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

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Offord V, Coffey T J, Werling D (2010)

LRRfinder: a web application for the identificationC of leucine-rich repeats and an integrative Toll-like receptor database

Developmental and Comparative Immunology 34 (10), 1035-1041
Publisher’s version: http://dx.doi.org/10.1016/j.dci.2010.05.004

Abstract

Homology modelling is considered the most accurate technique for computational prediction of protein structure. However, this technique comes with fundamental caveats of dependency on template quality, identification of structural features and accuracy of alignment. Leucine-rich repeats (LRRs) characterise a diverse family of proteins. Recently resolved structures reveal a highly conserved region in LRRs that assemble into the curved parallel beta-sheet lining the inner circumference of their solenoid structure. Thus, prediction of these structurally important regions is essential in the comparative modelling of LRR proteins and their interactions. Here, we describe the generation of tLRRdb, a database of selected Toll-like receptor (TLR) sequences with annotated co-ordinates. Derived from this is LRRfinder, a web application for the identification of LRRs within user-defined sequences to facilitate identification of structurally important regions, particularly relevant for protein-protein interaction studies and classification of novel sequences. LRRfinder is available at: www.lrrfinder.com.
O'Gorman G M, Al N A, Ellis S A, Mamo S, O'Doherty A M, Lonergan P, Fair T (2010)

Regulation of a bovine nonclassical major histocompatibility complex class I gene promoter

Biology of Reproduction 83 (2), 296-306
Publisher’s version: http://dx.doi.org/10.1095/biolreprod.109.082560

Abstract

Studies have shown in humans and other species that the major histocompatibility complex class I (MHC-I) region is involved at a number of levels in the establishment and maintenance of pregnancy. The aim of this study was to characterize how a bovine nonclassical MHC-I gene (NC1) is regulated. Initial serial deletion experiments of a 2-kb fragment of the NC1 promoter identified regions with positive regulatory elements in the proximal promoter and evidence for a silencer module(s) further upstream that cooperatively contributed to constitutive NC1 expression. The cytokines interferon tau (IFNT), interferon gamma (IFNG), and interleukin 4 (IL4) significantly increased luciferase expression in NC1 promoter reporter constructs and endogenous NC1 mRNA levels in a bovine endometrial cell line. In addition, IFNG, IL3, IL4, and progesterone significantly increased Day 7 bovine blastocyst NC1 mRNA expression when supplemented during in vitro embryo culture. Site-directed mutagenesis analysis identified a STAT6 binding site that conferred IL4 responsiveness in the NC1 proximal promoter. Furthermore, methylation treatment of the proximal promoter, which contains a CpG island, completely abrogated constitutive NC1 expression. Overall, the findings presented here suggest that constitutive NC1 expression is regulated positively by elements in the proximal promoter, which are further controlled by upstream silencer modules. The promoter is responsive to IFNT, IFNG, and IL4, suggesting possible roles for these cytokines in bovine preimplantation embryo survival and/or maternal-fetal tolerance. Our studies also suggest that methylation of the proximal promoter, in particular, could play a significant role in regulating NC1 expression.
Oura C A L, Wood J L N, Floyd T, Sanders A J, Bin-Tarif A, Henstock M, Edwards L, Simmons H, Batten C A (2010)

Colostral antibody protection and interference with immunity in lambs born from sheep vaccinated with an inactivated bluetongue serotype 8 vaccine

Vaccine 28 (15), 2749-2753
Publisher’s version: http://dx.doi.org/10.1016/j.vaccine.2010.01.028

Abstract

Widespread vaccination programmes against Bluetongue virus serotype 8 (BTV-8), using inactivated vaccines, are being carried out across many countries in northern, western and southern Europe. This study investigates the extent and length of colostral antibody protection, as well as the degree of colostral antibody induced interference of the immune response to BTV-8, in sheep. Significantly lower titres of neutralising antibodies were transferred in colostrum to lambs born from sheep vaccinated once as opposed those vaccinated twice (single vaccine in the first year and a booster vaccine in the second year). On BTV-8 challenge, lambs born from sheep vaccinated on two occasions, with the second booster vaccine given approximately 1 month prior to lambing, were protected from clinical disease for up to 14 weeks. BTV-8 was isolated from 5 of the 22 challenged lambs, although only one of these lambs showed a transient rise in body temperature with no other clinical signs. Lambs born from ewes given a second booster vaccine 1 month prior to lambing, are likely to be protected from clinical disease for at least 14 weeks, whereas lambs born from ewes vaccinated once are likely to be protected for a shorter time. Colostral antibodies present in the 13–14-week-old lambs appeared to interfere with the humoral response to challenge virus. These results suggest that colostral antibodies may interfere with vaccination in lambs up to at least 14 weeks of age.
Papadopoulos E, Rowlinson M, Bartram D, Carpenter S, Mellor P, Wall R (2010)

Treatment of horses with cypermethrin against the biting flies Culicoides nubeculosus, Aedes aegypti and Culex quinquefasciatus

Veterinary Parasitology 169 (1-2), 165-171
Publisher’s version: http://dx.doi.org/10.1016/j.vetpar.2009.12.023

Abstract

An in vitro assay was used to assess the efficacy of the proprietary pyrethroid insecticide cypermethrin applied to horses (Deosect spray, 5.0%, w/v Fort Dodge Animal Health) against the biting midge Culicoides nubeculosus (Meigen) (Diptera: Ceratopogonidae) and the mosquitoes Aedes aegypti Linneaus and Culex quinquefasciatus Say (Diptera: Culicidae). Hair was collected from the back, belly and legs of the horses immediately prior to treatment and 7, 14, 21, 28 and 35 days after treatment, and also from untreated controls. In laboratory assays groups of 10 adult female C. nubeculosus, Ae. aegypti or C. quinquefasciatus were exposed to 0.5 g of hair for 3 min. In all cases, little or no mortality was observed in insects kept in contact with the pre-treatment samples or the untreated controls. With post-treatment samples for C. nubeculosus, mortality was close to 80% 7 days after treatment and then declined gradually; mean mortality was still at around 50% for hair collected 35 days after treatment. In general, Ae. aegypti and C. quinquefasciatus appeared to be less susceptible to cypermethrin than C. nubeculosus and the attenuation of the toxic effect declined more quickly with time after treatment. There were differences in the toxicity of hair from different body regions, with hair from the back consistently inducing the highest mortality and hair from the legs the lowest; this effect was more pronounced for C. nubeculosus than Ae. aegypti or C. quinquefasciatus. The results demonstrate the potential for topical insecticide treatment to offer protection to horses against biting flies; but highlight the major differences that exist in susceptibility between different insect species.
Parvizi P, Andrzejewski K, Read L R, Behboudi S, Sharif S (2010)

Expression profiling of genes associated with regulatory functions of T-cell subsets in Marek's disease virus-infected chickens

Avian Pathology 39 (5), 367-373
Publisher’s version: http://dx.doi.org/10.1080/03079457.2010.508776

Abstract

The environment of tumours caused by Marek's disease virus (MDV) in chickens has been shown to have an immunoregulatory phenotype. The objective of the present study was to examine the expression of key T-regulatory markers during various stages of MDV pathogenesis. Specific-pathogen free (SPF) as well as major histocompatibility complex-defined chickens were infected with the RB1B and JM-16 strains of MDV, respectively. CD4+ and CD8+ T cells from the spleens of infected as well as age-matched controls were sorted by flow cytometry at 4, 10, and 21 days post infection (d.p.i.). The expression of molecules such as CTLA-4, IL-2aR (CD25), PD-1 and PDL-1 was quantified by real-time, quantitative, reverse-transcription polymerase chain reaction. There was an up-regulation of CTLA-4 in CD4+ T cells at 4 d.p.i. The expression of PD-1 was also up-regulated in the CD4+ T-cell subset of SPF birds at 21 d.p.i. Furthermore, the expression of PD-1 was enhanced in CD4+ and CD8+ T cells of genetically susceptible chickens, linking this molecule to susceptibility to disease. The expression of CD25 was down-regulated in both SPF and genetically defined birds after infection. This may be a mechanism through which the virus exerts its immunosuppressive effects. In conclusion, the results of the present study provide more insight into immunomodulatory processes that occur in the lymphoid tissues of MDV-infected chickens.
Paton D J, King D P, Knowles N J, Hammond J (2010)

Recent spread of foot-and-mouth disease in the Far East

Veterinary Record 166 (18), 569-570
Publisher’s version: http://dx.doi.org/10.1136/vr.c2300
Paton D J, Sinclair M, Rodriguez R (2010)

Qualitative assessment of the commodity risk for spread of foot-and-mouth disease associated with international trade in deboned beef

Transboundary and Emerging Diseases 57 (3), 115-134
Publisher’s version: http://dx.doi.org/10.1111/j.1865-1682.2010.01137.x

Abstract

The risk of importing foot-and-mouth disease virus (FMDV) restricts trade in livestock and their products from parts of the world where the virus is present. This reduces trade opportunities and investment in the livestock sector of many developing countries and constrains global food supply. This review focuses on the risks associated with trade in deboned beef (DB) from foot-and-mouth disease (FMD)-infected cattle, countries or zones. A definition of DB is provided along with a description of the procedures for its preparation within beef slaughtering operations. Evidence is reviewed for circumstances under which DB can be contaminated with FMDV, and a commodity risk factor approach is used to consider the mitigating efficacy of slaughterhouse procedures. A combination of pre-slaughter and slaughterhouse measures has enabled DB to be safely imported into FMD-free countries from countries that were not nationally or zonally FMD-free. Nevertheless, current evidence does not provide absolute assurance that abattoir procedures for producing DB can result, by themselves, in a commodity with a negligible risk of transmitting FMDV without complementary measures to reduce the likelihood of slaughtering infected cattle. The main areas of uncertainty are the amounts of residual FMDV-harbouring tissues within DB, and our understanding of what constitutes a safe level of contamination. More detailed guidance should be developed to specify the mitigating measures needed in support of the export of DB from regions that are not officially FMD-free. This will help to avoid differences in interpretation of what is needed that give rise to obstacles to trade.
Pedra J H F, Narasimhan S, Rendi? D, DePonte K, Bell-Sakyi L, Wilson I B H, Fikrig E (2010)

Fucosylation enhances colonization of ticks by Anaplasma phagocytophilum

Cellular Microbiology 12 (9), 1222-1234
Publisher’s version: http://dx.doi.org/10.1111/j.1462-5822.2010.01464.x

Abstract

Fucosylated structures participate in a wide range of pathological processes in eukaryotes and prokaryotes. The impact of fucose on microbial pathogenesis, however, has been less appreciated in arthropods of medical relevance. Thus, we used the tick-borne bacterium Anaplasma phagocytophilum– the agent of human granulocytic anaplasmosis to understand these processes. Here we show that A. phagocytophilum uses ?1,3-fucose to colonize ticks. We demonstrate that A. phagocytophilum modulates the expression of ?1,3-fucosyltransferases and gene silencing significantly reduces colonization of tick cells. Acquisition but not transmission of A. phagocytophilum was affected when ?1,3-fucosyltransferases were silenced during tick feeding. Our results uncover a novel mechanism of pathogen colonization in arthropods. Decoding mechanisms of pathogen invasion in ticks might expedite the development of new strategies to interfere with the life cycle of A. phagocytophilum.
Price S, Davies M, Villarreal-Ramos B, Hope J (2010)

Differential distribution of WC1(+) gammadelta TCR(+) T lymphocyte subsets within lymphoid tissues of the head and respiratory tract and effects of intranasal M. bovis BCG vaccination

Veterinary Immunology and Immunopathology 136 (1-2), 133-137
Publisher’s version: http://dx.doi.org/10.1016/j.vetimm.2010.02.010

Abstract

BCG vaccination of neonatal calves induces significant protection against bovine tuberculosis. The enhanced protection observed in neonatal calves may be linked to an enhanced capacity for IFN? production by innate cells, including WC1+ ?? T cells, which constitute a major population in young cattle. Intranasal BCG vaccination of mice induces high levels of IFN? in the lungs, which may enhance protection against subsequent challenge with virulent strains of mycobacteria. We used an intranasal BCG vaccination model in calves to study the effect on the distribution of WC1+ ?? T cells expressing two alternate forms of WC1: WC1.1 and WC1.2. These subsets of WC1+ ?? T cells have previously been shown to have a differential capacity for IFN? secretion. Our results indicate that there is a selective expansion/recruitment of ?? T cells expressing the IFN?-associated WC1.1 isoform in tissues of the lungs and upper respiratory tract following intranasal BCG vaccination.
Pullinger G D, Carnell S C, Sharaff F F, van D P M, Dziva F, Morgan E, Lyte M, Freestone P P, Stevens M P (2010)

Norepinephrine augments Salmonella enterica-induced enteritis in a manner associated with increased net replication but independent of the putative adrenergic sensor kinases QseC and QseE

Infection and Immunity 78 (1), 372-380
Publisher’s version: http://dx.doi.org/10.1128/IAI.01203-09

Abstract

Stress has long been correlated with susceptibility to microbial infection. One explanation for this phenomenon is the ability of pathogens to sense and respond to host stress-related catecholamines, such as norepinephrine (NE). In Gram-negative enteric pathogens, it has been proposed that NE may facilitate growth by mediating iron supply, or it may alter gene expression by activating adrenergic sensor kinases. The aim of this work was to investigate the relative importance of these processes in a model in which NE alters the outcome of Salmonella enterica serovar Typhimurium infection. A bovine ligated ileal loop model was used to study the effect of NE on enteritis induced by S. Typhimurium and on the bacterial in vivo replication rate. Mutants lacking putative adrenergic receptor genes were assessed in the loop model, in a calf intestinal colonization model, and in vitro. S. Typhimurium-induced enteritis was significantly enhanced by addition of 5 mM NE. This effect was associated with increased net bacterial replication in the same model. Exogenous ferric iron also stimulated bacterial replication in the medium used but not transcription of enteritis-associated loci. The putative adrenergic sensors QseC and QseE were not required for NE-enhanced enteritis, intestinal colonization of calves, or NE-dependent growth in iron-restricted medium and did not influence expression or secretion of enteritis-associated virulence factors. Our findings support a role for stress-related catecholamines in modulating the virulence of enteric bacterial pathogens in vivo but suggest that bacterial adrenergic sensors may not be the vital link in such interkingdom signaling in Salmonella.

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