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

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Banjara S, Caria S, Dixon L K, Hinds M G, Kvansakul M (2017)

Structural insight into African swine fever virus A179L mediated inhibition of apoptosis

Journal of Virology 91 (6), e02228-16


Programmed cell death is a tightly controlled process critical for the removal of damaged or infected cells. Pro- and anti-apoptotic proteins of the Bcl-2 family are pivotal mediators of this process. African Swine Fever virus (ASFV) is a large DNA virus, the only member of the Asfarviridae family, and harbors A179L, a putative Bcl-2 like protein. A179L has been shown to bind to several pro-apoptotic Bcl-2 proteins, however the hierarchy of binding and the structural basis for apoptosis inhibition are currently not understood. We systematically evaluated the ability of A179L to bind pro-apoptotic Bcl-2 family members, and show that A179L is the first anti-apoptotic Bcl-2 protein to bind to all major death inducing mammalian Bcl-2 proteins. We then defined the structural basis for apoptosis inhibition of A179L by determining crystal structures of A179L bound to both Bid and Bax BH3 motifs. Our findings provide a mechanistic understanding for the potent anti-apoptotic activity of A179L by identifying it as the first pan pro-death Bcl-2 binder, and serve as a platform for more detailed investigations into the role of A179L during ASFV infection.IMPORTANCE Numerous viruses have acquired strategies to subvert apoptosis by encoding proteins capable of sequestering pro-apoptotic host proteins. African Swine Fever virus (ASFV), a large DNA virus and the only member of the Asfarviridae family, encodes the protein A179L that functions to prevent apoptosis. We show that A179L is unusual amongst anti-apoptotic Bcl-2 proteins in being able to physically bind to all core death inducing mammalian Bcl-2 proteins. Currently, little is known regarding the molecular interactions between A179L and the pro-apoptotic Bcl-2 members. Using crystal structures of A179L bound to two of the identified pro-apoptotic Bcl-2 proteins, Bid and Bax, we now provide a 3D view of how A179L sequesters host pro-apoptotic proteins, which is crucial for subverting premature host cell apoptosis.

Baazizi R, Mahapatra M, Clarke B D, Ait-Oudhia K, Khelef D, Parida S (2017)

Peste des petits ruminants (PPR): A neglected tropical disease in Maghreb region of North Africa and its threat to Europe

PLOS ONE 12 (4), e0175461


Peste des petits ruminants (PPR) is a contagious disease listed by the World Organisation for Animal health (OIE) as being a specific hazard. It affects sheep, goats, and wild ungulates, and is prevalent throughout the developing world particularly Asia, the Middle East, and Africa. PPR has been targeted for eradication by 2030 by the Food and Agriculture Organization of the United Nations (FAO) and the OIE, after the successful eradication of the related disease, rinderpest in cattle. PPR was first reported in 1942 in the Ivory Coast in Western Africa and has since extended its range in Asia, the Middle East, and Africa posing an immediate threat of incursion into Europe, South East Asia and South Africa. Although robust vaccines are available, the use of these vaccines in a systematic and rational manner is not widespread, resulting in this devastating disease becoming an important neglected tropical disease in the developing world. Methodology We isolated and characterized the PPR virus from an outbreak in Cheraga, northern Algeria, during October 2015 by analyzing the partial N-gene sequence in comparison with other viruses from the Maghreb region. As well as sequencing the full length viral genome and performing real-time RT-PCR on clinical samples. Maximum-likelihood and Bayesian temporal and phylogeographic analyses were performed to assess the persistence and spread of PPRV circulation from Eastern Africa in the Maghreb region of North Africa. Conclusions Recent PPR outbreaks in Cheraga, in the northern part of Algiers (October 2015) and North-West Morocco (June, 2015) highlight that PPRV has spread to the northern border of North Africa and may pose a threat of introduction to Europe. Phylogeographic analysis suggests that lineage IV PPRV has spread from Eastern Africa, most likely from the Sudan 2000 outbreak, into Northern Africa resulting in the 2008 Moroccan outbreak. Maximum-likelihood and Bayesian analysis shows that these North African viruses cluster closely together suggesting the existence of continual regional circulation. Considering the same virus is circulating in Algeria, Morocco and Tunisia, implementation of a common Maghreb PPR eradication strategy would be beneficial for the region.

Brito B, Pauszek S J, Eschbaumer M, Stenfeldt C, de Carvalho Ferreira H C, Vu L T, Phuong N T, Hoang B H, Tho N D, Dong P V, Minh P Q, Long N T, King D P, Knowles N J, Dung D H, Rodriguez L L, Arzt J (2017)

Phylodynamics of foot-and-mouth disease virus O/PanAsia in Vietnam 2010 - 2014

Veterinary Research 48 (1), 24


Foot-and-mouth disease virus (FMDV) is endemic in Vietnam, a country that plays an important role in livestock trade within Southeast Asia. The large populations of FMDV-susceptible species in Vietnam are important components of food production and of the national livelihood. In this study, we investigated the phylogeny of FMDV O/PanAsia in Vietnam, reconstructing the virus’ ancestral host species (pig, cattle or buffalo), clinical stage (subclinical carrier or clinically affected) and geographical location. Phylogenetic divergence time estimation and character state reconstruction analyses suggest that movement of viruses between species differ. While inferred transmissions from cattle to buffalo and pigs and from pigs to cattle are well supported, transmission from buffalo to other species, and from pigs to buffalo may be less frequent. Geographical movements of FMDV O/PanAsia virus appears to occur in all directions within the country, with the South Central Coast and the Northeast regions playing a more important role in FMDV O/PanAsia spread. Genetic selection of variants with changes at specific sites within FMDV VP1 coding region was different depending on host groups analyzed. The overall ratio of non-synonymous to synonymous nucleotide changes was greater in pigs compared to cattle and buffalo, whereas a higher number of individual amino acid sites under positive selection were detected in persistently infected, subclinical animals compared to viruses collected from clinically diseased animals. These results provide novel insights to understand FMDV evolution and its association with viral spread within endemic countries. These findings may support animal health organizations in their endeavor to design animal disease control strategies in response to outbreaks.

Brugman V A, Hernández-Triana L M, England M E, Medlock J M, Mertens P P C, Logan J G, Wilson A J, Fooks A R, Johnson N, Carpenter S (2017)

Blood-feeding patterns of native mosquitoes and insights into their potential role as pathogen vectors in the Thames estuary region of the United Kingdom

Parasites and Vectors 10 (1), 163


The range of vertebrate hosts on which species of mosquito blood-feed is an important parameter for identifying potential vectors and in assessing the risk of incursion and establishment of vector-borne pathogens. In the United Kingdom, studies of mosquito host range have collected relatively few specimens and used techniques that could only broadly identify host species. This study conducted intensive collection and analysis of mosquitoes from a grazing marsh environment in southeast England. This site provides extensive wetland habitat for resident and migratory birds and has abundant human nuisance biting mosquitoes. The aim was to identify the blood-feeding patterns of mosquito species present at the site which could contribute to the transmission of pathogens.

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

Variability in H9N2 haemagglutinin receptor-binding preference and the pH of fusion

Emerging Microbes and Infections 6 (3), e11


H9N2 avian influenza viruses are primarily a disease of poultry; however, they occasionally infect humans and are considered a potential pandemic threat. Little work has been performed to assess the intrinsic biochemical properties related to zoonotic potential of H9N2 viruses. The objective of this study, therefore, was to investigate H9N2 haemagglutinins (HAs) using two well-known correlates for human adaption: receptor-binding avidity and pH of fusion. Receptor binding was characterized using bio-layer interferometry to measure virus binding to human and avian-like receptor analogues and the pH of fusion was assayed by syncytium formation in virus-infected cells at different pHs. We characterized contemporary H9N2 viruses of the zoonotic G1 lineage, as well as representative viruses of the zoonotic BJ94 lineage. We found that most contemporary H9N2 viruses show a preference for sulphated avian-like receptor analogues. However, the 'Eastern' G1 H9N2 viruses displayed a consistent preference in binding to a human-like receptor analogue. We demonstrate that the presence of leucine at position 226 of the HA receptor-binding site correlated poorly with the ability to bind a human-like sialic acid receptor. H9N2 HAs also display variability in their pH of fusion, ranging between pH 5.4 and 5.85 which is similar to that of the first wave of human H1N1pdm09 viruses but lower than the pH of fusion seen in zoonotic H5N1 and H7N9 viruses. Our results suggest possible molecular mechanisms that may underlie the relatively high prevalence of human zoonotic infection by particular H9N2 virus lineages.

Sanders C J, Harrup L E, Tugwell L A, Brugman V A, England M, Carpenter S (2017)

Quantification of within- and between-farm dispersal of Culicoides biting midges using an immunomarking technique

Journal of Applied Ecology early view,


Culicoides biting midges (Diptera, Ceratopogonidae) are vectors of arboviruses that cause significant economic and welfare impact. Local-scale spread of Culicoides-borne arboviruses is largely determined by the between-farm movement of infected Culicoides. * Study of the dispersal behaviour of Culicoides by capture–mark–recapture (CMR) is problematic due to the likelihood of mortality and changes in behaviour upon capture caused by the small size and fragility of these insects, evidenced by low recapture rates. To counter the problem of using CMR with Culicoides, this study utilised an ovalbumin immunomarking technique to quantify the within- and between-farm dispersal of Culicoides in southern England. * Both within- and between-farm dispersal of Culicoides was observed. Of the 9058 Culicoides collected over 22 nights of trapping, 600 ovalbumin-positive Culicoides, of 12 species including those implicated as arbovirus vectors, were collected with a maximum dispersal distance of 3125 m. * This study provides the first species-level data on the between-farm dispersal of potential bluetongue, Schmallenberg and African horse sickness virus vectors in northern Europe. High-resolution meteorological data determined upwind and downwind flight by Culicoides had occurred. Cumulative collection and meteorological data suggest 15·6% of flights over 1 km were upwind of the treatment area and 84·4% downwind. * Synthesis and applications. The use of immunomarking eliminates the potential adverse effects on survival and behaviour of insect collection prior to marking, substantially improving the resolution and accuracy of estimates of the dispersal potential of small and delicate vector species such as Culicoides. Using this technique, quantification of the range of Culicoides dispersal with regard to meteorological conditions including wind direction will enable improved, data-driven modelling of the spread of Culicoides-borne arboviruses and will inform policy response to incursions and outbreaks.

White S M, Sanders C J, Shortall C R, Purse B V (2017)

Mechanistic model for predicting the seasonal abundance of Culicoides biting midges and the impacts of insecticide control

Parasites and Vectors 10 (1), 162


Understanding seasonal patterns of abundance of insect vectors is important for optimisation of control strategies of vector-borne diseases. Environmental drivers such as temperature, humidity and photoperiod influence vector abundance, but it is not generally known how these drivers combine to affect seasonal population dynamics.

Yao Y, Vasoya D, Kgosana L, Smith L, Gao Y, Wang X, Watson M, Nair V (2017)

Activation of gga-miR-155 by reticuloendotheliosis virus T strain and its contribution to transformation

Journal of General Virology 98 (4), 810-820


The v-rel oncoprotein encoded by reticuloendotheliosis virus T strain (Rev-T) is a member of the rel/NF-kappaB family of transcription factors capable of transformation of primary chicken spleen and bone marrow cells. Rapid transformation of avian haematopoietic cells by v-rel occurs through a process of deregulation of multiple protein-encoding genes through its direct effect on their promoters. More recently, upregulation of oncogenic miR-155 and its precursor pre-miR-155 were demonstrated in Rev-T-infected chicken embryo fibroblast cultures as well as Rev-T-induced B-cell lymphomas. Through electrophoresis mobility shift assay and reporter analysis on gga-miR-155 promoter, we show that the v-rel-induced miR-155 overexpression occurs by the direct binding to one of the putative NF-kappaB binding sites. Using v-rel-induced transformation model on chicken embryonic splenocyte cultures, we could demonstrate dynamic increase in miR-155 levels during the transformation. Transcriptome profiles of lymphoid cells transformed by v-rel showed upregulation of miR-155 accompanied by downregulation of a number of putative miR-155 targets such as Pu.1 and CEBPbeta. We also show that v-rel can rescue the suppression of miR-155 expression observed in Marek's disease virus-transformed cell lines, where its functional viral homolog MDV-miR-M4 is overexpressed. Demonstration of gene expression changes affecting major molecular pathways including organismal injury and cancer in avian macrophages transfected with synthetic mature miR-155 underline its potential direct role in transformation. Our study suggests that v-rel-induced transformation involves complex set of events mediated by the direct activation of NF-kappaB targets together with the inhibitory effects on miRNA targets.

López-Osorio S, Piedrahita D, Espinal-Restrepo M A, Ramírez-Nieto G C, Nair V, Williams S M, Baigent S, Ventura-Polite C, Aranzazu-Taborda D A, Chaparro-Gutiérrez J J (2017)

Molecular characterization of Marek's disease virus in a poultry layer farm from Colombia

Poultry Science 96 (6), 1598-1608
Publisher’s version:


Marek's disease (MD) is a lymphoproliferative disease caused by an Alphaherpesvirus, genus Mardivirus, serotype 1 (Gallid Herpesvirus 2, GaHV-2) that includes all known pathogenic strains. In addition to Marek's disease virus (MDV) serotype 1, the genus includes 2 distinct nonpathogenic serotypes: serotype 2 (GaHV-3) and serotype 3 (Meleagridis Herpesvirus 1, MeHV-1) which are used in commercially available vaccines against MD. As a result of vaccination, clinical signs are not commonly observed, and new cases are usually associated with emerging variant strains against which the vaccines are less effective. In this study, a commercial layer farm showing clinical signs compatible with MDV infection was evaluated. Histological lesions and positive immunohistochemistry in the sciatic nerve and thymus were compatible with cytolytic phase of MD. GaHV-2, GaHV-3 and MeHV-1 were identified by PCR and qPCR in blood samples from 17 birds with suspected MD. Analysis of the Meq gene of the Colombian GaHV-2 isolate revealed a 99% sequence identity with Asian strains, and in the phylogenetic analysis clustered with vv+ MDV. The analysis of amino acid alignments demonstrated an interruption of the proline rich region in P176A, P217A and P233L positions, which are generally associated with vv+ strains. Some of these changes, such as P233L and L258S positions have not been reported previously. In addition, primary cell cultures inoculated with lymphocytes isolated from the spleen showed typical cytopathic effect of GaHV-2 at 5 d post infection. Based on the molecular analysis, the results from this study indicate the presence of vv+ MDV infection in commercial birds for the first time in Colombia. It is recommended to perform further assays in order to demonstrate the pathotype characteristics in vivo.

Nelson N, Paton D J, Gubbins S, Colenutt C, Brown E, Hodgson S, Gonzales J L (2017)

Predicting the ability of preclinical diagnosis to improve control of farm-to-farm foot-and-mouth disease transmission in cattle

Journal of Clinical Microbiology 55 (6), 1671-1681


Foot-and-mouth disease (FMD) can cause large disruptive epidemics in livestock. Current eradication measures rely on the rapid clinical detection and removal of infected herds. Here, we have evaluated the potential for preclinical diagnosis during reactive surveillance to reduce the risk of between farm transmission. We used data from transmission experiments in cattle where both individual animal samples, such as blood, probang, saliva or nasal swabs, and herd level samples, such as air samples, were taken daily during the course of infection. The sensitivity of each of these sample types for detection of infected cattle was quantified during different phases of the early infection period. The results were incorporated into a mathematical model for FMD, in a cattle herd, to evaluate the impact of early detection and culling of an infected herd on its infectious output. The latter was expressed as the between herd reproduction ratio Rh, where an effective surveillance approach would lead to a reduction in Rh < 1. Applying weekly surveillance, clinical inspection alone was found to be ineffective at blocking transmission. This was in contrast to the impact of weekly random sampling (i.e. using saliva swabs) of at least 10 animals per farm or daily air sampling (housed cattle), both of which were shown to reduce Rh < 1. In conclusion, preclinical detection during outbreaks has the potential to allow earlier culling of infected herds and thereby reduce transmission and aid the control of epidemics.


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