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

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Leftwich P T, Edgington M P, Harvey-Samuel T, Carabajal Paladino L Z, Norman V C, Alphey L (2018)

Recent advances in threshold-dependent gene drives for mosquitoes

Biochemical Society Transactions early view,


Mosquito-borne diseases, such as malaria, dengue and chikungunya, cause morbidity and mortality around the world. Recent advances in gene drives have produced control methods that could theoretically modify all populations of a disease vector, from a single release, making whole species less able to transmit pathogens. This ability has caused both excitement, at the prospect of global eradication of mosquito-borne diseases, and concern around safeguards. Drive mechanisms that require individuals to be released at high frequency before genes will spread can therefore be desirable as they are potentially localised and reversible. These include underdominance-based strategies and use of the reproductive parasite Wolbachia Here, we review recent advances in practical applications and mathematical analyses of these threshold-dependent gene drives with a focus on implementation in Aedes aegypti, highlighting their mechanisms and the role of fitness costs on introduction frequencies. Drawing on the parallels between these systems offers useful insights into practical, controlled application of localised drives, and allows us to assess the requirements needed for gene drive reversal.

Doyle N, Neuman B, Simpson J, Hawes P, Mantell J, Verkade P, Alrashedi H, Maier H (2018)

Infectious bronchitis virus nonstructural protein 4 alone induces membrane pairing

Viruses 10 (9), 477
Publisher’s version:


Positive-strand RNA viruses, such as coronaviruses, induce cellular membrane rearrangements during replication to form replication organelles allowing for efficient viral RNA synthesis. Infectious bronchitis virus (IBV), a pathogenic avian Gammacoronavirus of significant importance to the global poultry industry, has been shown to induce the formation of double membrane vesicles (DMVs), zippered endoplasmic reticulum (zER) and tethered vesicles, known as spherules. These membrane rearrangements are virally induced; however, it remains unclear which viral proteins are responsible. In this study, membrane rearrangements induced when expressing viral non-structural proteins (nsps) from two different strains of IBV were compared. Three non-structural transmembrane proteins, nsp3, nsp4, and nsp6, were expressed in cells singularly or in combination and the effects on cellular membranes investigated using electron microscopy and electron tomography. In contrast to previously studied coronaviruses, IBV nsp4 alone is necessary and sufficient to induce membrane pairing; however, expression of the transmembrane proteins together was not sufficient to fully recapitulate DMVs. This indicates that although nsp4 is able to singularly induce membrane pairing, further viral or host factors are required in order to fully assemble IBV replicative structures. This study highlights further differences in the mechanism of membrane rearrangements between members of the coronavirus family.

Chaters G, Rushton J, Dulu T D, Lyons N A (2018)

Impact of foot-and-mouth disease on fertility performance in a large dairy herd in Kenya

Preventive Veterinary Medicine 159, 57-64


This was a retrospective cohort study using data collected from a large-scale dairy herd in Kenya (n = 328 female animals), to investigate the effects of foot-and-mouth disease (FMD) on herd fertility performance following a confirmed outbreak in a regularly vaccinated herd. Kaplan-Meier graphs were used to depict differences in survival functions between exposure groups and Cox regression models were used to calculate hazard ratios (HR) for associations between being clinical FMD cases and the following fertility outcomes: age at first calving; fertility failure related culling (not in calf); time to first service; time to conception. Potential confounding variables investigated and controlled for were age, breed, parity, stage of lactation/gestation and eligibility for service. A case control study was nested within the cohort to investigate the effects of disease on conception HR following calving by comparing animals susceptible to fertility suppression at the time of the outbreak (cases) to animals that had conceived prior to the outbreak (controls). The median age of first calving in clinically affected young-stock was 2.7 months higher than non-clinical cases (adjusted HR = 0.37, 95%CI 0.21-0.67, P = 0.01). There was no evidence of a difference in fertility related culling and times to first service and conception. Animals susceptible to fertility suppression at the time of the outbreak had a lower hazard of conception compared to animals served prior to the outbreak (HR = 0.56, 95%CI 0.41-0.75, P = 0.01). Within the herd, the odds of being a case decreased with parity and age likely related to the lifetime number of vaccination doses received which may reduce the impact among older animals in the herd. Moreover, one would expect the impact to be higher in a non-vaccinating herd to be higher. Notwithstanding these limitations, the results of this study provide evidence that FMD outbreaks in endemic settings impact herd fertility performance. An increased age at first calving is likely to increase rearing costs and reduce an animal's lifetime productivity while poorer conception rates will likely extend calving intervals. Impaired herd fertility and production will incur higher costs to the farmer and society as animals are less productive which for FMD can extend beyond the outbreak period where economic studies tend to focus. These impacts of FMD on herd fertility should be considered when conducting benefit-cost analyses of FMD control to inform resource allocation.

Zhou D, Xue J, He S, Du X, Zhou J, Li C, Huang L, Nair V, Yao Y, Cheng Z (2018)

Reticuloendotheliosis virus and avian leukosis virus subgroup J synergistically increase the accumulation of exosomal miRNAs

Retrovirology 15 (1), 45


Co-infection with avian leukosis virus subgroup J and reticuloendotheliosis virus induces synergistic pathogenic effects and increases mortality. However, the role of exosomal miRNAs in the molecular mechanism of the synergistic infection of the two viruses remains unknown.

In this study, exosomal RNAs from CEF cells infected with ALV-J, REV or both at the optimal synergistic infection time were analysed by Illumina RNA deep sequencing. A total of 54 (23 upregulated and 31 downregulated) and 16 (7 upregulated and 9 downregulated) miRNAs were identified by comparing co-infection with two viruses, single-infected ALV-J and REV, respectively. Moreover, five key miRNAs, including miR-184-3p, miR-146a-3p, miR-146a-5p, miR-3538 and miR-155, were validated in both exosomes and CEF cells by qRT-PCR. GO annotation and KEGG pathway analysis of the miRNA target genes showed that the five differentially expressed miRNAs participated in virus-vector interaction, oxidative phosphorylation, energy metabolism and cell growth.

We demonstrated that REV and ALV-J synergistically increased the accumulation of exosomal miRNAs, which sheds light on the synergistic molecular mechanism of ALV-J and REV.

Shimmon G, Kotecha A, Ren J, Asfor A S, Newman J, Berryman S, Cottam E M, Gold S, Tuthill T J, King D P, Brocchi E, King A M Q, Owens R, Fry E E, Stuart D I, Burman A, Jackson T (2018)

Generation and characterisation of recombinant FMDV antibodies: Applications for advancing diagnostic and laboratory assays

PLoS ONE 13 (8), e0201853


Foot-and-mouth disease (FMD) affects economically important livestock and is one of the most contagious viral diseases. The most commonly used FMD diagnostic assay is a sandwich ELISA. However, the main disadvantage of this ELISA is that it requires anti-FMD virus (FMDV) serotype-specific antibodies raised in small animals. This problem can be, in part, overcome by using anti-FMDV monoclonal antibodies (MAbs) as detecting reagents. However, the long-term use of MAbs may be problematic and they may need to be replaced. Here we have constructed chimeric antibodies (mouse/rabbit D9) and Fabs (fragment antigen-binding) (mouse/cattle D9) using the Fv (fragment variable) regions of a mouse MAb, D9 (MAb D9), which recognises type O FMDV. The mouse/rabbit D9 chimeric antibody retained the FMDV serotype-specificity of MAb D9 and performed well in a FMDV detection ELISA as well as in routine laboratory assays. Cryo-electron microscopy analysis confirmed engagement with antigenic site 1 and peptide competition studies identified the aspartic acid at residue VP1 147 as a novel component of the D9 epitope. This chimeric expression approach is a simple but effective way to preserve valuable FMDV antibodies, and has the potential for unlimited generation of antibodies and antibody fragments in recombinant systems with the concomitant positive impacts on the 3Rs (Replacement, Reduction and Refinement) principles.

Morales-Hojas R, Hinsley M, Armean I M, Silk R, Harrup L E, Gonzalez-Uriarte A, Veronesi E, Campbell L, Nayduch D, Saski C, Tabachnick W J, Kersey P, Carpenter S, Fife M (2018)

The genome of the biting midge Culicoides sonorensis and gene expression analyses of vector competence for bluetongue virus

BMC Genomics 19 (1), 624


The new genomic technologies have provided novel insights into the genetics of interactions between vectors, viruses and hosts, which are leading to advances in the control of arboviruses of medical importance. However, the development of tools and resources available for vectors of non-zoonotic arboviruses remains neglected. Biting midges of the genus Culicoides transmit some of the most important arboviruses of wildlife and livestock worldwide, with a global impact on economic productivity, health and welfare. The absence of a suitable reference genome has hindered genomic analyses to date in this important genus of vectors. In the present study, the genome of Culicoides sonorensis, a vector of bluetongue virus (BTV) in the USA, has been sequenced to provide the first reference genome for these vectors. In this study, we also report the use of the reference genome to perform initial transcriptomic analyses of vector competence for BTV. Our analyses reveal that the genome is 189 Mb, assembled in 7974 scaffolds. Its annotation using the transcriptomic data generated in this study and in a previous study has identified 15,612 genes. Gene expression analyses of C. sonorensis females infected with BTV performed in this study revealed 165 genes that were differentially expressed between vector competent and refractory females. Two candidate genes, glutathione S-transferase (gst) and the antiviral helicase ski2, previously recognized as involved in vector competence for BTV in C. sonorensis (gst) and repressing dsRNA virus propagation (ski2), were confirmed in this study. The reference genome of C. sonorensis has enabled preliminary analyses of the gene expression profiles of vector competent and refractory individuals. The genome and transcriptomes generated in this study provide suitable tools for future research on arbovirus transmission. These provide a valuable resource for these vector lineage, which diverged from other major Dipteran vector families over 200 million years ago. The genome will be a valuable source of comparative data for other important Dipteran vector families including mosquitoes (Culicidae) and sandflies (Psychodidae), and together with the transcriptomic data can yield potential targets for transgenic modification in vector control and functional studies.

Leemans A, Boeren M, Van der Gucht W, Pintelon I, Roose K, Schepens B, Saelens X, Bailey D, Martinet W, Caljon G, Maes L, Cos P, Delputte P (2018)

Removal of the N-glycosylation sequon at position N116 located in P27 of the respiratory syncytial virus fusion protein elicits enhanced antibody responses after DNA immunization

Viruses 10 (8), 426
Publisher’s version:


Prevention of severe lower respiratory tract infections in infants caused by the human respiratory syncytial virus (hRSV) remains a major public health priority. Currently, the major focus of vaccine development relies on the RSV fusion (F) protein since it is the main target protein for neutralizing antibodies induced by natural infection. The protein conserves 5 N-glycosylation sites, two of which are located in the F2 subunit (N27 and N70), one in the F1 subunit (N500) and two in the p27 peptide (N116 and N126). To study the influence of the loss of one or more N-glycosylation sites on RSV F immunogenicity, BALB/c mice were immunized with plasmids encoding RSV F glycomutants. In comparison with F WT DNA immunized mice, higher neutralizing titres were observed following immunization with F N116Q. Moreover, RSV A2-K-line19F challenge of mice that had been immunized with mutant F N116Q DNA was associated with lower RSV RNA levels compared with those in challenged WT F DNA immunized animals. Since p27 is assumed to be post-translationally released after cleavage and thus not present on the mature RSV F protein, it remains to be elucidated how deletion of this glycan can contribute to enhanced antibody responses and protection upon challenge. These findings provide new insights to improve the immunogenicity of RSV F in potential vaccine candidates

Hope A, Gubbins S, Sanders C, Barber J, Stubbins F, Baylis M, Carpenter S (2018)

Sheep breed and shearing influences attraction and blood-feeding behaviour of Culicoides (Diptera: Ceratopogonidae) on a UK farm

Parasites and Vectors 11 (1), 473


Culicoides biting midges (Diptera: Ceratopogonidae) are responsible for the biological transmission of arboviruses of international importance between ruminant livestock. These arboviruses include bluetongue virus (BTV) and Schmallenberg virus (SBV), which have emerged in unprecedented outbreaks in northern Europe. The impact of breed and shearing of sheep on Culicoides: host contact rates has not been investigated in detail and has the potential to influence arbovirus transmission and control measures employed to limit spread.

Attraction of Culicoides to Hartline and Hartline/Suffolk cross-breed sheep was compared using 224 drop trap collections over 22 nights and 181 catches from sheared or unsheared Hartline/Suffolk ewes were made over 17 nights to compare Culicoides activity and rates of blood engorgement.

A total of 31,314 Culicoides was collected in the two trials and females of the subgenus Avaritia represented over 96.9% of individuals collected. Attraction to breed was dependent upon species of Culicoides and physiological status, with a significantly greater number of individuals collected on the cross-breed sheep. Shearing of sheep did not significantly increase or decrease the number of Culicoides attracted but increased the rate of successful engorgement.

Both breed and shearing were shown to influence Culicoides biting rate on sheep. These data are useful in a direct context in understanding the likely impact of control measures against arboviruses including BTV and SBV and additionally in providing data from field-based studies to enable modelling exercises of arbovirus transmission and spread.

Getachew B, Upmanyu V, Haq A A, Santhamani R, Rajak K K, Muthuchelvan D, Gupta S K, Yousuf R W, Mahapatra M, Parida S, Sharma B, Singh R P (2018)

Monoclonal antibody resistant mutant of Peste des petits ruminants vaccine virus

VirusDisease early view,


The available vaccines for control of Peste des petits ruminants do not favour differentiation of infected and vaccinated animals (DIVA). Hence, the present study was aimed to isolate and characterize monoclonal antibody resistant mutant of an Indian strain of vaccine virus "PPRV-Sungri/96" under selection pressure of virus neutralizing monoclonal antibody '4B11' specific to haemagglutinin (H) protein. We successfully isolated five monoclonal antibody resistant (mAr) mutants (PPRV-RM5, PPRV-RM6, PPRV-RM7, PPRV- E6 and PPRV- E7). The mAr mutants did not react with the anti-H mAb 4B11 whereas reacted with control anti-nucleoprotein mAb 4G6, similar to the parent vaccine virus "PPRV-Sungri/96" in indirect ELISA, cell ELISA and indirect immunofluorescence test. Cytometry analysis of mAr mutants revealed loss of binding to mAb 4B11 while maintaining binding to mAb 4G6, more or less similar to "PPRV-Sungri/96". The sequence analysis of the H-protein gene of the mAr mutants resulted in identification of two nucleotide changes leading to amino acid substitutions at position 263 and 502 (L263P and R502P) of the H protein indicating that the epitope of mAb 4B11 could be conformational in nature. Though, mAr mutant grew to a similar titre as parent vaccine virus (PPRV-Sungri/96), the in vivo work in goats to study the mAr mutant as possible negative marker vaccine candidate could not be successfully proved with mAb 4B11 based competitive ELISA. However, one of the nucleotide change (T-C) at position 788, unique to mAr mutant virus resulted in abolition of a restriction enzyme recognition site (BglII). This could be used to differentiate mAr mutant vaccine virus from other available vaccine and field strains using restriction fragment length polymorphism. However, the mAr mutant PPRV-E6 cannot be used as a candidate strain for DIVA vaccine as immune response against it cannot be differentiated based on serology.

Collins Á B, Mee J F, Doherty M L, Barrett D J, England M E (2018)

Culicoides species composition and abundance on Irish cattle farms: implications for arboviral disease transmission

Parasites and Vectors 11 (1), 472


Following the emergence of Schmallenberg virus (SBV) in Ireland in 2012, a sentinel herd surveillance program was established in the south of Ireland with the primary aim of investigating the species composition and abundance of Culicoides on livestock farms in the region.

Ultraviolet-light trapping for Culicoides was carried out on 10 sentinel farms. Each site was sampled fortnightly over 16 weeks (21st July to 5th November 2014). One Onderstepoort Veterinary Institute UV light trap was run overnight at each site and catches were transferred immediately into 70% ethanol. Culicoides were morphologically identified to species level. Collection site habitats were characterised using the Phase 1 habitat survey technique (Joint Nature Conservation Committee).

A total of 23,929 individual Culicoides from 20 species was identified, including one species identified in Ireland for the first time, Culicoides cameroni. The most abundant species identified were Culicoides obsoletus/Culicoides scoticus (38%), Culicoides dewulfi (36%), Culicoides pulicaris (9%), Culicoides chiopterus (5%) and Culicoides punctatus (5%), comprising 93% of all Culicoides specimens identified. Collection site habitats were dominated by improved grassland and a combination of broadleaf woodland and native woodland species.

The most abundant species of Culicoides identified were the putative vectors of bluetongue virus (BTV) and SBV in northern Europe. Their presence and abundance demonstrates the potential for future transmission of arboviruses among livestock in this region.


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