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

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Dietrich I, McEwan W A, Hosie M J, Willett B J (2011)

Restriction of the felid lentiviruses by a synthetic feline TRIM5-CypA fusion

Veterinary Immunology and Immunopathology 143 (03-Apr), 235-42


Gene therapy approaches to the treatment of HIV infection have targeted both viral gene expression and the cellular factors that are essential for virus replication. However, significant concerns have been raised regarding the potential toxic effects of such therapies, the emergence of resistant viral variants and unforeseen biological consequences such as enhanced susceptibility to unrelated pathogens. Novel restriction factors formed by the fusion of the tripartite motif protein (TRIM5) and cyclophilin A (CypA), or "TRIMCyps", offer an effective antiviral defence strategy with a very low potential for toxicity. In order to investigate the potential therapeutic utility of TRIMCyps in gene therapy for AIDS, a synthetic fusion protein between feline TRIM5 and feline CypA was generated and transduced into cells susceptible to infection with feline immunodeficiency virus (FIV). The synthetic feline TRIMCyp was highly efficient at preventing infection with both HIV and FIV and the cells resisted productive infection with FIV from either the domestic cat or the puma. Feline TRIMCyp and FIV infection of the cat offers a unique opportunity to evaluate TRIMCyp-based approaches to genetic therapy for HIV infection and the treatment of AIDS.

Dietrich I, McMonagle E L, Petit S J, Vijayakrishnan S, Logan N, Chan C N, Towers G J, Hosie M J, Willett B J (2011)

Feline tetherin efficiently restricts release of feline immunodeficiency virus but not spreading of infection

Journal of Virology 85 (12), 5840-5852


Domestic cats endure infections by all three subfamilies of the retroviridae: lentiviruses (feline immunodeficiency virus [FIV]), gammaretroviruses (feline leukemia virus [FeLV]), and spumaretroviruses (feline foamy virus [FFV]). Thus, cats present an insight into the evolution of the host-retrovirus relationship and the development of intrinsic/innate immune mechanisms. Tetherin (BST-2) is an interferon-inducible transmembrane protein that inhibits the release of enveloped viruses from infected cells. Here, we characterize the feline homologue of tetherin and assess its effects on the replication of FIV. Tetherin was expressed in many feline cell lines, and expression was induced by interferons, including alpha interferon (IFN-alpha), IFN-omega, and IFN-gamma. Like human tetherin, feline tetherin displayed potent inhibition of FIV and HIV-1 particle release; however, this activity resisted antagonism by either HIV-1 Vpu or the FIV Env and "OrfA" proteins. Further, as overexpression of complete FIV genomes in trans could not overcome feline tetherin, these data suggest that FIV lacks a functional tetherin antagonist. However, when expressed stably in feline cell lines, tetherin did not abrogate the replication of FIV; indeed, syncytium formation was significantly enhanced in tetherin-expressing cells infected with cell culture-adapted (CD134-independent) strains of FIV (FIV Fca-F14 and FIV Pco-CoLV). Thus, while tetherin may prevent the release of nascent viral particles, cell-to-cell spread remains efficient in the presence of abundant viral receptors and tetherin upregulation may enhance syncytium formation. Accordingly, tetherin expression in vivo may promote the selective expansion of viral variants capable of more efficient cell-to-cell spread.

Ratinier M, Caporale M, Golder M, Franzoni G, Allan K, Nunes S F, Armezzani A, Bayoumy A, Rixon F, Shaw A, Palmarini M (2011)

Identification and characterization of a novel non-structural protein of bluetongue virus

PLOS Pathogens 7 (12), e1002477


Bluetongue is a major infectious disease of ruminants caused by bluetongue virus (BTV), an "arbovirus" transmitted from infected to susceptible hosts by biting midges. Historically, bluetongue has been endemic almost exclusively in temperate and tropical areas of the world. However, in the last decade BTV has spread extensively in several geographical areas causing a serious burden to both animal health and the economy. BTV possesses a double-stranded RNA segmented genome. For over two decades, it has been widely accepted that the 10 segments of BTV genome encode for 7 structural and 3 non-structural proteins. In this study we discovered that BTV expresses a previously uncharacterized non-structural protein that we designated NS4. Although BTV replicates exclusively in the cytoplasm, we found NS4 to localize in the nucleoli of the infected cells. Our study shows that NS4 is not needed for viral replication both in mammalian and insect cells, and in mice. However, NS4 confers a replication advantage to BTV in cells in an antiviral state induced by interferon. In conclusion, we have elucidated a possible route by which BTV can counteract the defences of the host.


Cape buffalo (Syncerus caffer) are considered to be an important reservoir for various tick-borne haemoparasites of veterinary importance. In this study we have compared the haemoparasite carrier prevalence in buffalo from four geographically isolated national parks in Uganda [Lake Mburo National Park (LMNP), Queen Elizabeth National Park (QENP), Murchison Falls National Park (MFNP) and Kidepo Valley National Park (KVNP)]. Differences were seen in haemoparasite prevalence in buffalo from the four national parks. All the buffalo sampled in LMNP were carriers of Theileria parva however, buffalo from MFNP and KVNP, which are both located in the north of Uganda, were negative for T. parva. Interestingly, 95% of buffalo in the northern part of QENP were T. parva positive, however all buffalo sampled in the south of the park were negative. A high multiplicity of infection was recorded in all the buffalo found to be carrying T. parva, with evidence of at least nine parasite genotypes in some animals. Most of the buffalo sampled in all four national parks were carriers of T. mutans and T. velifera, however none were carriers of T. taurotragi, Babesia bovis, Babesia bigemina, Ehrlichia bovis or Ehrlichia ruminantium. All the buffalo sampled from LMNP were positive for T. buffeli and T. sp. (buffalo) however, buffalo from the parks in the north of the country (KVNP and MFNP) were negative for these haemoparasites. Anaplasma centrale and Anaplasma marginale were circulating in buffalo from all four national parks. T. parva gene pools from two geographically separated populations of buffalo in two of the national parks in Uganda (LMNP and QENP) were compared. The T. parva populations in the two national parks were distinct, indicating that there was limited gene flow between the populations. The results presented highlight the complexity of tick-borne pathogen infections in buffalo and the significant role that buffalo may play as reservoir hosts for veterinary haemoparasites that have the potential to cause severe disease in domestic cattle.
Sanders C J, Shortall C R, Gubbins S, Burgin L, Gloster J, Harrington R, Reynolds D R, Mellor P S, Carpenter S (2011)

Influence of season and meteorological parameters on flight activity of Culicoides biting midges

Journal of Applied Ecology 48 (6), 1355-1364


Culicoides biting midges are vectors of internationally important arboviruses including bluetongue virus (BTV). The ecological constraints imposed by the small body size of these insects strongly influence the epidemiology of the diseases they can carry. Bluetongue virus recently emerged in northern Europe, and atmospheric dispersion models have subsequently been employed to simulate vector movement (and hence likely spread of BTV). The data underlying such models, however, have hitherto either been obtained from small-scale studies or from outside the north-western Palaearctic. The effects of seasonality and local meteorological conditions upon the daily presence and abundance of Culicoides vectors were examined using 2760 samples collected across a network of 12 different habitat types in England during 2008. Over 50 000 individuals were estimated to be in the samples with males constituting 62% of the total collection, allowing straightforward comparison between potential vector species in terms of their activity rates and seasonality. Culicoides abundance was linked to livestock density and land use. Farm-associated Culicoides species were recorded at all sites including species thought to be restricted to this ecosystem by larval habitat, suggesting a greater potential for dispersal over land than previously thought. Synthesis and applications. The model developed has already been applied in a functional dispersion model to predict disease risk from wind-borne infected Culicoides incursion into the UK and elsewhere. The study has expounded the long-distance dispersal potential of Culicoides, essential for future prediction of the incursion and spread of Culicoides-borne pathogens. It has additionally contributed to the understanding of the ecology of highly dispersive insect vectors.


The aims of this study were to statistically reassess the likelihood that windborne spread of foot-and-mouth disease (FMD) virus (FMDV) occurred at the start of the UK 1967 to 1968 FMD epidemic at Oswestry, Shropshire, and to derive dose-response probability of infection curves for farms exposed to airborne FMDV. To enable this, data on all farms present in 1967 in the parishes near Oswestry were assembled. Cases were infected premises whose date of appearance of first clinical signs was within 14 days of the depopulation of the index farm. Logistic regression was used to evaluate the association between infection status and distance and direction from the index farm. The UK Met Office's NAME atmospheric dispersion model (ADM) was used to generate plumes for each day that FMDV was excreted from the index farm based on actual historical weather records from October 1967. Daily airborne FMDV exposure rates for all farms in the study area were calculated using a geographical information system. Probit analyses were used to calculate dose-response probability of infection curves to FMDV, using relative exposure rates on case and control farms. Both the logistic regression and probit analyses gave strong statistical support to the hypothesis that airborne spread occurred. There was some evidence that incubation period was inversely proportional to the exposure rate.


Salivary gland proteins of Culicoides spp. have been suggested to be among the main allergens inducing IgE-mediated insect bite hypersensitivity (IBH), an allergic dermatitis of the horse. The aim of our study was to identify, produce and characterize IgE-binding salivary gland proteins of Culicoides nubeculosus relevant for IBH by phage surface display technology. A cDNA library constructed with mRNA derived from C. nubeculosus salivary glands was displayed on the surface of filamentous phage M13 and enriched for clones binding serum IgE of IBH-affected horses. Ten cDNA inserts encoding putative salivary gland allergens were isolated and termed Cul n 2 to Cul n 11. However, nine cDNA sequences coded for truncated proteins as determined by database searches. The cDNA sequences were amplified by PCR, subcloned into high level expression vectors and expressed as hexahistidine-tagged fusion proteins in Escherichia coli. Preliminary ELISA results obtained with these fusions confirmed the specific binding to serum IgE of affected horses. Therefore, the putative complete open reading frames derived from BLAST analyses were isolated by RACE-PCR and subcloned into expression vectors. The full length proteins expressed in Escherichia coli showed molecular masses in the range of 15.5-68.7 kDa in SDS-PAGE in good agreement with the masses calculated from the predicted protein sequences. Western blot analyses of all recombinant allergens with a serum pool of IBH-affected horses showed their ability to specifically bind serum IgE of sensitized horses, and ELISA determinations yielded individual horse recognition patterns with a frequency of sensitization ranging from 13 to 57%, depending on the allergen tested. The in vivo relevance of eight of the recombinant allergens was demonstrated in intradermal skin testing. For the two characterized allergens Cul n 6 and Cul n 11, sensitized horses were not available for intradermal tests. Control horses without clinical signs of IBH did not develop any relevant immediate hypersensitivity reactions to the recombinant allergens. The major contribution of this study was to provide a repertoire of recombinant salivary gland allergens repertoire from C. nubeculosus potentially involved in the pathogenesis of IBH as a starting basis for the development of a component-resolved serologic diagnosis of IBH and, perhaps, for the development of single horse tailored specific immunotherapy depending on their component-resolved sensitization patterns.


Foot-and-mouth disease virus (FMDV) causes an economically important disease of cloven-hoofed livestock; of interest here is the difference in lytic behaviour that is observed in bovine epithelium. On the skin around the feet and tongue, the virus rapidly replicates, killing cells, and resulting in growing lesions, before eventually being cleared by the immune response. In contrast, there is usually minimal lysis in the soft palate, but virus may persist in tissue long after the animal has recovered from the disease. Persistence of virus has important implications for disease control, while identifying the determinant of lysis in epithelium is potentially important for the development of prophylactics. To help identify which of the differences between oral and pharyngeal epithelium are responsible for such dramatically divergent FMDV dynamics, a simple model has been developed, in which virus concentration is made explicit to allow the lytic behaviour of cells to be fully considered. Results suggest that localised structuring of what are fundamentally similar cells can induce a bifurcation in the behaviour of the system, explicitly whether infection can be sustained or results in mutual extinction, although parameter estimates indicate that more complex factors may be involved in maintaining viral persistence, or that there are as yet unquantified differences between the intrinsic properties of cells in these regions.


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