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

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Bruhn C A W, Nielsen S C A, Samaniego J A, Wadsworth J, Knowles N J, Gilbert M T P (2015)

Viral meningitis epidemics and a single, recent, recombinant and anthroponotic origin of swine vesicular disease virus

Evolution, Medicine, and Public Health 2015 (1), 289-303
Publisher’s version: http://dx.doi.org/10.1093/emph/eov026

Abstract

Background and objectives: Swine vesicular disease virus (SVDV) is a close relative of the human Enterovirus B serotype, coxsackievirus B5. As the etiological agent of a significant emergent veterinary disease, several studies have attempted to explain its origin. However, several key questions remain, including the full biological ancestry of the virus, and its geographical and temporal origin.Methodology: We sequenced near-complete genomes of 27 SVDV and 13 coxsackievirus B5 samples, all originally isolated between 1966 and 2006, and analysed these in conjunction with existing sequences and historical information.Results: While analyses incorporating 24 additional near-complete SVDV genomic sequences indicate clear signs of within-SVDV recombination, all 51 SVDV isolates remain monophyletic. This supports a hypothesis of a single anthroponotic transfer origin. Analysis of individual coding and non-coding regions support that SVDV has a recombinant origin between coxsackievirus B5 and another Enterovirus B serotype, most likely coxsackievirus A9. Extensive Bayesian sequence-based analysis of the time of the most recent common ancestor of all analysed sequences places this within a few years around 1961. Epidemiological evidence points to China as an origin, but there are no available samples to test this conclusively.Conclusions and implications: Historical investigation and the clinical aspects of the involved Enterovirus B serotypes, makes the current results consistent with a hypothesis stating that SVDV originated through co-infection, recombination, and a single anthroponotic event, during large viral meningitis epidemics around 1960/1961 involving the ancestral serotypes. The exact geographical origin of SVDV may remain untestable due to historical aspects.

Calvo-Pinilla E, de la Poza F, Gubbins S, Mertens P P C, Ortego J, Castillo-Olivares J (2015)

Antiserum from mice vaccinated with modified vaccinia Ankara virus expressing African horse sickness virus (AHSV) VP2 provides protection when it is administered 48 h before, or 48 h after challenge

Antiviral Research 116, 27-33
Publisher’s version: http://dx.doi.org/10.1016/j.antiviral.2015.01.009

Abstract

Previous studies show that a recombinant modified vaccinia Ankara (MVA) virus expressing VP2 of AHSV serotype 4 (MVA-VP2) induced virus neutralising antibodies in horses and protected interferon alpha receptor gene knock-out mice (IFNAR ?/?) against challenge. Follow up experiments indicated that passive transfer of antiserum, from MVA-VP2 immune donors to recipient mice 1 h before challenge, conferred complete clinical protection and significantly reduced viraemia. These studies have been extended to determine the protective effect of MVA-VP2 vaccine-induced antiserum, when administered 48 h before, or 48 h after challenge. In addition, passive transfer of splenocytes was undertaken to assess if they confer any degree of immunity to immunologically naïve recipient mice. Thus, antisera and splenocytes were collected from groups of mice that had been vaccinated with MVA-VP2, or wild type MVA (MVA-wt), for passive immunisation of recipient mice. The latter were subsequently challenged with AHSV-4 (together with appropriate vaccinated or unvaccinated control animals) and protection was assessed by comparing clinical signs, lethality and viraemia between treated and control groups. All antiserum recipients showed high protection against disease (100% survival rates even in mice that were immunised 48 h after challenge) and statistically significant reduction or viraemia in comparison with the control groups. The mouse group receiving splenocytes from MVA-VP2 vaccinates, showed only a 40% survival rate, with a small reduction in viraemia, compared to those mice that had received splenocytes from MVA-wt vaccinates. These results confirm the primarily humoral nature of protective immunity conferred by MVA-VP2 vaccination and show the potential of administering MVA-VP2 specific antiserum as an emergency treatment for AHSV.
Carpenter S, Veronesi E, Mullens B A, Venter G (2015)

Vector competence of Culicoides for arboviruses: three major periods of research, their influence on current studies and future directions.

Revue Scientifique et Technique 34 (1), 97-112
Publisher’s version: http://web.oie.int/boutique/extrait/07carpenter97112.pdf

Abstract

The spectacular and unprecedented outbreaks of bluetongue virus (BTV) that have occurred in Europe since 1998 have led to increased interest in those factors that determine competence of Culicoides biting midges (Diptera: Ceratopogonidae) for arboviruses. In this review the authors critically examine three major periods of research into the biological transmission by Culicoides of two economically important arboviruses of the family Reoviridae: African horse sickness virus (AHSV) and BTV. First they examine early studies, largely conducted in southern Africa, that played a key role in initially implicating Culicoides as agents of AHSV and BTV transmission. Then they examine advances in understanding made following the establishment of colonies of the BTV vector species Culicoides sonorensis, which have largely shaped our current understanding of BTV and AHSV transmission. They then consider attempts in recent years to implicate vectors of BTV in the European Union during what has become the most economically damaging series of outbreaks in recorded history. In some cases the origin of these outbreaks was uncertain and unexpected, particularly in northern Europe, where BTV had not previously occurred. Limitations imposed on studies of vector competence by the biology of Culicoides are then discussed, along with advances in the technologies now available and the logistics of working upon agents requiring biosecure containment outside their endemic range. Finally, the authors suggest areas that have either been poorly addressed to date or entirely ignored and ways in which studies could be conducted to provide standardised data for comparison worldwide.
Carvalho D O, McKemey A R, Garziera L, Lacroix R, Donnelly C A, Alphey L, Malavasi A, Capurro M L (2015)

Suppression of a field population of Aedes aegypti in Brazil by sustained release of transgenic male mosquitoes

PLoS Neglected Tropical Diseases 9 (7), e0003864
Publisher’s version: http://dx.doi.org/10.1371%2Fjournal.pntd.0003864

Abstract

Dengue is a major mosquito-borne disease, increasing in prevalence and severity; there are no specific drugs or licensed vaccine. It is primarily transmitted by one mosquito species, Aedes aegypti. We released transgenic ‘sterile’ male mosquitoes in Itaberaba, a suburb of Juazeiro, a Brazilian city. Sustained release of these males, whose offspring typically die before adulthood as a consequence of the transgenic modification, strongly suppressed the target wild population—by 80–95% according to different measures. These data are consistent with previous releases in the Cayman Islands, suggesting that differences between the two locations, including the environment or wild mosquito strain, made little difference. Mathematical models suggest that this degree of suppression would be highly effective in preventing epidemic dengue.
Chacon A, Marco-Sola S, Espinosa A, Ribeca P, Moure J C (2015)

Boosting the FM-index on the GPU: effective techniques to mitigate random memory access

EEE/ACM Transactions Computational Biology and Bioinformatics 12 (5), 1048-1059
Publisher’s version: http://dx.doi.org/10.1109/TCBB.2014.2377716

Abstract

The recent advent of high-throughput sequencing machines producing big amounts of short reads has boosted the interest in efficient string searching techniques. As of today, many mainstream sequence alignment software tools rely on a special data structure, called the FM-index, which allows for fast exact searches in large genomic references. However, such searches translate into a pseudo-random memory access pattern, thus making memory access the limiting factor of all computation-efficient implementations, both on CPUs and GPUs. Here we show that several strategies can be put in place to remove the memory bottleneck on the GPU: more compact indexes can be implemented by having more threads work cooperatively on larger memory blocks, and a k-step FM-index can be used to further reduce the number of memory accesses. The combination of those and other optimisations yields an implementation that is able to process about 2 Gbases of queries per second on our test platform, being about 8 faster than a comparable multi-core CPU version, and about 3 to 5 faster than the FM-index implementation on the GPU provided by the recently announced Nvidia NVBIO bioinformatics library.
Li X, Fu Y, Yang J, Guo J, He J, Guo J, Weng S, Jia Y, Liu B, Li X, Zhu Q, Chen H (2015)

Genetic and biological characterization of two novel reassortant H5N6 swine influenza viruses in mice and chickens

Infection, Genetics and Evolution 36, 462-466
Publisher’s version: https://doi.org/10.1016/j.meegid.2015.08.017

Abstract

Novel H5N6 influenza A viruses have infected birds and human beings and caused four human clinical cases in China since 2014. The pig, as a mixing vessel, plays an important role for influenza virus reassortment and transmission. Towards this, routine surveillance for swine influenza in Guangdong province was conducted in 2014. In this study, we reported the biological characterization of two H5N6 influenza viruses isolated from healthy pigs in Guangdong province. Genetic analysis indicates that the two viruses are reassortants of 2.3.4.4 H5N1 and H6N6 avian influenza viruses with a high similarity to duck and human H5N6 influenza viruses isolated from Guangdong province. The data from chicken and mouse experiments show that the viruses are highly pathogenic in chickens and result in a systemic infection, and replicate in the mouse lung accompanying with a clinical inflammatory pathology. The results of the study demonstrate that the two H5N6 influenza viruses isolated from swine are the avian-originated viruses and have not adapted to swine population yet. However, they might keep evolving and pose a potential risk to public health and the continued surveillance of swine influenza should be strengthened.

Burgers W A, Ginbot Z, Shen Y J, Chege G K, Soares A P, Muller T L, Bunjun R, Kiravu A, Munyanduki H, Douglass N, Williamson A L (2014)

The novel capripoxvirus vector lumpy skin disease virus efficiently boosts modified vaccinia Ankara human immunodeficiency virus responses in rhesus macaques

Journal of General Virology 95 (10), 2267-2272
Publisher’s version: https://doi.org/10.1099/vir.0.067835-0

Abstract

Poxvirus vectors represent promising human immunodeficiency virus (HIV) vaccine candidates and were a component of the only successful HIV vaccine efficacy trial to date. We tested the immunogenicity of a novel recombinant capripoxvirus vector, lumpy skin disease virus (LSDV), in combination with modified vaccinia Ankara (MVA), both expressing genes from HIV-1. Here, we demonstrated that the combination regimen was immunogenic in rhesus macaques, inducing high-magnitude, broad and balanced CD4(+) and CD8(+) T-cell responses, and transient activation of the immune response. These studies support further development of LSDV as a vaccine vector.

Kabuuka T, Kasaija P D, Mulindwa H, Shittu A, Bastos A D, Fasina F O (2014)

Drivers and risk factors for circulating African swine fever virus in Uganda, 2012–2013

Research in Veterinary Science 97 (2), 218-225
Publisher’s version: https://doi.org/10.1016/j.rvsc.2014.07.001

Abstract

We explored observed risk factors and drivers of infection possibly associated with African swine fever (ASF) epidemiology in Uganda. Representative sub-populations of pig farms and statistics were used in a case-control model. Indiscriminate disposal of pig viscera and waste materials after slaughter, including on open refuse dumps, farm-gate buyers collecting pigs and pig products from within a farm, and retention of survivor pigs were plausible risk factors. Wire mesh-protected windows in pig houses were found to be protective against ASF infection. Sighting engorged ticks on pigs, the presence of a lock for each pig pen and/or a gate at the farm entrance were significantly associated with infection/non-infection; possible explanations were offered. Strict adherence to planned within-farm and community-based biosecurity, and avoidance of identified risk factors is recommended to reduce infection. Training for small-scale and emerging farmers should involve multidimensional and multidisciplinary approaches to reduce human-related risky behaviours driving infection.

Stern A, Bianco S, Yeh M T, Wright C, Butcher K, Tang C, Nielsen R, Andino R (2014)

Costs and benefits of mutational robustness in RNA viruses

Cell Reports 8 (4), 1026-1036
Publisher’s version: https://doi.org/10.1016/j.celrep.2014.07.011

Abstract

The accumulation of mutations in RNA viruses is thought to facilitate rapid adaptation to changes in the environment. However, most mutations have deleterious effects on fitness, especially for viruses. Thus, tolerance to mutations should determine the nature and extent of genetic diversity that can be maintained in the population. Here, we combine population genetics theory, computer simulation, and experimental evolution to examine the advantages and disadvantages of tolerance to mutations, also known as mutational robustness. We find that mutational robustness increases neutral diversity and, as expected, can facilitate adaptation to a new environment. Surprisingly, under certain conditions, robustness may also be an impediment for viral adaptation, if a highly diverse population contains a large proportion of previously neutral mutations that are deleterious in the new environment. These findings may inform therapeutic strategies that cause extinction of otherwise robust viral populations.

Kumar P, Sweeney T R, Skabkin M A, Skabkina O V, Hellen C U, Pestova T V (2014)

Inhibition of translation by IFIT family members is determined by their ability to interact selectively with the 5'-terminal regions of cap0-, cap1- and 5'ppp- mRNAs

Nucleic Acids Research 42 (5), 3228-3245
Publisher’s version: https://doi.org/10.1093/nar/gkt1321

Abstract

Ribosomal recruitment of cellular mRNAs depends on binding of eIF4F to the mRNA’s 5′-terminal ‘cap’. The minimal ‘cap0’ consists of N7-methylguanosine linked to the first nucleotide via a 5′-5′ triphosphate (ppp) bridge. Cap0 is further modified by 2′-O-methylation of the next two riboses, yielding ‘cap1’ (m7GpppNmN) and ‘cap2’ (m7GpppNmNm). However, some viral RNAs lack 2′-O-methylation, whereas others contain only ppp- at their 5′-end. Interferon-induced proteins with tetratricopeptide repeats (IFITs) are highly expressed effectors of innate immunity that inhibit viral replication by incompletely understood mechanisms. Here, we investigated the ability of IFIT family members to interact with cap1-, cap0- and 5′ppp- mRNAs and inhibit their translation. IFIT1 and IFIT1B showed very high affinity to cap-proximal regions of cap0-mRNAs (K1/2,app ∼9 to 23 nM). The 2′-O-methylation abrogated IFIT1/mRNA interaction, whereas IFIT1B retained the ability to bind cap1-mRNA, albeit with reduced affinity (K1/2,app ∼450 nM). The 5′-terminal regions of 5′ppp-mRNAs were recognized by IFIT5 (K1/2,app ∼400 nM). The activity of individual IFITs in inhibiting initiation on a specific mRNA was determined by their ability to interact with its 5′-terminal region: IFIT1 and IFIT1B efficiently outcompeted eIF4F and abrogated initiation on cap0-mRNAs, whereas inhibition on cap1- and 5′ppp- mRNAs by IFIT1B and IFIT5 was weaker and required higher protein concentrations.

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