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

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Shaw A E, Ratinier M, Nunes S F, Nomikou K, Caporale M, Golder M, Allan K, Hamers C, Hudelet P, Zientara S, Breard E, Mertens P, Palmarini M (2013)

Reassortment between two serologically unrelated bluetongue virus strains is flexible and can involve any genome segment

Journal of Virology 87 (1), 543-557
Publisher’s version: http://dx.doi.org/10.1128/jvi.02266-12

Abstract

Coinfection of a cell by two different strains of a segmented virus can give rise to a “reassortant” with phenotypic characteristics that might differ from those of the parental strains. Bluetongue virus (BTV) is a double-stranded RNA (dsRNA) segmented virus and the cause of bluetongue, a major infectious disease of livestock. BTV exists as at least 26 different serotypes (BTV-1 to BTV-26). Prompted by the isolation of a field reassortant between BTV-1 and BTV-8, we systematically characterized the process of BTV reassortment. Using a reverse genetics approach, our study clearly indicates that any BTV-1 or BTV-8 genome segment can be rescued in the heterologous “backbone.” To assess phenotypic variation as a result of reassortment, we examined viral growth kinetics and plaque sizes in in vitro experiments and virulence in an experimental mouse model of bluetongue disease. The monoreassortants generated had phenotypes that were very similar to those of the parental wild-type strains both in vitro and in vivo. Using a forward genetics approach in cells coinfected with BTV-1 and BTV-8, we have shown that reassortants between BTV-1 and BTV-8 are generated very readily. After only four passages in cell culture, we could not detect wild-type BTV-1 or BTV-8 in any of 140 isolated viral plaques. In addition, most of the isolated reassortants contained heterologous VP2 and VP5 structural proteins, while only 17% had homologous VP2 and VP5 proteins. Our study has shown that reassortment in BTV is very flexible, and there is no fundamental barrier to the reassortment of any genome segment. Given the propensity of BTV to reassort, it is increasingly important to have an alternative classification system for orbiviruses.
Shelton H, Roberts K L, Molesti E, Temperton N, Barclay W S (2013)

Mutations in haemagglutinin that affect receptor binding and pH stability increase replication of a PR8 influenza virus with H5 HA in the upper respiratory tract of ferrets and may contribute to transmissibility

Journal of General Virology 94 (6), 1220-1229
Publisher’s version: http://dx.doi.org/10.1099/vir.0.050526-0

Abstract

The H5N1 influenza A viruses have circulated widely in the avian population for 10 years with only sporadic infection of humans observed and no sustained human to human transmission. Vaccination against potential pandemic strains is one strategy in planning for future influenza pandemics; however, the success of live attenuated vaccines for H5N1 has been limited, due to poor replication in the human upper respiratory tract (URT). Mutations that increase the ability of H5N1 viruses to replicate in the URT will aid immunogenicity of these vaccines and provide information about humanizing adaptations in H5N1 strains that may signal transmissibility. As well as mediating receptor interactions, the haemagglutinin (HA) protein of influenza facilitates fusion of the viral membrane and genome entry into the host cell; this process is pH dependent. We have shown in this study that the pH at which a panel of avian influenza HA proteins, including H5, mediate fusion is higher than that for human influenza HA proteins, and that mutations in the H5 HA can reduce the pH of fusion. Coupled with receptor switching mutations, increasing the pH stability of the H5 HA resulted in increased viral shedding of H5N1 from the nasal cavity of ferrets and contact transmission to a co-housed animal. Ferret serum antibodies induced by infection with any of the mutated H5 HA viruses neutralized HA pseudotyped lentiviruses bearing homologous or heterologous H5 HAs, suggesting that this strategy to increase nasal replication of a vaccine virus would not compromise vaccine efficacy.
Siddiqui N, Hope J (2013)

Differential recruitment and activation of natural killer cell sub-populations by Mycobacterium bovis-infected dendritic cells

European Journal of Immunology 43 (1), 159-169
Publisher’s version: http://dx.doi.org/10.1002/eji.201242736

Abstract

Through complex interplay with APCs, subsets of NK cells play an important role in shaping adaptive immune responses. Bovine tuberculosis, caused by Mycobacterium bovis, is increasing in incidence and detailed knowledge of host–pathogen interactions in the natural host is essential to facilitate disease control. We investigated the interactions of NK-cell sub-populations and M. bovis-infected DCs to determine early innate mechanisms in the response to infection. A sub-population of NK cells (NKp46+CD2?) selectively expressing lymphoid homing and inflammatory chemokine receptors were induced to migrate towards M. bovis-infected DCs. This migration was associated with increased expression of chemokines CCL3, 4, 5, 20 and CXCL8 by M. bovis-infected DCs. Activation of NKp46+CD2? NK cells and secretion of IFN-? was observed, a response reliant on localised IL-12 release and direct cellular interaction. In a reciprocal manner, NKp46+CD2? cells induced an increase in the intensity of cell surface MHC class II expression on DCs. In contrast, NKp46+CD2+ NK cells were unable to secrete IFN-? and did not reciprocally affect DCs. This study provides novel evidence to demonstrate distinct effector responses between bovine NK-cell subsets during mycobacterial infection.
Smith S E, Gibson M S, Wash R S, Ferrara F, Wright E, Temperton N, Kellam P, Fife M (2013)

Chicken interferon-inducible transmembrane protein 3 restricts influenza viruses and lyssaviruses in vitro

Journal of Virology 87 (23), 12957-12966
Publisher’s version: http://dx.doi.org/10.1128/jvi.01443-13

Abstract

Interferon-inducible transmembrane protein 3 (IFITM3) is an effector protein of the innate immune system. It confers potent, cell-intrinsic resistance to infection by diverse enveloped viruses both in vitro and in vivo, including influenza viruses, West Nile virus, and dengue virus. IFITM3 prevents cytosolic entry of these viruses by blocking complete virus envelope fusion with cell endosome membranes. Although the IFITM locus, which includes IFITM1, -2, -3, and -5, is present in mammalian species, this locus has not been unambiguously identified or functionally characterized in avian species. Here, we show that the IFITM locus exists in chickens and is syntenic with the IFITM locus in mammals. The chicken IFITM3 protein restricts cell infection by influenza A viruses and lyssaviruses to a similar level as its human orthologue. Furthermore, we show that chicken IFITM3 is functional in chicken cells and that knockdown of constitutive expression in chicken fibroblasts results in enhanced infection by influenza A virus. Chicken IFITM2 and -3 are constitutively expressed in all tissues examined, whereas IFITM1 is only expressed in the bursa of Fabricius, gastrointestinal tract, cecal tonsil, and trachea. Despite being highly divergent at the amino acid level, IFITM3 proteins of birds and mammals can restrict replication of viruses that are able to infect different host species, suggesting IFITM proteins may provide a crucial barrier for zoonotic infections.
Staines K, Young J R, Butter C (2013)

Expression of chicken DEC205 reflects the unique structure and function of the avian immune system

PLoS ONE 8 (1), e51799
Publisher’s version: http://dx.doi.org/10.1371/journal.pone.0051799

Abstract

The generation of appropriate adaptive immune responses relies critically on dendritic cells, about which relatively little is known in chickens, a vital livestock species, in comparison with man and mouse. We cloned and sequenced chicken DEC205 cDNA and used this knowledge to produce quantitative PCR assays and monoclonal antibodies to study expression of DEC205 as well as CD83. The gene structure of DEC205 was identical to those of other species. Transcripts of both genes were found at higher levels in lymphoid tissues and the expression of DEC205 in normal birds had a characteristic distribution in the primary lymphoid organs. In spleen, DEC205 was seen on cells ideally located to trap antigen. In thymus it was found on cells thought to participate in the education of T cells, and in the bursa on cells that may be involved in presentation of antigen to B cells and regulation of B cell migration. The expression of DEC205 on cells other than antigen presenting cells (APC) is also described. Isolated splenocytes strongly expressing DEC205 but not the KUL01 antigen have morphology similar to mammalian dendritic cells and the distinct expression of DEC205 within the avian-specific Bursa of Fabricius alludes to a unique function in this organ of B cell diversification.
Sumner T, Burgin L, Gloster J, Gubbins S (2013)

Comparison of pre-emptive and reactive strategies to control an incursion of bluetongue virus serotype 1 to Great Britain by vaccination

Epidemiology and Infection 141 (1), 102-114
Publisher’s version: http://dx.doi.org/10.1017/S0950268812000532

Abstract

Bluetongue (BT) is a disease of ruminants caused by bluetongue virus (BTV), which is spread between its hosts by Culicoides midges. Vaccination is the most effective way to protect susceptible animals against BTV and was used reactively to control the recent northern European outbreak. To assess the consequences of using vaccination pre-emptively we used a stochastic, spatially explicit model to compare reactive and pre-emptive vaccination strategies against an incursion of BTV serotype 1 (BTV-1) into Great Britain. Both pre-emptive and reactive vaccination significantly reduced the number of affected farms and limited host morbidity and mortality. In addition, vaccinating prior to the introduction of disease reduced the probability of an outbreak occurring. Of the strategies simulated, widespread reactive vaccination resulted in the lowest levels of morbidity. The predicted effects of vaccination were found to be sensitive to vaccine efficacy but not to the choice of transmission kernel.
Tahiri-Alaoui A, Smith L P, Kgosana L, Petherbridge L J, Nair V (2013)

Identification of a neurovirulence factor from Marek's disease virus

Avian Diseases 57 (2 S1), 387-394
Publisher’s version: http://dx.doi.org/10.1637/10322-080912-Reg.1

Abstract

In addition to tumors, Marek's disease (MD) virus (MDV) can induce a variety of syndromes linked to the central nervous system. In fact, early descriptions of MD suggested that it was a condition affecting mainly the nervous system. Cytokines and other immune-related genes have been suggested to play a crucial role in MDV-mediated neuropathology, but the mechanisms behind the viral-induced neurologic dysfunction are still poorly understood. In the present study we have used reverse genetic strategies to show that pp14 is not involved in the oncogenic phenotype of MDV1 and is not required for viral replication; however, we provide evidence indicating that the absence of pp14 expression is correlated with increased survival of MDV1-infected chickens, and that its expression is associated with enhanced viral neurovirulence. Our data identify for the first time pp14 as a neurovirulence factor from MDV1 and open the possibility to investigate the molecular mechanisms by which pp14 mediates the damage to the avian nervous system.
Takamatsu H-H, Denyer M S, Lacasta A, Stirling C M A, Argilaguet J M, Netherton C L, Oura C A L, Martins C, Rodriguez F (2013)

Cellular immunity in ASFV responses

Virus Research 173 (1), 110-121
Publisher’s version: http://dx.doi.org/10.1016/j.virusres.2012.11.009

Abstract

African swine fever virus (ASFV) infection usually results in an acute haemorrhagic disease with a mortality rate approaching 100% in domestic pigs. However, pigs can survive infection with less-virulent isolates of ASFV and may become chronically infected. Surviving animals are resistant to challenge with homologous or, in some cases, closely related isolates of the virus indicating that pigs can develop protective immunity against ASFV. During asymptomatic, non-virulent ASFV infections natural killer cell activity increases in pigs, suggesting this cell type plays a role in ASFV immunity. Furthermore, depletion of CD8+ lymphocytes from ASFV immune pigs demolishes protective immunity against related virulent viruses. This suggests that ASFV specific antibody alone is not sufficient for protection against ASFV infection and that there is an important role for the CD8+ lymphocyte subset in ASFV protective immunity. These results were supported by DNA immunization studies, demonstrating a correlation between the protection afforded against lethal challenge and the detection of a large number of vaccine-induced antigen-specific CD8+ T-cells. Peripheral blood mononuclear cells (PBMCs) from ASF immune pigs protected from clinical disease show higher proportions of ASFV specific CD4+CD8high+ double positive cytotoxic T cells than PBMCs from ASF immune but clinically diseased pig. The frequency of ASFV specific IFN? producing T cells induced by immunization correlates to the degree of protection from ASFV challenge, and this may prove to be a useful indicator of any potential cross-protection against heterologous ASFV isolates.
Tan A, Fu G, Jin L, Guo Q, Li Z, Niu B, Meng Z, Morrison N I, Alphey L, Huang Y (2013)

Transgene-based, female-specific lethality system for genetic sexing of the silkworm, Bombyx mori

Proceedings of the National Academy of Sciences of the United States of America 110 (17), 6766-6770
Publisher’s version: http://dx.doi.org/10.1073/pnas.1221700110

Abstract

Transgene-based genetic sexing methods are being developed for insects of agricultural and public health importance. Male-only rearing has long been sought in sericulture because males show superior economic characteristics, such as better fitness, lower food consumption, and higher silk yield. Here we report the establishment of a transgene-based genetic sexing system for the silkworm, Bombyx mori. We developed a construct in which a positive feedback loop regulated by sex-specific alternative splicing leads to high-level expression of the tetracycline-repressible transactivator in females only. Transgenic animals show female-specific lethality during embryonic and early larval stages, leading to male-only cocoons. This transgene-based female-specific lethal system not only has wide application in sericulture, but also has great potential in lepidopteran pest control.
Taylor G (2013)

Bovine model of respiratory syncytial virus infection

Current Topics in Microbiology and Immunology 372, 327-345
Publisher’s version: http://dx.doi.org/10.1007/978-3-642-38919-1_16

Abstract

Bovine respiratory syncytial virus (BRSV), which is an important cause of respiratory disease in young calves, is genetically and antigenically closely related to human (H)RSV. The epidemiology and pathogenesis of infection with these viruses are similar. The viruses are host-specific and infection produces a spectrum of disease ranging from subclinical to severe bronchiolitis and pneumonia, with the peak incidence of severe disease in individuals less than 6 months of age. BRSV infection in calves reproduces many of the clinical signs associated with HRSV in infants, including fever, rhinorrhoea, coughing, harsh breath sounds and rapid breathing. Although BRSV vaccines have been commercially available for decades, there is a need for greater efficacy. The development of effective BRSV and HRSV vaccines face similar challenges, such as the need to vaccinate at an early age in the presence of maternal antibodies, the failure of natural infection to prevent reinfection, and a history of vaccine-augmented disease. Neutralising monoclonal antibodies (mAbs) to the fusion (F) protein of HRSV, which can protect infants from severe HRSV disease, recognise the F protein of BRSV, and vice versa. Furthermore, bovine and human CD8+ T-cells, which are known to be important in recovery from RSV infection, recognise similar proteins that are conserved between HRSV and BRSV. Therefore, not only can the bovine model of RSV be used to evaluate vaccine concepts, it can also be used as part of the preclinical assessment of certain HRSV candidate vaccines.

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