Publications

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

There were a total of 2599 results for your search.

Abstract

Following the incursions into the UK of bluetongue virus (BTV) in 2007 and Schmallenberg virus (SBV) in 2011, an increasingly pertinent question for those tasked with predicting and responding to outbreaks of livestock arboviruses in the UK is, what is next? Culicoides, the biting midges that transmit BTV and SBV, also act as vectors for over 50 described arboviruses worldwide, although we currently know very little about the vast majority of these, even in the countries in which they were originally identified. In addition, it is likely there are a large number of previously unidentified Culicoides-borne arboviruses that have the potential to arrive in northern Europe with little warning (as in the case of SBV). While unidentified viruses pose serious challenges for the prediction of epidemiology and pathogenicity (Carpenter and others 2013), perhaps the greatest concern in Europe currently surrounds the potential for the emergence of a well-known Culicoides-borne arbovirus, African horse sickness virus (AHSV).
Casey M B, Lembo T, Knowles N J, Fyumagwa R, Kivaria F, Maliti H, Kasanga C, Sallu R, Reeve R, Parida S, King D P, Cleaveland S (2014)

Patterns of foot-and-mouth disease virus distribution in Africa: the role of livestock and wildlife in virus emergence

The Role of Animals in Emerging Viral Diseases (edited by N Johnson, Academic Press), 21-38

Abstract

Foot-and-mouth disease (FMD) is one of the most highly contagious diseases of animals. The disease is distributed on three continents (Asia, Africa and South America) where it disrupts the food security of people who depend on livestock and animal products. Substantial economic losses are associated with controlling FMD outbreaks in many countries. For example, during the epidemic in the UK in 2001, losses to agriculture were estimated to be £3.1 billion, with similar losses arising from negative impacts on tourism. Over 4 million animals were slaughtered as part of FMD control measures and a further 2 million were slaughtered due to welfare issues associated with animal movement bans. FMD also has a devastating impact on rural livelihoods and livestock trade opportunities in developing countries where it is endemic. In Africa, historic patterns of FMD virus (FMDV) emergence are likely to have been shaped by the introduction and subsequent eradication of rinderpest. However, important questions remain about contemporary drivers of disease distribution. In particular, the relative contribution of wildlife as sources of infection for livestock and factors affecting the potential for cross-species transmission, and mechanisms of viral maintenance in endemic regions are poorly understood. These issues encompass a complex suite of interacting social, ecological and economic factors that act as drivers of change in patterns of land-use, livestock movements, international trade, and conservation of wildlife-protected areas. Understanding patterns of FMDV infection at the livestock-wildlife interface is of particular importance for designing and developing appropriate disease control strategies in sub-Saharan Africa, and of increasing interest as momentum grows for global control of FMD within the framework of the Progressive Control Pathway (PCP-FMD). This chapter reviews the historical distribution and emergence of FMDV in Africa, and factors that govern the current circulation and maintenance of FMDV in sub-Saharan Africa.

Abstract

We aimed to assess the status of naturally occurring CD4(+) and CD8(+) T cell responses to a tumour associated antigen, Mesothelin, in patients with pancreatic carcinoma and study the effects of elevated IL-10 on Mesothelin-specific T cell responses. For that sake, short term T cell lines were generated from PBMCs of 16 healthy controls, 15 patients with benign pancreatic diseases and 25 patients with pancreatic carcinoma and Mesothelin-specific CD4(+) and CD8(+) T cell responses were analysed using intracellular cytokine assays for IFN-gamma. Plasma levels of IL-10 and Mesothelin were measured using cytometric bead array and ELISA assay, respectively. The blocking assays were performed to assess the effects of IL-10 on Mesothelin-specific T cell responses. Here, we demonstrate that the plasma levels of Mesothelin and IL-10 are significantly increased in patients with pancreatic carcinoma. Additionally, we found that (a) Mesothelin-specific T cell responses are significantly expanded in cancer patients (p = 0.0053), (b) the multifunctional CD4(+) T cell response is directed toward a broad repertoire of epitopes within the Mesothelin protein. (c) Mesothelin-specific CD4+ T cell response is directly inhibited by elevated IL-10 in cancer patients. These data provides evidence for the use of Mesothelin as an immunogen for tumourspecific T cell response.

Abstract

The V proteins of paramyxoviruses are composed of two evolutionarily distinct domains, the amino-terminal 75% being common to the viral P, V and W proteins and not highly conserved between viruses, while the remaining 25% consists of a cysteine-rich V-specific domain which is conserved across almost all paramyxoviruses. There is evidence supporting a number of different functions of the V proteins of morbilliviruses in blocking the signalling pathways of type I and II interferons, but it is not clear which domains of V are responsible for which activities, and whether all these activities are required for effective blockade of interferon signalling. We show here that the two domains of rinderpest virus V protein have distinct functions, the N-terminal domain acting to bind STAT1 while the C-terminal V-specific domain interacts with the interferon-receptor associated kinases Jak1 and Tyk2. Effective blockade of interferon signalling required the intact V protein.

Abstract

The mechanisms by which viruses modulate the immune system include changes in host genomic methylation. 5-hydroxmethylcytosine (5hmC) is the catalytic product of the Tet (Ten-11 translocation) family of enzymes and may serve as an intermediate of DNA demethylation. Recent reports suggest that 5hmC may confer consequences on cellular events including the pathogenesis of disease; in order to explore this possibility further we investigated both 5-methylcytosine (5mC) and 5hmC levels in healthy and diseased chicken bursas of Fabricius. We discovered that embryonic B-cells have high 5mC content while 5hmC decreases during bursa development. We propose that a high 5mC level protects from the mutagenic activity of the B-cell antibody diversifying enzyme activation induced deaminase (AID). In support of this view, AID mRNA increases significantly within the developing bursa from embryonic to post hatch stages while mRNAs that encode Tet family members 1 and 2 reduce over the same period. Moreover, our data revealed that infectious bursal disease virus (IBDV) disrupts this genomic methylation pattern causing a global increase in 5hmC levels in a mechanism that may involve increased Tet 1 and 2 mRNAs. To our knowledge this is the first time that a viral infection has been observed to cause global increases in genomic 5hmC within infected host tissues, underlining a mechanism that may involve the induction of B-cell genomic instability and cell death to facilitate viral egress.
Colling A, Morrissy C, Barr J, Meehan G, Wright L, Goff W, Gleeson L, van der Heide B, Riddell S, Yu M, Eagles D, Lunt R, Khounsy S, Than Long N, Phong Vu P, Than Phuong N, Tung N, Linchongsubongkoch W, Hammond J, Johnson M, Johnson W, Unger H, Daniels P, Crowther J (2014)

Development and validation of a 3ABC antibody ELISA in Australia for foot and mouth disease

Australian Veterinary Journal 92 (6), 192-199

Abstract

Objective: To measure the diagnostic performance of an Australian-developed ELISA for the detection of antibodies against the non-structural proteins (NSP) 3ABC of the foot and mouth disease (FMD) virus. Methods: The diagnostic specificity was determined using 2535 sera from naïve animals and 1112 sera from vaccinated animals. Diagnostic sensitivity was calculated from the data for 995 sera from experimentally and field-infected animals from FMD-endemic countries in South East Asia. A commercial ELISA detecting antibodies against FMD virus NSP was used as the reference test to establish relative sensitivity and specificity. Bayesian latent class analysis was performed to corroborate results. The diagnostic window and rate of detection were determined at different times using sera from cattle, sheep and pigs before and after infection, and after vaccination and subsequent infection. Repeatability and reproducibility data were established. Results: At 35% test cut-off, the 3ABC ELISA had an overall diagnostic sensitivity of 91.5% and diagnostic specificity of 96.4%. The diagnostic sensitivity in vaccinated and subsequently infected cattle was 68.4% and diagnostic specificity in vaccinated cattle was 98.0%. Conclusions: The 3ABC ELISA identified field and experimentally infected animals, as well as vaccinated and subsequently infected animals. Diagnostic sensitivity and specificity estimates for other FMD NSP tests are comparable with the results obtained in this study. This NSP ELISA was found to be ‘fit for purpose’ as a screening assay at the herd level to detect viral infection and also to substantiate absence of infection.

Abstract

The NKp46 receptor demonstrates a high degree of lineage specificity, being expressed almost exclusively in NK cells. Previous studies have demonstrated NKp46 expression by T cells, but NKp46+CD3+ cells are rare and almost universally associated with NKp46 acquisition by T cells following stimulation. In this study we demonstrate the existence of a population of NKp46+CD3+ cells resident in normal bovine PBMCs that includes cells of both the ?? TCR+ and ?? TCR+ lineages and is present at a frequency of 0.1–1.7%. NKp46+CD3+ cells express transcripts for a broad repertoire of both NKRs and TCRs and also the CD3?, DAP10, and Fc?R1? but not DAP12 adaptor proteins. In vitro functional analysis of NKp46+CD3+ cells confirm that NKp46, CD16, and CD3 signaling pathways are all functionally competent and capable of mediating/redirecting cytolysis. However, only CD3 cross-ligation elicits IFN-? release. NKp46+CD3+ cells exhibit cytotoxic activity against autologous Theileria parva–infected cells in vitro, and during in vivo challenge with this parasite an expansion of NKp46+CD3+ cells was observed in some animals, indicating the cells have the potential to act as an anti-pathogen effector population. The results in this study identify and describe a novel nonconventional NKp46+CD3+ T cell subset that is phenotypically and functionally distinct from conventional NK and T cells. The ability to exploit both NKRs and TCRs suggests these cells may fill a functional niche at the interface of innate and adaptive immune responses.
Crisci E, Fraile L, Valentino S, Martinez-Guino L, Bottazzi B, Mantovani A, Montoya M (2014)

Immune characterization of long pentraxin 3 in pigs infected with influenza virus

Veterinary Microbiology 168 (1), 185-192

Abstract

Long pentraxin 3 (PTX3) is a conserved pattern-recognition secreted protein and a hostdefence-related component of the humoral innate immune system. The aim of the present study was to characterize swine PTX3 (SwPTX3) protein expression in influenza virus infected pigs. First, we performed in silico studies to evaluate the cross-reactivity of PTX3 human antibodies against SwPTX3. Secondly, we used in vitro analysis to detect SwPTX3 presence in swine bone marrow dendritic cells (SwBMDC) upon stimulation with different agents by Western blot and immunofluorescence. Finally, the levels of SwPTX3 were assessed in experimental infection of pigs with different strains of influenza virus. This is a novel study where the expression of SwPTX3 was evaluated in the context of a pathogen infection. The initial characterization of SwPTX3 in influenza virus infected pigs contributes to understand the role of PTX proteins in the immune response.

Abstract

A complete phylogenetic analysis of all of the H9N2 hemagglutinin sequences that were collected between 1966 and 2012 was carried out in order to build a picture of the geographical and host specific evolution of the hemagglutinin protein. To improve the quality and applicability of the output data the sequences were divided into subsets based upon location and host species. The phylogenetic analysis of hemagglutinin reveals that the protein has distinct lineages between China and the Middle East, and that wild birds in both regions retain a distinct form of the H9 molecule, from the same lineage as the ancestral hemagglutinin. The results add further evidence to the hypothesis that the current predominant H9N2 hemagglutinin lineage might have originated in Southern China. The study also shows that there are sampling problems that affect the reliability of this and any similar analysis. This raises questions about the surveillance of H9N2 and the need for wider sampling of the virus in the environment. The results of this analysis are also consistent with a model where hemagglutinin has predominantly evolved by neutral drift punctuated by occasional selection events. These selective events have produced the current pattern of distinct lineages in the Middle East, Korea and China. This interpretation is in agreement with existing studies that have shown that there is widespread intra-country sequence evolution.
Dhanasekaran S, Biswas M, Vignesh A R, Ramya R, Raj G D, Tirumurugaan K G, Raja A, Kataria R S, Parida S, Subbiah E (2014)

Toll-Like receptor responses to peste des petits ruminants virus in goats and water buffalo

PLoS ONE 9 (11), e111609

Abstract

Ovine rinderpest or goat plague is an economically important and contagious viral disease of sheep and goats, caused by the Peste des petits ruminants virus (PPRV). Differences in susceptibility to goat plague among different breeds and water buffalo exist. The host innate immune system discriminates between pathogen associated molecular patterns and self antigens through surveillance receptors known as Toll like receptors (TLR). We investigated the role of TLR and cytokines in differential susceptibility of goat breeds and water buffalo to PPRV. We examined the replication of PPRV in peripheral blood mononuclear cells (PBMC) of Indian domestic goats and water buffalo and demonstrated that the levels of TLR3 and TLR7 and downstream signalling molecules correlation with susceptibility vs resistance. Naturally susceptible goat breeds, Barbari and Tellichery, had dampened innate immune responses to PPRV and increased viral loads with lower basal expression levels of TLR 3/7. Upon stimulation of PBMC with synthetic TLR3 and TLR7 agonists or PPRV, the levels of proinflammatory cytokines were found to be significantly higher while immunosuppressive interleukin (IL) 10 levels were lower in PPRV resistant Kanni and Salem Black breeds and water buffalo at transcriptional level, correlating with reduced viralloads in infected PBMC. Water buffalo produced higher levels of interferon (IFN) ? in comparison with goats at transcriptional and translational levels. Pre-treatment of Vero cells with human IFN? resulted in reduction of PPRV replication, confirming the role of IFN? in limiting PPRV replication. Treatment with IRS66, a TLR7 antagonist, resulted in the reduction of IFN? levels, with increased PPRV replication confirming the role of TLR7. Single nucleotide polymorphism analysis of TLR7 of these goat breeds did not show any marked nucleotide differences that might account for susceptibility vs resistance to PPRV. Analyzing other host genetic factors might provide further insights on susceptibility to PPRV and genetic polymorphisms in the host.

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