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

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Altan E, Parida S, Mahapatra M, Turan N, Huseyin Y (2018)

Molecular characterization of peste des petits ruminants viruses in the Marmara Region of Turkey

Transboundary and Emerging Diseases early view,
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Recent outbreaks of Peste des petits ruminants (PPR) in the Marmara region of Turkey including the European part of Thrace is important due to its proximity to Europe (Greece and Bulgaria) and the potential threat of spread of PPR into mainland Europe. In order to investigate the circulation of PPRV in the region suspect clinical and necropsy samples were collected from domestic sheep (n=211) in the Marmara region of Turkey between 2011 and 2012. PPR virus (PPRV) genome was detected in 10.4% (22 out of 211) of sheep samples by real-time RT-PCR, and PPR virus was isolated from lungs of two sheep that died from infection. Of the 22 positive samples nine were used for partial N gene amplification and sequencing. The phylogenetic analyses indicated that the virus belongs to lineage IV, the same lineage that is circulating in eastern and central part of Turkey since its first official report in 1999. In addition, samples from 100 cattle were collected to investigate potential subclinical circulation of PPRV. However all were found to be negative by real-time RT-PCR, and also in serological tests indicating the large ruminants were likely not exposed or infected with the virus. The impact of these findings on the potential threat of spread of PPR to Europe including the first PPR outbreak in Europe in Bulgaria on 23rd June 2018 is discussed.

Boulton K, Nolan M J, Wu Z, Riggio V, Matika O, Harman K, Hocking P M, Bumstead N, Hesketh P, Archer A, Bishop S C, Kaiser P, Tomley F M, Hume D A, Smith A L, Blake D P, Psifidi A (2018)

Dissecting the genomic architecture of resistance to Eimeria maxima parasitism in the chicken

Frontiers in Genetics 9, 528


Coccidiosis in poultry, caused by protozoan parasites of the genus Eimeria, is an intestinal disease with substantial economic impact. With the use of anticoccidial drugs under public and political pressure, and the comparatively higher cost of live-attenuated vaccines, an attractive complementary strategy for control is to breed chickens with increased resistance to Eimeria parasitism. Prior infection with Eimeria maxima leads to complete immunity against challenge with homologous strains, but only partial resistance to challenge with antigenically diverse heterologous strains. We investigate the genetic architecture of avian resistance to E. maxima primary infection and heterologous strain secondary challenge using White Leghorn populations of derived inbred lines, C.B12 and 15I, known to differ in susceptibility to the parasite. An intercross population was infected with E. maxima Houghton (H) strain, followed 3 weeks later by E. maxima Weybridge (W) strain challenge, while a backcross population received a single E. maxima W infection. The phenotypes measured were parasite replication (counting fecal oocyst output or qPCR for parasite numbers in intestinal tissue), intestinal lesion score (gross pathology, scale 0–4), and for the backcross only, serum interleukin-10 (IL-10) levels. Birds were genotyped using a high density genome-wide DNA array (600K, Affymetrix). Genome-wide association study located associations on chromosomes 1, 2, 3, and 5 following primary infection in the backcross population, and a suggestive association on chromosome 1 following heterologous E. maxima W challenge in the intercross population. This mapped several megabases away from the quantitative trait locus (QTL) linked to the backcross primary W strain infection, suggesting different underlying mechanisms for the primary- and heterologous secondary- responses. Underlying pathways for those genes located in the respective QTL for resistance to primary infection and protection against heterologous challenge were related mainly to immune response, with IL-10 signaling in the backcross primary infection being the most significant. Additionally, the identified markers associated with IL-10 levels exhibited significant additive genetic variance. We suggest this is a phenotype of interest to the outcome of challenge, being scalable in live birds and negating the requirement for single-bird cages, fecal oocyst counts, or slaughter for sampling (qPCR).

Haga I R, Simpson J L, Hawes P C, Beard P M (2018)

Carbenoxolone-mediated cytotoxicity inhibits Vaccinia virus replication in a human keratinocyte cell line

Scientific Reports 8 (1), 16956


The re-emergence of poxviral zoonotic infections and the threat of bioterrorism emphasise the demand for effective antipoxvirus therapies. Here, we show that carbenoxolone, a pharmacological inhibitor of gap junction function and a compound widely used in cell culture, is capable of hindering the replication of Vaccinia virus, the prototypical poxvirus, in a gap junction-independent manner in a human keratinocyte cell line. Viral protein synthesis occurs in the presence of carbenoxolone but infectious virion formation is minimal, indicating that carbenoxolone blocks viral morphogenesis. Initial viability tests suggested that carbenoxolone was not toxic to cells. However, electron microscopic analysis of carbenoxolone treated cells revealed that it alters the cellular endomembrane system. This widespread ultrastructural damage prevents Vaccinia virus virion assembly. These results strengthen the need for thorough characterisation of the effects of antiviral compounds on the cellular ultrastructure.

Huang K A, Rijal P, Jiang H, Wang B, Schimanski L, Dong T, Liu Y M, Chang P, Iqbal M, Wang M C, Chen Z, Song R, Huang C C, Yang J H, Qi J, Lin T Y, Li A, Powell T J, Jan J T, Ma C, Gao G F, Shi Y, Townsend A R (2018)

Structure-function analysis of neutralizing antibodies to H7N9 influenza from naturally infected humans

Nature Microbiology early view,


Little is known about the specificities and neutralization breadth of the H7-reactive antibody repertoire induced by natural H7N9 infection in humans. We have isolated and characterized 73 H7-reactive monoclonal antibodies from peripheral B cells from four donors infected in 2013 and 2014. Of these, 45 antibodies were H7-specific, and 17 of these neutralized the virus, albeit with few somatic mutations in their variable domain sequences. An additional set of 28 antibodies, isolated from younger donors born after 1968, cross-reacted between H7 and H3 haemagglutinins in binding assays, and had accumulated significantly more somatic mutations, but were predominantly non-neutralizing in vitro. Crystal structures of three neutralizing and protective antibodies in complex with the H7 haemagglutinin revealed that they recognize overlapping residues surrounding the receptor-binding site of haemagglutinin. One of the antibodies, L4A-14, bound into the sialic acid binding site and made contacts with haemagglutinin residues that were conserved in the great majority of 2016-2017 H7N9 isolates. However, only 3 of the 17 neutralizing antibodies retained activity for the Yangtze River Delta lineage viruses isolated in 2016-2017 that have undergone antigenic change, which emphasizes the need for updated H7N9 vaccines.

Leftwich P T, Hutchings M I, Chapman T (2018)

Diet, gut microbes and host mate choice: understanding the significance of microbiome effects on host mate choice requires a case by case evaluation

BioEssays 40 (12), 1800053


All organisms live in close association with microbes. However, not all such associations are meaningful in an evolutionary context. Current debate concerns whether hosts and microbes are best described as communities of individuals or as holobionts (selective units of hosts plus their microbes). Recent reports that assortative mating of hosts by diet can be mediated by commensal gut microbes have attracted interest as a potential route to host reproductive isolation (RI). Here, the authors discuss logical problems with this line of argument. The authors briefly review how microbes can affect host mating preferences and evaluate recent findings from fruitflies. Endosymbionts can potentially influence host RI given stable and recurrent co-association of hosts and microbes over evolutionary time. However, observations of co-occurrence of microbes and hosts are ripe for misinterpretation and such associations will rarely represent a meaningful holobiont. A framework in which hosts and their microbes are independent evolutionary units provides the only satisfactory explanation for the observed range of effects and associations.

Pandit R J, Hinsu A T, Patel N V, Koringa P G, Jakhesara S J, Thakkar J R, Shah T M, Limon G, Psifidi A, Guitian J, Hume D A, Tomley F M, Rank D N, Raman M, Tirumurugaan K G, Blake D P, Joshi C G (2018)

Microbial diversity and community composition of caecal microbiota in commercial and indigenous Indian chickens determined using 16s rDNA amplicon sequencing

Microbiome 6 (1), 115


The caecal microbiota plays a key role in chicken health and performance, influencing digestion and absorption of nutrients, and contributing to defence against colonisation by invading pathogens. Measures of productivity and resistance to pathogen colonisation are directly influenced by chicken genotype, but host driven variation in microbiome structure is also likely to exert a considerable indirect influence. Here, we define the caecal microbiome of indigenous Indian Aseel and Kadaknath chicken breeds and compare them with the global commercial broiler Cobb400 and Ross 308 lines using 16S rDNA V3-V4 hypervariable amplicon sequencing. Each caecal microbiome was dominated by the genera Bacteroides, unclassified bacteria, unclassified Clostridiales, Clostridium, Alistipes, Faecalibacterium, Eubacterium and Blautia. Geographic location (a measure recognised to include variation in environmental and climatic factors, but also likely to feature varied management practices) and chicken line/breed were both found to exert significant impacts (p < 0.05) on caecal microbiome composition. Linear discriminant analysis effect size (LEfSe) revealed 42 breed-specific biomarkers in the chicken lines reared under controlled conditions at two different locations. Chicken breed-specific variation in bacterial occurrence, correlation between genera and clustering of operational taxonomic units indicate scope for quantitative genetic analysis and the possibility of selective breeding of chickens for defined enteric microbiota.

Psifidi A, Russell K M, Matika O, Sanchez-Molano E, Wigley P, Fulton J E, Stevens M P, Fife M S (2018)

The genomic architecture of fowl typhoid resistance in commercial layers

Frontiers in Genetics 9, 519


Salmonella enterica serovar Gallinarum causes devastating outbreaks of fowl typhoid across the globe, especially in developing countries. With the use of antimicrobial agents being reduced due to legislation and the absence of licensed vaccines in some parts of the world, an attractive complementary control strategy is to breed chickens for increased resistance to Salmonella. The potential for genetic control of salmonellosis has been demonstrated by experimental challenge of inbred populations. Quantitative trait loci (QTL) associated with resistance have been identified in many genomic regions. A major QTL associated with systemic salmonellosis has been identified in a region termed SAL1. In the present study, two outbreaks of fowl typhoid in 2007 and 2011 in the UK were used to investigate the genetic architecture of Salmonella resistance in commercial laying hens. In the first outbreak 100 resistant and 150 susceptible layers were genotyped using 11 single nucleotide polymorphism (SNP) and 3 microsatellite markers located in the previously identified SAL1 region on chromosome 5. From the second outbreak 100 resistant and 200 susceptible layers, belonging to a different line, were genotyped with a high-density (600K) genome-wide SNP array. Substantial heritability estimates were obtained in both populations (h2=0.22 and 0.26, for the layers in the first and second outbreak, respectively). Significant associations with three markers on chromosome 5 located close to AKT1 and SIVA1 genes, coding for RAC-alpha serine/threonine protein kinase, and the CD27-binding protein Siva1, respectively, were identified in the first outbreak. From analysis of the second outbreak, eight genome-wide significant associations with Salmonella resistance were identified on chromosomes 1, 6, 7, 11, 23, 24, 26, 28 and several others with suggestive genome-wide significance were found. Pathway and network analysis revealed the presence of many innate immune pathways related to Salmonella resistance. Although, significant associations with SNPs located in the SAL1 locus were not identified by the genome-wide scan for layers from the second outbreak, pathway analysis revealed P13K/AKT signalling as the most significant pathway. In summary, resistance to fowl typhoid is a heritable polygenic trait that could possibly be enhanced through selective breeding.

Shrestha A, Sadeyen J-R, Iqbal M (2018)

Enhancing protective efficacy of poultry vaccines through targeted delivery of antigens to antigen-presenting cells

Vaccines 6 (4), 75


Avian viral diseases including avian influenza, Marek’s disease and Newcastle disease are detrimental to economies around the world that depend on the poultry trade. A significant zoonotic threat is also posed by avian influenza viruses. Vaccination is an important and widely used method for controlling these poultry diseases. However, the current vaccines do not provide full protection or sterile immunity. Hence, there is a need to develop improved vaccines. The major aim of developing improved vaccines is to induce strong and specific humoral and cellular immunity in vaccinated animals. One strategy used to enhance the immunogenicity of vaccines is the selective delivery of protective antigens to antigen-presenting cells (APCs) including dendritic cells, macrophages and B cells. APCs have a central role in the initiation and maintenance of immune responses through their ability to capture, process and present antigens to T and B cells. Vaccine technology that selectively targets APCs has been achieved by coupling antigens to monoclonal antibodies or ligands that are targeted by APCs. The aim of this review is to discuss existing strategies of selective delivery of antigens to APCs for effective vaccine development in poultry.

Hussain S, Turnbull M L, Wise H M, Jagger B W, Beard P M, Kovacikova K, Taubenberger J K, Vervelde L, Engelhardt O G, Digard P (2018)

Mutation of influenza A virus PA-X decreases pathogenicity in chicken embryos and can increase the yield of reassortant candidate vaccine viruses

Journal of Virology early view,


The PA-X protein of influenza A virus has roles in host cell shut-off and viral pathogenesis. While most strains are predicted to encode PA-X, strain-dependent variations in activity have been noted. We found that PA-X protein from A/PR/8/34 (PR8) strain had significantly lower repressive activity against cellular gene expression compared with PA-Xs from the avian strains A/turkey/England/50-92/91 (H5N1) (T/E) and A/chicken/Rostock/34 (H7N1). Loss of normal PA-X expression, either by mutation of the frameshift site or by truncating the X-ORF, had little effect on the infectious virus titre of PR8 or PR8 7:1 reassortants with T/E segment 3 grown in embryonated hens' eggs. However, in both virus backgrounds, mutation of PA-X led to decreased embryo mortality and lower overall pathology; effects that were more pronounced in the PR8 strain than the T/E reassortant, despite the low shut-off activity of the PR8 PA-X. Purified PA-X mutant virus particles displayed an increased ratio of HA to NP and M1 compared to their WT counterparts, suggesting altered virion composition. When the PA-X gene was mutated in the background of poorly growing PR8 6:2 vaccine reassortant analogues containing the HA and NA segments from H1N1 2009 pandemic viruses or an avian H7N3 strain, HA yield increased up to 2-fold. This suggests that the PR8 PA-X protein may harbour a function unrelated to host cell shut-off and that disruption of the PA-X gene has the potential to improve the HA yield of vaccine viruses.

Influenza A virus is a widespread pathogen that affects both man and a variety of animal species, causing regular epidemics and sporadic pandemics with major public health and economic consequences. A better understanding of virus biology is therefore important. The primary control measure is vaccination, which for humans, mostly relies on antigens produced in eggs from PR8-based viruses bearing the glycoprotein genes of interest. However, not all reassortants replicate well enough to supply sufficient virus antigen for demand. The significance of our research lies in identifying that mutation of the PA-X gene in the PR8 strain of virus can improve antigen yield, potentially by decreasing the pathogenicity of the virus in embryonated eggs.

Guzman E, Montoya M (2018)

Contributions of farm animals to immunology

Frontiers in Veterinary Science 5, 307


By their very nature, great advances in immunology are usually underpinned by experiments carried out in animal models and inbred lines of mice. Also, their corresponding knock-out or knock-in derivatives have been the most commonly used animal systems in immunological studies. With much credit to their usefulness, laboratory mice will never provide all the answers to fully understand immunological processes. Large animal models offer unique biological and experimental advantages that have been and continue to be of great value to the understanding of biological and immunological processes. From the identification of B cells to the realization that γδ T cells can function as professional antigen presenting cells, farm animals have contributed significantly to a better understanding of immunity.


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