Publications

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

There were a total of 1875 results for your search.
Zhang Y, Luo J, Tang N, Teng M, Reddy V, Moffat K, Shen Z, Nair V, Yao Y (2019)

Targeted editing of the pp38 gene in Marek's disease virus-transformed cell lines using CRISPR/Cas9 system

Viruses 11 (5), 391
Publisher’s version: https://doi.org/10.3390/v11050391

Abstract

Marek's disease virus (MDV), a lymphotropic alpha-herpesvirus associated with T-cell lymphomas in chickens, is an excellent model for herpesvirus biology and virus-induced oncogenesis. Marek's disease (MD) is also one of the cancers against which a vaccine was first used. In the lymphomas and lymphoblastoid cell lines (LCLs) derived from them, MDV establishes latent infection with limited gene expression. Although LCLs are valuable for interrogating viral and host gene functions, molecular determinants associated with the maintenance of MDV latency and lytic switch remain largely unknown, mainly due to the lack of tools for in situ manipulation of the genomes in these cell lines. Here we describe the first application of CRISPR/Cas9 editing approach for precise editing of the viral gene phosphoprotein 38 (pp38), a biomarker for latent/lytic switch in MDV-transformed LCLs MDCC-MSB-1 (Marek's disease cell line MSB-1) and MDCC-HP8. Contradictory to the previous reports suggesting that pp38 is involved in the maintenance of transformation of LCL MSB-1 cells, we show that pp38-deleted cells proliferated at a significant higher rate, suggesting that pp38 is dispensable for the transformed state of these cell lines. Application of CRISPR/Cas9-based gene editing of MDV-transformed cell lines in situ opens up further opportunities towards a better understanding of MDV pathogenesis and virus-host interactions.

Netherton C L, Connell S, Benfield C T O, Dixon L K (2019)

The genetics of life and death: virus-host interactions underpinning resistance to African swine fever, a viral haemorrhagic disease

Frontiers in Genetics 10, 402

Abstract

Pathogen transmission from wildlife hosts to genetically distinct species is a major driver of disease emergence. African swine fever virus (ASFV) persists in sub-Saharan Africa through a sylvatic cycle between warthogs and soft ticks that infest their burrows. The virus does not cause disease in these animals, however transmission of the virus to domestic pigs or wild boar causes a hemorrhagic fever that is invariably fatal. ASFV transmits readily between domestic pigs and causes economic hardship in areas where it is endemic. The virus is also a significant transboundary pathogen that has become established in Eastern Europe, and has recently appeared in China increasing the risk of an introduction of the disease to other pig producing centers. Although a DNA genome mitigates against rapid adaptation of the virus to new hosts, extended epidemics of African swine fever (ASF) can lead to the emergence of viruses with reduced virulence. Attenuation in the field leads to large deletions of genetic material encoding genes involved in modulating host immune responses. Therefore resistance to disease and tolerance of ASFV replication can be dependent on both virus and host factors. Here we describe the different virus-host interfaces and discuss progress toward understanding the genetic determinants of disease outcome after infection with ASFV.

Mahapatra M, Upadhyaya S, Parida S (2019)

Identification of novel epitopes in serotype O foot-and-mouth disease virus by in vitro immune selection

Journal of General Virology 100 (5), 804-811

Abstract

Foot-and-mouth disease virus (FMDV) displays various epitopes on the capsid outer surface. In addition to the five neutralizing antigenic sites, there is evidence of the existence of other, yet unidentified, epitopes that are believed to play a role in antibody-mediated protection. Previous attempts to identify these epitopes revealed two additional substitutions at positions VP2-74 and -191 (5M2/5 virus) to be of antigenic significance. However, complete resistance to neutralization was not obtained in the neutralization assay, indicating the existence of other, undisclosed epitopes. Results from this study provides evidence of at least two new neutralizing epitopes involving residues VP3-116 and -195 around the threefold axis that have significant impact on the antigenic nature of the virus. These findings extend our knowledge of the surface features of the FMDV capsid known to elicit neutralizing antibodies, and should help with rational vaccine design.

Gubbins S (2019)

Using the basic reproduction number to assess the risk of transmission of lumpy skin disease virus by biting insects

Transboundary and Emerging Diseases early view,
Publisher’s version: https://doi.org/10.1111/tbed.13216

Abstract

In recent years, lumpy skin disease virus (LSDV) has emerged as a major threat to cattle outside Africa, where it is endemic. Although evidence suggests that LSDV is transmitted by the bites of blood sucking arthropods, few studies have assessed the risk of transmission posed by particular vector species. Here this risk is assessed by calculating the basic reproduction number (R0) for transmission of LSDV by five species of biting insect: the stable fly, Stomoxys calcitrans, the biting midge, Culicoides nubeculosus, and three mosquito species, Aedes aegypti, Anopheles stephensi and Culex quinquefasciatus. Parameters relating to mechanical transmission of LSDV were estimated using new analyses of previously-published data from transmission experiments, while vector life history parameters were derived from the published literature. Uncertainty and sensitivity analyses were used to compute R0 for each species and to identify those parameters which influence its magnitude. Results suggest that S. calcitrans is likely to be the most efficient at transmitting LSDV, with Ae. aegypti also an efficient vector. By contrast, C. nubeculosus, An. stephensi, and Cx. quinquefasciatus are likely to be inefficient vectors of LSDV. However, there is considerable uncertainty associated with the estimates of R0, reflecting uncertainty in most of the constituent parameters. Sensitivity analysis suggests that future experimental work should focus on estimating the probability of transmission from insect to bovine and on the virus inactivation rate in insects.

Dixon L K, Islam M, Nash R, Reis A L (2019)

African swine fever virus evasion of host defences

Virus Research 266, 25-33

Abstract

African swine fever virus causes a haemorrhagic fever in domestic pigs and wild boar. The continuing spread in Africa, Europe and Asia threatens the global pig industry. The lack of a vaccine limits disease control. To underpin rational strategies for vaccine development improved knowledge is needed of how the virus interacts with and modulates the host’s responses to infection. The virus long double-stranded DNA genome codes for more than 160 proteins of which many are non-essential for replication in cells but can have important roles in evading the host’s defences. Here we review knowledge of the pathways targeted by ASFV and the mechanisms by which these are inhibited. The impact of deleting single or multiple ASFV genes on virus replication in cells and infection in pigs is summarised providing information on strategies for rational development of modified live vaccines.

Dascalu S (2019)

Measles epidemics in Romania: lessons for public health and future policy

Frontiers in Public Health 7,

Abstract

Measles is a highly infectious viral disease that continues to be a challenge for many countries worldwide. Although significant improvements have been observed since the introduction of vaccines, measles remains endemic in Romania. Contributing factors include vaccine hesitancy, difficulties in delivering doses to the population, and even the lack of sufficient vaccine supplies. These problems are further exacerbated by an inadequate implementation of public health measures, ranging from inefficient communication programs to the absence of a legislative framework concerning immunization. Moreover, many of the recent outbreaks were associated with chains of transmission in other countries, thus making the control of measles in Romania relevant at an international level. As many difficulties exist, understanding the key factors that limit the success of public health programs may provide guidance in shaping future strategies. Because similar issues are being faced in various other countries, the management of measles in Romania offers valuable lessons for researchers and policy-makers alike.

Bassano I, Ong S H, Sanz-Hernandez M, Vinkler M, Kebede A, Hanotte O, Onuigbo E, Fife M, Kellam P (2019)

Comparative analysis of the chicken IFITM locus by targeted genome sequencing reveals evolution of the locus and positive selection in IFITM1 and IFITM3

BMC Genomics 20, 272

Abstract

The interferon-induced transmembrane (IFITM) protein family comprises a class of restriction factors widely characterised in humans for their potent antiviral activity. Their biological activity is well documented in several animal species, but their genetic variation and biological mechanism is less well understood, particularly in avian species. Here we report the complete sequence of the domestic chicken Gallus gallus IFITM locus from a wide variety of chicken breeds to examine the detailed pattern of genetic variation of the locus on chromosome 5, including the flanking genes ATHL1 and B4GALNT4. We have generated chIFITM sequences from commercial breeds (supermarket-derived chicken breasts), indigenous chickens from Nigeria (Nsukka) and Ethiopia, European breeds and inbred chicken lines from the Pirbright Institute, totalling of 206 chickens. Through mapping of genetic variants to the latest chIFITM consensus sequence our data reveal that the chIFITM locus does not show structural variation in the locus across the populations analysed, despite spanning diverse breeds from different geographic locations. However, single nucleotide variants (SNVs) in functionally important regions of the proteins within certain groups of chickens were detected, in particular the European breeds and indigenous birds from Ethiopia and Nigeria. In addition, we also found that two out of four SNVs located in the chIFITM1 (Ser36 and Arg77) and chIFITM3 (Val103) proteins were simultaneously under positive selection. Together these data suggest that IFITM genetic variation may contribute to the capacities of different chicken populations to resist virus infection.

Lee H J, Park K J, Lee K Y, Yao Y, Nair V, Han J Y (2019)

Sequential disruption of ALV host receptor genes reveals no sharing of receptors between ALV subgroups A, B, and J

Journal of Animal Science and Biotechnology 10 (1), 23

Abstract

Previously, we showed that targeted disruption of viral receptor genes in avian leukosis virus (ALV) subgroups using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9))-based genome editing confers resistance to ALV subgroups B and J. Here, we used the same strategy to target the receptor expressed by ALV subgroup A (TVA) and generate chicken cells resistant to infection by this virus.

Lycett S, Tanya V N, Hall M, King D P, Mazeri S, Mioulet V, Knowles N J, Wadsworth J, Bachanek-Bankowska K, Ngu Ngwa V, Morgan K L, Bronsvoort B M C (2019)

The evolution and phylodynamics of serotype A and SAT2 foot-and-mouth disease viruses in endemic regions of Africa

Scientific Reports 9, 5614

Abstract

Foot-and-mouth disease (FMD) is a major livestock disease with direct clinical impacts as well as indirect trade implications. Control through vaccination and stamping-out has successfully reduced or eradicated the disease from Europe and large parts of South America. However, sub-Saharan Africa remains endemically affected with 5/7 serotypes currently known to be circulating across the continent. This has significant implications both locally for livestock production and poverty reduction but also globally as it represents a major reservoir of viruses, which could spark new epidemics in disease free countries or vaccination zones. This paper describes the phylodynamics of serotypes A and SAT2 in Africa including recent isolates from Cameroon in Central Africa. We estimated the most recent common ancestor for serotype A was an East African virus from the 1930s (median 1937; HPD 1922-1950) compared to SAT2 which has a much older common ancestor from the early 1700s (median 1709; HPD 1502-1814). Detailed analysis of the different clades shows clearly that different clades are evolving and diffusing across the landscape at different rates with both serotypes having a particularly recent clade that is evolving and spreading more rapidly than other clades within their serotype. However, the lack of detailed sequence data available for Africa seriously limits our understanding of FMD epidemiology across the continent. A comprehensive view of the evolutionary history and dynamics of FMD viruses is essential to understand many basic epidemiological aspects of FMD in Africa such as the scale of persistence and the role of wildlife and thus the opportunities and scale at which vaccination and other controls could be applied. Finally we ask endemic countries to join the OIE/FAO supported regional networks and take advantage of new cheap technologies being rolled out to collect isolates and submit them to the World Reference Laboratory.

Everett H E, Aramouni M, Coward V, Ramsay A, Kelly M, Morgan S, Tchilian E, Canini L, Woolhouse M E J, Gilbert S, Charleston B, Brown I H, Brookes S M (2019)

Vaccine-mediated protection of pigs against infection with pandemic H1N1 2009 swine influenza A virus requires a close antigenic match between the vaccine antigen and challenge virus

Vaccine 37 (17), 2288-2293

Abstract

Swine influenza A virus (SwIV) infection has considerable economic and animal welfare consequences and, because of the zoonotic potential, can also have public health implications. The 2009 pandemic H1N1 ‘swine-origin’ infection is now endemic in both pigs and humans. In Europe, avian-like H1avN1, human-like H1huN2, human-like swine H3N2 and, since 2009, pandemic H1N1 (pH1N1) lineage viruses and reassortants, constitute the dominant subtypes. In this study, we used a swine pH1N1 challenge virus to investigate the efficacy of whole inactivated virus vaccines homologous or heterologous to the challenge virus as well as a commercial vaccine. We found that vaccine-mediated protection was most effective when vaccine antigen and challenge virus were homologous and correlated with the specific production of neutralising antibodies and a cellular response to the challenge virus. We conclude that a conventional whole inactivated SwIV vaccine must be antigenically matched to the challenge strain to be an effective control measure.

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