Publications

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

There were a total of 1759 results for your search.
Graham S P, Brown D J, Vatansever Z, Waddington D, Taylor L H, Nichani A K, Campbell J D, Adamson R E, Glass E J, Spooner R L (2001)

Proinflammatory cytokine expression by Theileria annulata infected cell lines correlates with the pathology they cause in vivo

Vaccine 19 (20-22), 2932-2944

Abstract

Control of Theileria annulata is currently best achieved by the use of live attenuated cell line vaccines. However, the mechanisms underlying attenuation are unclear and there is a need to rapidly produce new cell line vaccines, which could safely and effectively vaccinate cattle against tropical theileriosis. There is increasing evidence to suggest that proinflammatory cytokines produced by T. annulata infected cells play a central role in both pathology and immune evasion. This study aimed to test this hypothesis and to evaluate cytokine expression as a marker of virulence. The pathogenicity and protective efficacy of cloned T. annulata cell lines that expressed different levels of proinflammatory cytokines were compared. In two independent trials using different stocks of T. annulata, cell lines that expressed higher levels of proinflammatory cytokines induced severe reactions, and in some cases death, when used to vaccinate groups of cattle. In contrast, low cytokine expressing lines induced low post-vaccinal reactions. The results clearly demonstrated that cytokine expression by T. annulata infected cells could be used as a marker of virulence and provided strong evidence to support a role for cytokines in the induction of pathology. Both high and low cytokine expressing cell lines protected cattle against heterologous challenge infection, offering the possibility of using cytokine expression to rapidly select new safe, potent vaccines against tropical theileriosis without the need for culture attenuation.
Charleston B, Fray M D, Baigent S, Carr B V, Morrison W I (2001)

Establishment of persistent infection with non-cytopathic bovine viral diarrhoea virus in cattle is associated with a failure to induce type 1 interferon

Journal of General Virology 82, 1893-1897

Abstract

The establishment of persistent infections with non-cytopathic bovine virus diarrhoea virus (ncpBVDV) is crucial for the maintenance of BVDV in cattle populations. Also, super-infection of persistently infected individuals with antigenically homologous cytopathic BVDV (cpBVDV) results in fatal mucosal disease. Persistent infection with ncpBVDV is established by infection of the foetus during the first trimester of pregnancy. It has been shown previously that foetal infection with cpBVDV does not result in persistent infection. Infection of cells in vitro has demonstrated that cpBVDV induces type I interferon (IFN), whereas ncpBVDV fails to induce IFN. In this study we demonstrate that foetal challenge with cpBVDV results in IFN production, whereas ncpBVDV does not. These findings strongly suggest that the ability of ncpBVDV to inhibit the induction of type I IFN has evolved to enable the virus to establish persistent infection in the early foetus.
Tchilian E Z, Wallace D L, Imami N, Liao H X, Burton C, Gotch F, Martinson J, Haynes B F, Beverley P C L (2001)

The Exon A (C77G) mutation is a common cause of abnormal CD45 splicing in humans

Journal of Immunology 166 (10), 6144-6148

Abstract

The leukocyte common (CD45) Ag is essential for normal T lymphocyte function and alternative splicing at the N terminus of the gene is associated with changes in T cell maturation and differentiation. Recently, a statistically significant association was reported in a large series of human thymus samples between phenotypically abnormal CD45 splicing and the presence of the CC chemokine receptor 5 deletion 32 (CCR5del32) allele, which confers resistance to HIV infection in homozygotes. We show here that abnormal splicing in these thymus samples is associated with the presence of the only established cause of CD45 abnormal splicing, a C77G transversion in exon A. In addition we have examined 227 DNA samples from peripheral blood of healthy donors and find no association between the exon A (C77G) and CCR5del32 mutations. Among 135 PBMC samples, tested by flow cytometric analysis, all those exhibiting abnormal splicing of CD45 also showed the exon A C77G transversion. We conclude that the exon A (C77G) mutation is a common cause of abnormal CD45 splicing and that further disease association studies of this mutation are warranted.
Graham S P, Trees A J, Collins R A, Moore D M, Guy F M, Taylor M J, Bianco A E (2001)

Down-regulated lymphoproliferation coincides with parasite maturation and with the collapse of both gamma interferon and interleukin-4 responses in a bovine model of onchocerciasis

Infection and Immunity 69 (7), 4313-9

Abstract

Onchocerciasis is a debilitating parasitic infection caused by the filarial nematode Onchocerca volvulus. Infections are chronic, and persistence of the parasites for several years argues for highly adapted mechanisms of immune evasion. Due to the restricted host repertoire of O. volvulus, we have used the cattle parasite Onchocerca ochengi to investigate the nature of immunomodulation underpinning these long-term infections. Cattle were infected with a single inoculation of 350 infective-stage larvae under laboratory conditions (n = 6). Intradermal nodules containing immature adult worms were detected from 110 days postinfection, and microfilariae in skin were detected from day 280 postinfection. Parasite-specific responses during early infection were nonpolarized with respect to the major Th cytokines (interleukin-4 [IL-4], IL-2, and gamma interferon [IFN-gamma]) produced by antigen-stimulated peripheral blood mononuclear cells (PBMC) or serum antibody isotypes. Antigen-induced proliferation of PBMC peaked shortly after exposure and remained high during the prepatent infection. As the parasites matured and animals developed patent infections, there was a profound down-regulation of lymphoproliferation, accompanied by sharp falls in the expression of both IL-4 and IFN-gamma and a gradual decline in IL-2. Levels of immunoglobulin G2 (IgG2) fell, while those of IgG1 remained high. We conclude that neither a classical Th2 response nor a simple Th1-to-Th2 switch is sufficient to explain the immunomodulation associated with patent Onchocerca infections. Instead, there is an initial Th0 response, which matures into a response with some, but not all of the features of a Th2 response. The natural host-parasite relationship of O. ochengi in cattle may be useful as both a descriptive and predictive tool to test more refined models of immunomodulation in onchocerciasis.
Charleston B, Hope J C, Carr B V, Howard C J (2001)

Masking of two in vitro immunological assays for Mycobacterium bovis (BCG) in calves acutely infected with non-cytopathic bovine viral diarrhoea virus

Veterinary Record 149, 481-484

Abstract

Acute infection of calves, previously vaccinated with bacille Calmette-Guerin (BCG), with non-cytopathic viral diarrhoea virus (BVDV) resulted in the temporary suppression of two in vitro assays used to monitor Mycobacterium bovis infection. Lymphocyte proliferation and interferon-gamma production by whole blood cultures containing purified protein derivatives prepared from Mycobacterium avium (PPD-A) and M bovis (PPD-B) were markedly suppressed. The implication is that acute infections of cattle with non-cytopathic BVDV may temporarily compromise diagnostic tests for M bovis infections and result in a failure to identify cattle with tuberculosis.
Tchilian E Z, Wallace D L, Wells R S, Flower D R, Morgan G, Beverley P C L (2001)

A deletion in the gene encoding the CD45 antigen in a patient with SCID

Journal of Immunology 166 (2), 1308-1313

Abstract

SCID is a heterogeneous group of hereditary diseases. Mutations in the common gamma -chain (gamma (c)) of cytokine receptors, including those for IL-2, IL-4, IL-7, IL-9, and IL-15, are responsible for an X-linked form of the disease, while mutations of several other genes, including Janus-associated kinase-3, may cause autosomal recessive forms of SCID. We investigated the first SCID patient to be described with minimal cell surface expression of the leukocyte common (CD45) Ag. CD45 is an abundant transmembrane tyrosine phosphatase, expressed on all leukocytes, and is required for efficient lymphocyte signaling. CD45-deficient mice are severely immunodeficient and have very few peripheral T lymphocytes. We report here that a homozygous 6-bp deletion in the gene encoding CD45 (PTPRC, gene map locus 1q31-32), which results in a loss of glutamic acid 339 and tyrosine 340 in the first fibronectin type III module of the extracellular domain of CD45, is associated with failure of surface expression of CD45 and SCID. Molecular modeling suggests that tyrosine 340 is crucial for the structural integrity of CD45 protein. This is the second description of a clinically relevant CD45 mutation, provides direct evidence for the importance of CD45 in immune function in humans, and suggests that abnormalities in CD45 expression are a possible cause of SCID in humans.
Hiscox J A, Wurm T, Wilson L, Britton P, Cavanagh D, Brooks G (2001)

The coronavirus infectious bronchitis virus nucleoprotein localizes to the nucleolus

Journal of Virology 75, 506-512

Abstract

The coronavirus nucleoprotein (N) has been reported to be involved in various aspects of virus replication. We examined by confocal microscopy the subcellular localization of the avian infectious bronchitis virus N protein both in the absence and in the context of an infected cell and found that N protein localizes both to the cytoplasmic and nucleolar compartments.
Chernukhin I V, Seago J E, Newbury S F (2001)

Drosophila 5? ? 3?-exoribonuclease Pacman

Methods in Enzymology: Ribonucleases, Pt B edited by A. W. Nicholson 342, 293-302

Abstract

This chapter concentrates on the methods used to express a Drosophila recombinat 5? ? 3?-exoribonuclease, purify the protein, and analyze its activity in vitro. Analysis of early development in Drosophila has shown that RNA localization, control of translation, and mRNA stability are intimately linked. Generally, translational repression leads to degradation of an RNA, and failure of an RNA to localize correctly also leads to its degradation. Work on the yeast Saccharomyces cerevisiae has identified many ribonucleases and associated factors that control mRNA decay, RNA splicing, and rRNA processing. In yeast, it has been shown that 3? ? 5? degradation/processing of RNA requires the exosome, which is a complex of at least 10 proteins. Degradation of RNA in a 5? ? 3? direction occurs by initial decapping of the mRNA, followed by 5? ? 3? degradation of the RNA by Xrn1p. The two decapping proteins (Dcp1p and Dcp2p) and Xrnlp have been shown to be complexed to seven Lsm proteins, which are likely to form a ring encircling the RNA. To understand the role of RNA stability in development, a number of approaches can be used. Once the genes encoding particular ribonucleases or associated factors have been identified, then expression of the RNA during development can be determined. These techniques have been used to show that the 5? ? 3?-exoribonuclease Pacman is differentially expressed during development.
Beard P M, Rhind S M, Sinclair M C, Wildblood L A, Stevenson K, McKendrick I J, Sharp J M, Jones D G (2000)

Modulation of gamma delta T cells and CD1 in Mycobacterium avium subsp paratuberculosis infection

Veterinary Immunology and Immunopathology 77 (3-4), 311-319

Abstract

M.a. paratuberculosis is the causal agent of paratuberculosis (Johne's disease). Recent work has suggested that gamma delta T cells may play an important role in the early immunological response to mycobacterial diseases, and that CD1 may act as a non-classical MHC molecule in antigen presentation to these gamma delta T cells. Experimental infection of neonatal lambs with M.a. paratuberculosis was used to investigate the changes in gamma delta T cells and CD1 molecules in the gut associated lymphoid tissue 4 weeks after inoculation. Immunohistochemistry was used to label the gamma delta lymphocytes and CD1 molecules. An increase in the number of gamma delta T cells was noted in both the jejunal and ileal Peyer's patches in the gut of infected lambs, but no statistically significant change was found in the mesenteric lymph nodes. There were no obvious changes in the CD1 molecules in any tissue. This work suggests that gamma delta T cells may play a role in the initial immunological events of paratuberculosis infection.

Tait S W G, Reid E B, Greaves D R, Wileman T E, Powell P P (2000)

Mechanism of inactivation of NF-κB by a viral homologue of IκBα: signal-induced release of IκBα results in binding of the viral homologue to NF-κB

Journal of Biological Chemistry 275 (44), 34656-34664

Abstract

Activation of the nuclear factor κB plays a key role in viral pathogenesis, resulting in inflammation and modulation of the immune response. We have previously shown that A238L, an open reading frame from African swine fever virus (ASFV), encoding a protein with 40% homology to porcine IκBα exerts a potent anti-inflammatory effect in host macrophages, where it down-regulates NF-κB-dependent gene transcription and proinflammatory cytokine production. This paper reveals the mechanism of suppression of NF-κB activity by A238Lp. A238Lp is synthesized throughout infection as two molecular mass forms of 28 and 32 kDa, and vaccinia-mediated expression of A238L demonstrated that both proteins are produced from a single gene. Significantly, the higher 32-kDa form of A238L, but not the 28-kDa form, interacts directly with RelA, the 65-kDa subunit of NF-κB, indicating that the binding is dependent on a post-translational modification. Immunoprecipitation analysis shows the NF-κB p65-A238L p32 heterodimer is a separate complex from NF-κB-IκBα, and it resides in the cytoplasm. Moreover, we show that ASFV infection stimulates the NFκB signal transduction pathway, which results in the rapid degradation of endogenous IκBα, although both forms of A238Lp are resistant to stimulus-induced degradation. Using the proteasome inhibitor MG132, we show that when degradation of IκBα is inhibited, A238Lp binding to NF-κB p65 is reduced. The results suggest that the virus exploits its activation of the NF-κB pathway to enable its own IκB homologue to bind to NF-κB p65. Last, we show that synthesis of IκBα is increased during ASFV infection, indicating RelA-independent transcription of the IκBα gene.

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