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

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Brenner J, Batten C, Yadin H, Bumbarov V, Friedgut O, Rotenberg D, Golender N, Oura C A L (2011)

Clinical syndromes associated with the circulation of multiple serotypes of bluetongue virus in dairy cattle in Israel

Veterinary Record 169 (15), 389-394
Publisher’s version: http://dx.doi.org/10.1136/vr.d4629

Abstract

From 2008 to 2011, seven distinct bluetongue virus (BTV) serotypes (BTV-2, BTV-4, BTV-5, BTV-8, BTV-15, BTV-16 and BTV-24) have been identified to be circulating in diseased sheep and cattle in Israel. This paper describes the array of clinical manifestations caused by BTV in cattle in Israel. Each set of clinical manifestations has been categorised as a syndrome and six distinct clinical syndromes have been observed in dairy cattle: 'footrot-like syndrome', 'sore nose syndrome', 'subcutaneous emphysema syndrome', 'red/rough udder syndrome', 'bluetongue/epizootic haemorrhagic disease systemic syndrome' and 'maladjustment syndrome'.
Brisbarre N, Attoui H, Gallian P, Di Bonito P, Giorgi C, Cantaloube J F, Biagini P, Touinssi M, Jordier F, de Micco P (2011)

Seroprevalence of Toscana virus in blood donors, France, 2007 (Letter)

Emerging Infectious Diseases 17 (5), 941-943
Publisher’s version: http://dx.doi.org/10.3201/eid1705.101052
Mbanga J, Dube S, Munyanduki H (2010)

Prevalence and drug resistance in bacteria of the urinary tract infections in Bulawayo province, Zimbabwe

East African Journal of Public Health 7 (3), 229-232
Publisher’s version: https://doi.org/10.4314/eajph.v7i3.64733

Abstract

OBJECTIVE: To obtain data on the prevalence of antibiotic resistance in bacteria isolated from patients with suspected urinary tract infection in Bulawayo province, Zimbabwe. METHOD: Over a period of one year, 257 urine samples were analyzed for bacteria by standard procedures. Antimicrobial susceptibility testing of isolated bacteria was done using the disk diffusion method. RESULTS: The isolated bacteria were Escherichia coli (40.3%), coagulase negative Staphylococcus (16.1%), Klebsiella spp (11.2%), Staphylococcus aureus (8%), Group A Streptococcus (8%) and Klebsiella oxytoca (8%). Antibiotic susceptibility testing was done using the disc diffusion method on Mueller-Hinton agar. It revealed a high resistance to ampicillin (84.5%) and cotrimoxazole (68.5%) among the Gram negative bacilli. Gram positive cocci showed resistance to Nalidixic acid (81%) and cotrimoxazole (69%). E. coli was susceptible to most of the drugs but 84% of the strains were resistant to ampicillin, and 68% to cotrimoxazole. All isolates were sensitive to Nicene. CONCLUSION: The high levels of ampicillin and cotrimoxazole resistance in E. coli and other enterobactericiae suggest the need to perform urinalysis and antibiotic susceptibility testing in all patients. Nicene should be considered as the first line therapy for all age groups. It is important for physicians to know susceptibility data for UTIs in order to optimize the use of empirical therapy.

Sweeney T R, Cisnetto V, Bose D, Bailey M, Wilson J R, Zhang X, Belsham G J, Curry S (2010)

Foot-and-mouth disease virus 2C is a hexameric AAA+ protein with a coordinated ATP hydrolysis mechanism

Journal of Biological Chemistry 285 (32), 24347-24359
Publisher’s version: https://doi.org/10.1074/jbc.m110.129940

Abstract

Foot-and-mouth disease virus (FMDV), a positive sense, single-stranded RNA virus, causes a highly contagious disease in cloven-hoofed livestock. Like other picornaviruses, FMDV has a conserved 2C protein assigned to the superfamily 3 helicases a group of AAA+ ATPases that has a predicted N-terminal membrane-binding amphipathic helix attached to the main ATPase domain. In infected cells, 2C is involved in the formation of membrane vesicles, where it co-localizes with viral RNA replication complexes, but its precise role in virus replication has not been elucidated. We show here that deletion of the predicted N-terminal amphipathic helix enables overexpression in Escherichia coli of a highly soluble truncated protein, 2C(34–318), that has ATPase and RNA binding activity. ATPase activity was abrogated by point mutations in the Walker A (K116A) and B (D160A) motifs and Motif C (N207A) in the active site. Unliganded 2C(34–318) exhibits concentration-dependent self-association to yield oligomeric forms, the largest of which is tetrameric. Strikingly, in the presence of ATP and RNA, FMDV 2C(34–318) containing the N207A mutation, which binds but does not hydrolyze ATP, was found to oligomerize specifically into hexamers. Visualization of FMDV 2C-ATP-RNA complexes by negative stain electron microscopy revealed hexameric ring structures with 6-fold symmetry that are characteristic of AAA+ ATPases. ATPase assays performed by mixing purified active and inactive 2C(34–318) subunits revealed a coordinated mechanism of ATP hydrolysis. Our results provide new insights into the structure and mechanism of picornavirus 2C proteins that will facilitate new investigations of their roles in infection.

Zunszain P A, Knox S R, Sweeney T R, Yang J, Roque-Rosell N, Belsham G J, Leatherbarrow R J, Curry S (2010)

Insights into cleavage specificity from the crystal structure of foot-and-mouth disease virus 3C protease complexed with a peptide substrate

Journal of Molecular Biology 395 (2), 375-389
Publisher’s version: https://doi.org/10.1016/j.jmb.2009.10.048

Abstract

Picornavirus replication is critically dependent on the correct processing of a polyprotein precursor by 3C protease(s) (3Cpro) at multiple specific sites with related but non-identical sequences. To investigate the structural basis of its cleavage specificity, we performed the first crystallographic structural analysis of non-covalent complexes of a picornavirus 3Cpro with peptide substrates. The X-ray crystal structure of the foot-and-mouth disease virus 3Cpro, mutated to replace the catalytic Cys by Ala and bound to a peptide (APAKQ|LLNFD) corresponding to the P5–P5′ region of the VP1-2A cleavage junction in the viral polyprotein, was determined up to 2.5 Å resolution. Comparison with free enzyme reveals significant conformational changes in 3Cpro on substrate binding that lead to the formation of an extended interface of contact primarily involving the P4–P2′ positions of the peptide. Strikingly, the deep S1′ specificity pocket needed to accommodate P1′-Leu only forms when the peptide binds. Substrate specificity was investigated using peptide cleavage assays to show the impact of amino acid substitutions within the P5–P4′ region of synthetic substrates. The structure of the enzyme–peptide complex explains the marked substrate preferences for particular P4, P2 and P1 residue types, as well as the relative promiscuity at P3 and on the P′ side of the scissile bond. Furthermore, crystallographic analysis of the complex with a modified VP1-2A peptide (APAKE|LLNFD) containing a Gln-to-Glu substitution reveals an identical mode of peptide binding and explains the ability of foot-and-mouth disease virus 3Cpro to cleave sequences containing either P1-Gln or P1-Glu. Structure-based mutagenesis was used to probe interactions within the S1′ specificity pocket and to provide direct evidence of the important contribution made by Asp84 of the Cys-His-Asp catalytic triad to proteolytic activity. Our results provide a new level of detail in our understanding of the structural basis of polyprotein cleavage by 3Cpro.

Maringer K, Elliott G (2010)

Recruitment of Herpes simplex virus type 1 immediate-early protein ICP0 to the virus particle

Journal of Virology 84 (9), 4682-4696
Publisher’s version: https://doi.org/10.1128/JVI.00126-10

Abstract

Although the herpes simplex virus type 1 (HSV-1) tegument is comprised of a large number of viral and cellular proteins, how and where in the cell these proteins are recruited into the virus structure is poorly understood. We have shown previously that the immediate-early gene product ICP0 is packaged by a mechanism dependent on the major tegument protein VP22, while others have shown a requirement for ICP27. We now extend our studies to show that ICP0 packaging correlates directly with the ability of ICP0 to complex with VP22 in infected cells. ICP27 is not, however, present in this VP22-ICP0 complex but is packaged into the virion in a VP22- and ICP0-independent manner. Biochemical fractionation of virions indicated that ICP0 associates tightly with the virus capsid, but intranuclear capsids contained no detectable ICP0. The RING finger domain of ICP0 and the N terminus of VP22 were both shown to be essential but not sufficient for ICP0 packaging and complex formation. Strikingly, however, the N-terminal region of VP22, while unable to form a complex with ICP0, inhibited its translocation from the nucleus to the cytoplasm. PML degradation by ICP0 was efficient in cells infected with this VP22 mutant virus, confirming that ICP0 retains activity. Hence, we would suggest that VP22 is an important molecular partner of ICP0 that controls at least one of its activities: its assembly into the virion. Moreover, we propose that the pathway by which VP22 recruits ICP0 to the virion may begin in the nucleus prior to ICP0 translocation to its final site of assembly in the cytoplasm.

Dietrich I, Macintyre A, McMonagle E, Price A J, James L C, McEwan W A, Hosie M J, Willett B J (2010)

Potent lentiviral restriction by a synthetic feline TRIM5 cyclophilin A fusion

Journal of Virology 84 (17), 8980-8985
Publisher’s version: https://doi.org/10.1128/jvi.00858-10

Abstract

A synthetic feline TRIM5-cyclophilin A fusion protein (feTRIMCyp) was generated and transduced into feline cells. feTRIMCyp was highly efficient at preventing infection with human (HIV) and feline (FIV) immunodeficiency virus pseudotypes, and feTRIMCyp-expressing cells resisted productive infection with either FIV-Fca or FIV-Pco. The restriction of FIV infection by feTRIMCyp was reversed by the cyclosporine (Cs) derivatives NIM811 and Debio-025 but less so by Cs itself. FeTRIMCyp and FIV infections of the cat offer a unique opportunity to evaluate TRIMCyp-based approaches to genetic therapy for HIV infection and the treatment of AIDS.

Limon G, Guitian J, Gregory N G (2010)

An evaluation of the humaneness of puntilla in cattle

Meat Science 84 (3), 352-355
Publisher’s version: https://doi.org/10.1016/j.meatsci.2009.09.001

Abstract

Slaughter by puntilla followed by neck sticking was examined in 309 cattle, to assess the humaneness of this method. After the neck stab, brain and spinal function as well as presence of selected cognitive responses were measured. In addition breed, sex, live weight, body condition score, number of stabs given and level of experience of the slaughterman were recorded. Repeat stabbing was needed to penetrate the foramen ovale in 24% of the animals, and was significantly less frequent in slaughtermen who were experienced, and more frequent in heavy weight animals (>380 kg). Prevalence of brain and spinal function was 91%. When animals attempted to stand after the neck stab they were more likely to have rhythmic breathing, positive palpebral response and responsiveness to threat, noise and short air stimulus. These findings indicate that nerve pathways are often functional after neck stab and therefore it is highly likely that the animals are still conscious.

Banyard A C, Simpson J, Monaghan P, Barrett T (2010)

Rinderpest virus expressing enhanced green fluorescent protein as a separate transcription unit retains pathogenicity for cattle

Journal of General Virology 91 (12), 2918-2927
Publisher’s version: http://dx.doi.org/10.1099/vir.0.023598-0

Abstract

A full-length DNA clone of a virulent strain of rinderpest virus was constructed with the gene for the enhanced green fluorescent protein (eGFP) inserted as a separate transcription unit between the P and M genes. Rescue of the virus from the modified clone using reverse genetics generated a virus that grew to the same levels as the virus rescued from the unmodified DNA clone in cell culture. The recombinant virus expressed eGFP to a high level and was used to follow virus replication in real-time using live-cell imaging. Cattle infected with both the recombinant wild-type virus and the recombinant eGFP expressing virus developed clinical disease similar to that of the wild-type natural virus isolate. Detection of virus in circulating peripheral blood leukocytes was equivalent to that of the animals infected with the wild-type virus. The high level of expression of soluble eGFP by this virus allowed us to detect viral replication in infected animals by confocal microscopy. Imaging vibrating microtome sections by confocal microscopy provided good preservation of tissue and cellular architecture as well as revealing the sites of replication of the virus in different tissues of infected animals.
Gale P, Estrada-Peña A, Martinez M, Ulrich R G, Wilson A, Capelli G, Phipps P, De La Torre A, Muñoz M J, Dottori M, Mioulet V, Fooks A R (2010)

The feasibility of developing a risk assessment for the impact of climate change on the emergence of Crimean-Congo haemorrhagic fever in livestock in Europe: a review

Journal of Applied Microbiology 108 (6), 1859-1870
Publisher’s version: http://dx.doi.org/10.1111/j.1365-2672.2009.04638.x

Abstract

Crimean-Congo haemorrhagic fever virus (CCHFV) is one of the most widespread of all medically important arboviruses with ticks of the Hyalomma spp. serving as the main vectors. Infection of livestock by CCHFV serves as a route of exposure to humans, as a reservoir of disease and as a route of importation. This study discusses the pathways and data requirements for a qualitative risk assessment for the emergence of CCHFV in livestock in Europe. A risk map approach is proposed based on layers that include the potential routes of release (e.g. by migrating birds carrying infected ticks) together with the main components for exposure, namely the distributions of the tick vectors, the small vertebrate host reservoirs and the livestock. A layer on landscape fragmentation serves as a surrogate for proximity of livestock to the tick cycle. Although the impact of climate change on the emergence of CCHF is not clear, comparing the distribution of risk factors in each layer currently with those predicted in the 2080s with climate change can be used to speculate how potential high-risk areas may shift. According to the risk pathway, transstadial and/or transovarial transmission in the tick vector are crucial for CCHFV spread. Vector competence and tick vector switching, however, remain critical factors for CCHFV colonization of new regions in Europe. The species of migratory bird is also an important consideration in the release assessment with greater abundance and biodiversity of ground-dwelling birds in southern Europe than in northern Europe.

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