions are able to escape polyclonal antisera binding and are able to infect and transmit 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 a reduced pH and thermal stability. In summary we infer that variant influenza viruses with deletions in 220 loop could arise in the field due to immune selection pressure; however, due to reduced HA stability, we conclude these viruses would be unlikely to transmit human-to-human by an 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.IMPORTANCE Avian influenza viruses, such as H9N2, cause disease in poultry as well as occasionally infecting humans and are therefore considered viruses with pandemic potential. Many countries have introduced vaccination of poultry to try to control the disease burden, however, influenza viruses are able to rapidly evolve to escape immune pressure in a process known as ‘antigenic drift’. Previously we experimentally generated antigenic drift variants in the laboratory, and here we test our ‘drifted’ viruses to assess their zoonotic infection characteristics and transmissibility in chickens. We found that the ‘drifted’ viruses were able to infect and transmit between chickens and showed increased binding to human-like receptors. However the ‘drift’ mutant viruses displayed reduced stability and, we predict, would be unlikely to be able to transmit human-to-human and cause an influenza pandemic. These results demonstrate the complex relationship between antigenic drift and potential of avian influenza viruses to infect humans.

Kotecha A, Wang Q, Dong X, Ilca S L, Ondiviela M, Zihe R, Seago J, Charleston B, Fry E E, Abrescia N G A, Springer T A, Huiskonen J T, Stuart D I (2017)

Rules of engagement between αvβ6 integrin and foot-and-mouth disease virus

Nature Communications 8, 15408


Foot-and-mouth disease virus (FMDV) mediates cell entry by attachment to an integrin receptor, generally alphavbeta6, via a conserved arginine-glycine-aspartic acid (RGD) motif in the exposed, antigenic, GH loop of capsid protein VP1. Infection can also occur in tissue culture adapted virus in the absence of integrin via acquired basic mutations interacting with heparin sulphate (HS); this virus is attenuated in natural infections. HS interaction has been visualized at a conserved site in two serotypes suggesting a propensity for sulfated-sugar binding. Here we determined the interaction between alphavbeta6 and two tissue culture adapted FMDV strains by cryo-electron microscopy. In the preferred mode of engagement, the fully open form of the integrin, hitherto unseen at high resolution, attaches to an extended GH loop via interactions with the RGD motif plus downstream hydrophobic residues. In addition, an N-linked sugar of the integrin attaches to the previously identified HS binding site, suggesting a functional role.


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