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

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Howson E L A, Armson B, Lyons N A, Chepkwony E, Kasanga C J, Kandusi S, Ndusilo N, Yamazaki W, Gizaw D, Cleaveland S, Lembo T, Rauh R, Nelson W M, Wood B A, Mioulet V, King D P, Fowler V L (2017)

Direct detection and characterisation of foot-and-mouth disease virus in East Africa using a field-ready real-time PCR platform

Transboundary and Emerging Diseases early view,


Effective control and monitoring of foot-and-mouth disease (FMD) relies upon rapid and accurate disease confirmation. Currently, clinical samples are usually tested in reference laboratories using standardized assays recommended by The World Organisation for Animal Health (OIE). However, the requirements for prompt and serotype-specific diagnosis during FMD outbreaks, and the need to establish robust laboratory testing capacity in FMD-endemic countries have motivated the development of simple diagnostic platforms to support local decision-making. Using a portable thermocycler, the T-COR™ 8, this study describes the laboratory and field evaluation of a commercially available, lyophilized pan-serotype-specific real-time RT-PCR (rRT-PCR) assay and a newly available FMD virus (FMDV) typing assay (East Africa-specific for serotypes: O, A, Southern African Territories [SAT] 1 and 2). Analytical sensitivity, diagnostic sensitivity and specificity of the pan-serotype-specific lyophilized assay were comparable to that of an OIE-recommended laboratory-based rRT-PCR (determined using a panel of 57 FMDV-positive samples and six non-FMDV vesicular disease samples for differential diagnosis). The FMDV-typing assay was able to correctly identify the serotype of 33/36 FMDV-positive samples (no cross-reactivity between serotypes was evident). Furthermore, the assays were able to accurately detect and type FMDV RNA in multiple sample types, including epithelial tissue suspensions, serum, oesophageal–pharyngeal (OP) fluid and oral swabs, both with and without the use of nucleic acid extraction. When deployed in laboratory and field settings in Tanzania, Kenya and Ethiopia, both assays reliably detected and serotyped FMDV RNA in samples (n = 144) collected from pre-clinical, clinical and clinically recovered cattle. These data support the use of field-ready rRT-PCR platforms in endemic settings for simple, highly sensitive and rapid detection and/or characterization of FMDV.

Belova O A, Litov A G, Kholodilov I S, Kozlovskaya L I, Bell-Sakyi L, Romanova L I, Karganova G G (2017)

Properties of the tick-borne encephalitis virus population during persistent infection of ixodid ticks and tick cell lines

Ticks and Tick-borne Diseases 8 (6), 895-906


Tick-borne encephalitis virus (TBEV) is the causative agent of tick-borne encephalitis (TBE), a vector-borne zoonotic neuroinfection. For successful circulation in natural foci the virus has to survive in the vector for a long period of time. Information about the effect of long-term infection of ticks on properties of the viral population is of great importance. In recent years, changes in the eco-epidemiology of TBEV due to changes in distribution of ixodid ticks have been observed. These changes in TBEV-endemic areas could result in a shift of the main tick vector species, which in turn may lead to changes in properties of the virus. In the present study we evaluated the selective pressure on the TBEV population during persistent infection of various species of ticks and tick cell lines. TBEV effectively replicated and formed persistent infection in ticks and tick cell lines of the vector species (Ixodes spp.), potential vectors (Dermacentor spp.) and non-vector ticks (Hyalomma spp.). During TBEV persistence in Ixodes and Dermacentor ticks, properties of the viral population remained virtually unchanged. In contrast, persistent TBEV infection of tick cell lines from both vector and non-vector ticks favoured selection of viral variants with low neuroinvasiveness for laboratory mice and substitutions in the E protein that increased local positive charge of the virion. Thus, selective pressure on viral population may differ in ticks and tick cell lines during persistent infection. Nevertheless, virus variants with properties of the original strain adapted to mouse CNS were not eliminated from the viral population during long-term persistence of TBEV in ticks and tick cell lines.

Chen Y, Xue S A, Behboudi S, Mohammad G H, Pereira S P, Morris E (2017)

Ex vivo PD-L1/PD-1 pathway blockade reverses dysfunction of circulating CEA specific T cells in pancreatic cancer patients

Clinical Cancer Research 23 (20), 6178-6189


Carcinoembryonic antigen (CEA) is a candidate target for cellular immunotherapy of pancreatic cancer (PC). In this study, we have characterised the antigen-specific function of autologous cytotoxic T lymphocytes (CTL) specific for the HLA-A2 restricted peptide, pCEA691-699, isolated from the peripheral T cell repertoire of PC patients and sought to determine if ex vivo PD-L1 & TIM3 blockade could enhance CTL function. CD8+ T cell lines were generated from peripheral blood mononuclear cells (PBMCs) of 18 HLA-A2+ patients with PC and from 15 healthy controls. In vitro peptide specific responses were evaluated by flow cytometry after staining for intracellular cytokine production and CSFE cytotoxicity assays using pancreatic cancer cell lines as targets. Cytokine secreting functional CEA691-specific CTL lines were successfully generated from 10 of 18 PC patients, with two CTL lines able to recognise and kill both CEA691 peptide-loaded T2 cells and CEA+ HLA-A2+ pancreatic cancer cell lines. In the presence of ex vivo PD-L1 blockade, functional CEA691-specific CD8+ T cell responses, including IFN-g secretion and proliferation, were enhanced and this effect was more pronounced on Ag-specific T cells isolated from tumor draining lymph nodes. These data demonstrate that CEA691-specific CTL can be readily expanded from the self-restricted T cell repertoire of PC patients and that their function can be enhanced by PD-L1 blockade.

Edgington M P, Alphey L S (2017)

Conditions for success of engineered underdominance gene drive systems

Journal of Theoretical Biology 430, 128-140


Engineered underdominance is one of a number of different gene drive strategies that have been proposed for the genetic control of insect vectors of disease. Here we model a two-locus engineered underdominance based gene drive system that is based on the concept of mutually suppressing lethals. In such a system two genetic constructs are introduced, each possessing a lethal element and a suppressor of the lethal at the other locus. Specifically, we formulate and analyse a population genetics model of this system to assess when different combinations of release strategies (i.e. single or multiple releases of both sexes or males only) and genetic systems (i.e. bisex lethal or female-specific lethal elements and different strengths of suppressors) will give population replacement or fail to do so. We anticipate that results presented here will inform the future design of engineered underdominance gene drive systems as well as providing a point of reference regarding release strategies for those looking to test such a system. Our discussion is framed in the context of genetic control of insect vectors of disease. One of several serious threats in this context are Aedes aegypti mosquitoes as they are the primary vectors of dengue viruses. However, results are also applicable to Ae. aegypti as vectors of Zika, yellow fever and chikungunya viruses and also to the control of a number of other insect species and thereby of insect-vectored pathogens.

Ansari-Lari M, Mohebbi-Fani M, Lyons N A, Azizi N (2017)

Impact of FMD outbreak on milk production and heifers' growth on a dairy herd in southern Iran

Preventive Veterinary Medicine 144, 117-122


Foot and mouth disease is endemic in Middle Eastern countries including Iran but its impact is poorly characterized. The present study was conducted to evaluate the impact of FMD outbreak on milk production and heifers' growth in an industrial dairy herd located in Fars province, southern Iran. Data about individual milk production, heifers' growth and total daily milk (sold for manufacturing), its fat and protein content and somatic cell counts were collected from the herd database. Based on the results of the linear mixed models, a significant decline in individual milk production after the outbreak was observed compared with before the outbreak. There was a total reduction of 8.0 and 4.7% in mean daily milk production per cow after the outbreak when compared with before (over a 42days outbreak period) in lactation one (P<0.001) and lactation >/=2 cows (P=0.024), respectively. The total daily milk (P=0.027) and protein (P=0.002) showed significant decline during the outbreak period. The fat content decreased after the outbreak (P=0.014). Somatic cell counts did not show significant changes. The recorded heifers' weights (4-17 months of age) showed 7.1kg decrease after the outbreak in comparison with the period before that (P<0.001). In conclusion, we observed a negative impact of FMD outbreak on milk production and heifers' growth in study herd. The impact on daily milk production was less than the values reported previously. This difference could be attributed at least partly to differences in livestock genetics and management practices. Lower growth rate of heifers after the outbreak period could potentially extend the age at first calving. It is suggested that farmers are educated on awareness and preparation for infectious disease outbreaks and to practice good management routines that could potentially reduce the economic impact of these diseases.

Pollock N, Taylor G, Jobe F, Guzman E (2017)

Modulation of the transcription factor NF-kappaB in antigen-presenting cells by bovine respiratory syncytial virus small hydrophobic protein

Journal of General Virology 98 (7), 1587-1599


Bovine respiratory syncytial virus (BRSV) is an important cause of respiratory disease in young cattle and is closely related to human RSV (HRSV), which causes severe respiratory disease in infants and the elderly. The RSV genome encodes a small hydrophobic (SH) protein with viroporin activity. Previous studies have shown that recombinant BRSV lacking the SH gene (rBRSVDeltaSH) is attenuated in the lungs, but not in the upper respiratory tract, of calves and mucosal vaccination with rBRSVDeltaSH induced long-lasting protective immunity. Attenuation of rBRSVDeltaSH may be due to the ability of this virus to induce an early innate response as rBRSVDeltaSH induces higher levels of pro-inflammatory cytokines than wild-type (wt) rBRSV. In this study, we investigated the effects of the BRSV SH protein on NF-kappaB p65 phosphorylation, a master step in the regulation of pro-inflammatory cytokines. Expression of SH resulted in the inhibition of NF-kappaB p65 phosphorylation in response to BRSV infection and extracellular lipopolysaccharide, and a reduction in the production of pro-inflammatory cytokines. In contrast, rBRSVDeltaSH does not inhibit NF-kappaB p65 phosphorylation in bovine antigen-presenting cells, including monocytes, macrophages and dendritic cells, resulting in increased expression of pro-inflammatory cytokines and increased activation of T cells compared to cells infected with wt BRSV. These findings highlight an important role for the BRSV SH protein in immune modulation.

Roedig P, Ginn H M, Pakendorf T, Sutton G, Harlos K, Walter T S, Meyer J, Fischer P, Duman R, Vartiainen I, Reime B, Warmer M, Brewster A S, Young I D, Michels-Clark T, Sauter N K, Kotecha A, Kelly J, Rowlands D J, Sikorsky M, Nelson S, Damiani D S, Alonso-Mori R, Ren J, Fry E E, David C, Stuart D I, Wagner A, Meents A (2017)

High-speed fixed-target serial virus crystallography

Nature Methods 14 (8), 805-810


We report a method for serial X-ray crystallography at X-ray free-electron lasers (XFELs), which allows for full use of the current 120-Hz repetition rate of the Linear Coherent Light Source (LCLS). Using a micropatterned silicon chip in combination with the high-speed Roadrunner goniometer for sample delivery, we were able to determine the crystal structures of the picornavirus bovine enterovirus 2 (BEV2) and the cytoplasmic polyhedrosis virus type 18 polyhedrin, with total data collection times of less than 14 and 10 min, respectively. Our method requires only micrograms of sample and should therefore broaden the applicability of serial femtosecond crystallography to challenging projects for which only limited sample amounts are available. By synchronizing the sample exchange to the XFEL repetition rate, our method allows for most efficient use of the limited beam time available at XFELs and should enable a substantial increase in sample throughput at these facilities.

Ferretti L, Ledda A, Wiehe T, Achaz G, Ramos-Onsins S E (2017)

Decomposing the site frequency spectrum: the impact of tree topology on neutrality tests

Genetics 207 (1), 229-240


We investigate the dependence of the site frequency spectrum (SFS) on the topological structure of genealogical trees. We show that basic population genetic statistics-for instance estimators of theta or neutrality tests such as Tajima's D-can be decomposed into components of waiting times between coalescent events and of tree topology. Our results clarify the relative impact of the two components on these statistics. We provide a rigorous interpretation of positive or negative values of an important class of neutrality tests in terms of the underlying tree shape. In particular, we show that values of Tajima's D and Fay and Wu's H depend in a direct way on a peculiar measure of tree balance which is mostly determined by the root balance of the tree. We present a new test for selection in the same class as Fay and Wu's H and discuss its interpretation and power. Finally, we determine the trees corresponding to extreme expected values of these neutrality tests and present formulae for these extreme values as a function of sample size and number of segregating sites.

Werling D, Hope J C, Siddiqui N, Widdison S, Russell C, Sopp P, Coffey T J (2017)

Subset-specific expression of toll-like receptors by bovine afferent lymph dendritic cells

Frontiers in Veterinary Science 4 (44),


Within the ruminant system, several possibilities exist to generate dendritic cells migrating out from the tissue into the regional draining lymphnodes as afferent lymph dendritic cells (ALDC). Here, we analysed Toll-like receptor (TLR) 1–10 mRNA expression by using quantitative real-time PCR in highly purified subsets of bovine ALDC. As TLR expression may be influenced by pathogens or vaccines and their adjuvant, it is necessary to understand what TLRs are expressed in a steady-state system to elucidate specific differences and to potentially optimise targeted vaccines. In this study we have assessed the TLR expression profiles of the four main bovine ALDC subsets (cDC1 and cDC2-4). We demonstrate differences in TLR expression between the four subsets that may reflect the ability of these cells to respond to different pathogens or to respond to adjuvants.


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