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.
Stevens L M, Moffat K, Cooke L, Nomikou K, Mertens P P C, Jackson T, Darpel K E (2019)

A low-passage insect-cell isolate of bluetongue virus uses a macropinocytosis-like entry pathway to infect natural target cells derived from the bovine host

Journal of General Virology 100 (4), 568-582

Abstract

Bluetongue virus (BTV) causes an economically important disease in domestic and wildlife ruminants and is transmitted by Culicoides biting midges. In ruminants, BTV has a wide cell tropism that includes endothelial cells of vascular and lymphatic vessels as important cell targets for virus replication, and several cell types of the immune system including monocytes, macrophages and dendritic cells. Thus, cell-entry represents a particular challenge for BTV as it infects many different cell types in widely diverse vertebrate and invertebrate hosts. Improved understanding of BTV cell-entry could lead to novel antiviral approaches that can block virus transmission from cell to cell between its invertebrate and vertebrate hosts. Here, we have investigated BTV cell-entry using endothelial cells derived from the natural bovine host (BFA cells) and purified whole virus particles of a low-passage, insect-cell isolate of a virulent strain of BTV-1. Our results show that the main entry pathway for infection of BFA cells is dependent on actin and dynamin, and shares certain characteristics with macropinocytosis. The ability to use a macropinocytosis-like entry route could explain the diverse cell tropism of BTV and contribute to the efficiency of transmission between vertebrate and invertebrate hosts.

Thakur N, Bailey D (2019)

Advances in diagnostics, vaccines and therapeutics for Nipah virus

Microbes and Infection early view,

Abstract

Nipah virus is an emerging zoonotic paramyxovirus that causes severe and often fatal respiratory and neurological disease in humans. The virus was first discovered after an outbreak of encephalitis in pig farmers in Malaysia and Singapore with subsequent outbreaks in Bangladesh or India occurring almost annually. Due to the highly pathogenic nature of NiV, its pandemic potential, and the lack of licensed vaccines or therapeutics, there is a requirement for research and development into highly sensitive and specific diagnostic tools as well as antivirals and vaccines to help prevent and control future outbreak situations.

Tennant R K, Holzer B, Love J, Tchilian E, White H N (2019)

Higher levels of B-cell mutation in the early germinal centres of an inefficient secondary antibody response to a variant Influenza Haemagglutinin

Immunology early view,
Publisher’s version: https://doi.org/10.1111/imm.13052

Abstract

Designing improved vaccines against mutable viruses such as Dengue and Influenza would be helped by a better understanding of how the B-cell memory compartment responds to variant antigens. Towards this we have recently shown after secondary immunization of mice with a widely variant Dengue envelope protein, with only 63% amino-acid identity, that IgM+ memory B-cells with few mutations supported an efficient secondary germinal centre (GC) and serum response, superior to a primary response to the same protein. Here, further investigation of memory responses to variant proteins, using more closely related Influenza haemagglutinins (HA), that were 82% identical, produced a variant-induced boost response in the GC dominated by highly mutated B-cells that failed, not efficiently improving serum avidity even in the presence of extra adjuvant, and that was worse than a primary response. This supports a hypothesis that over certain antigenic differences, cross-reactive memory B-cell populations have reduced competency for affinity maturation. Combined with our previous observations these findings also provide new parameters of success and failure in antibody memory responses.

Naguib M M, Verhagen J H, Samy A, Eriksson P, Fife M, Lundkvist Å, Ellström P, Järhult J D (2019)

Avian influenza viruses at the wild-domestic bird interface in Egypt

Infection Ecology and Epidemiology 9 (1), 1575687

Abstract

Wild birds of the orders Anseriformes (mainly ducks, geese and swans) and Charadriiformes (mainly gulls, terns and waders) constitute the natural reservoir for low pathogenic avian influenza (LPAI) viruses. In Egypt, highly pathogenic avian influenza (HPAI) H5N1 and LPAI H9N2 viruses are endemic in domestic poultry, forming a threat to animal and human health and raising questions about the routes of introduction and mechanisms of persistence. Recently, HPAI H5N8 virus was also introduced into Egyptian domestic birds. Here we review the literature on the role of wild birds in the introduction and endemicity of avian influenza viruses in Egypt. Dabbling ducks in Egypt harbor an extensive LPAI virus diversity and may constitute the route of introduction for HPAI H5N1 and HPAI H5N8 viruses into Egypt through migration, however their role in the endemicity of HPAI H5N1, LPAI H9N2 and potentially other avian influenza virus (AIV) strains – by means of reassortment of viral genes – is less clear. Strengthened surveillance programs, in both domestic and wild birds, that include all LPAI virus subtypes and full genome sequencing are needed to better assess the wild–domestic bird interface and form a basis for evidence-based measures to limit and prevent AIV transmission between wild and domestic birds.

Armson B, Wadsworth J, Kibona T, Mshanga D, Fowler V L, Knowles N J, Mioulet V, Reeve R, King D P, Bachanek-Bankowska K, Lembo T (2019)

Opportunities for enhanced surveillance of foot-and-mouth disease in endemic settings using milk samples

Transboundary and Emerging Diseases early view,
Publisher’s version: https://doi.org/10.1111/tbed.13146

Abstract

Under-reporting of foot-and-mouth disease (FMD) masks the true prevalence in parts of the world where the disease is endemic. Laboratory testing for the detection of FMD virus (FMDV) is usually reliant upon the collection of vesicular epithelium and fluid samples that can only be collected from acutely infected animals, and therefore animals with sub-clinical infection may not be identified. Milk is a non-invasive sample type routinely collected from dairy farms that has been utilised for surveillance of a number of other diseases. The aim of this study was to examine the application of milk as an alternative sample type for FMDV detection and typing, and to evaluate milk as a novel approach for targeted surveillance of FMD in East Africa. FMDV RNA was detected in 73/190 (38%) individual milk samples collected from naturally infected cattle in northern Tanzania. Further, typing information by lineage-specific rRT-PCR assays was obtained for 58% of positive samples, and corresponded with the virus types identified during outbreak investigations in the study area. The VP1-coding sequence data obtained from milk samples corresponded with the sequence data generated from paired epithelial samples collected from the same animal. This study demonstrates that milk represents a potentially valuable sample type for FMDV surveillance and might be used to overcome some of the existing biases of traditional surveillance methods. However, it is recommended that care is taken during sample collection and testing to minimise the likelihood of cross-contamination. Such approaches could strengthen FMDV surveillance capabilities in East Africa, both at the individual animal and herd level.

McLean R K, Graham S (2019)

Vaccine development for Nipah virus infection in pigs

Frontiers in Veterinary Science 6, 16

Abstract

Nipah virus (NiV) causes a severe and often fatal neurological disease in humans. Whilst fruit bats are considered the natural reservoir, NiV also infects pigs and may cause an unapparent or mild disease. Direct pig-to-human transmission was responsible for the first and still most devastating NiV outbreaks in Malaysia and Singapore in 1998-99, with nearly 300 human cases and over 100 fatalities. Pigs can therefore play a key role in the epidemiology of NiV by acting as an ‘amplifying’ host. The outbreak in Singapore ended with the prohibition of pig imports from Malaysia and the Malaysian outbreak was ended by culling 45% of the country’s pig population with costs exceeding US$500 million. Despite the importance of NiV as an emerging disease with the potential for pandemic, no vaccines or therapeutics are currently approved for human or livestock use. In this mini-review, we will discuss current knowledge of NiV infection in pigs; our ongoing work to develop a NiV vaccine for use in pigs; and the pig as a model to support human vaccine development.

Holzer B, Martini V, Edmans M, Tchilian E (2019)

T and B cell immune responses to influenza viruses in pigs

Frontiers in Immunology 10, 98

Abstract

Influenza viruses are an ongoing threat to humans and are endemic in pigs, causing considerable economic losses to farmers. Pigs are also a source of new viruses potentially capable of initiating human pandemics. Many tools including monoclonal antibodies, recombinant cytokines and chemokines, gene probes, tetramers and inbred pigs allow refined analysis of immune responses against influenza. Recent advances in understanding of the pig innate system indicate that it shares many features with that in humans, although there is a larger gamma delta component. The fine specificity and mechanisms of cross-protective T cell immunity have yet to be fully defined, although it is clear that the local immune response is important. The repertoire of pig antibody response to influenza has not been thoroughly explored. Here we review current understanding of innate and adaptive immune responses against influenza in pigs and the use of the pig as a model to study human disease.

Siddell S G, Walker P J, Lefkowitz E J, Mushegian A R, Adams M J, Dutilh B E, Gorbalenya A E, Harrach B, Harrison R L, Junglen S, Knowles N J, Kropinski A M, Krupovic M, Kuhn J H, Nibert M, Rubino L, Sabanadzovic S, Sanfaçon H, Simmonds P, Varsani A, Zerbini F M, Davison A J (2019)

Additional changes to taxonomy ratified in a special vote by the International Committee on Taxonomy of Viruses (October 2018)

Archives of Virology early view,

Abstract

This article reports the changes to virus taxonomy approved and ratified by the International Committee on Taxonomy of Viruses (ICTV) in October 2018. Of note, the ICTV has approved, by an absolute majority, the creation of additional taxonomical ranks above those recognized previously. A total of 15 ranks (realm, subrealm, kingdom, subkingdom, phylum, subphylum, class, subclass, order, suborder, family, subfamily, genus, subgenus, and species) are now available to encompass the entire spectrum of virus diversity. Classification at ranks above genus is not obligatory but can be used by the authors of new taxonomic proposals when scientific justification is provided.

Lyons N A, Knight-Jones T J D, Bartels C, Paton D J, Ferrari G, Vermillion M S, Brooks A W, Motroni R, Parker E, Hefferin Berquist M L, Sumption K J, Klement E (2019)

Considerations for design and implementation of vaccine field trials for novel foot-and-mouth disease vaccines

Vaccine early view,

Abstract

Vaccines are commonly used to control Foot-and-Mouth Disease (FMD) in endemic regions and form an important part of contingency plans for FMD-free countries. Conventional FMD vaccines have numerous limitations, and the U.S. government supports the development of next-generation vaccines. In the U.S., vaccine efficacy is typically demonstrated through experimental vaccination and challenge of animals using the World Organization for Animal Health (OIE) standards. Although conventional challenge and immunogenicity studies provide useful information, they have limitations and results do not always accurately predict field performance. Consequently, there is a need to test next-generation vaccines under field conditions to gain a better understanding of field performance to inform policy decisions and support their viability as a commercial product. In June 2017, an expert consultation was organised to discuss and define an optimal field study design for novel FMD vaccines. Cattle were the primary species considered, although parallel strategies for swine and small ruminants were also discussed. Many methodological and logistical considerations in the study design were identified, including: (1) study site selection and the importance of baseline studies to understand exposure risk, (2) ethics of using a placebo and assessing equivalence with conventional vaccines, (3) merits of using individual randomised versus cluster randomised trials, (4) preventive versus reactive vaccination, and (5) methods of randomisation and blinding. The proposed optimal study design was a multicentre (i.e. farm), three-arm, double-blind randomised controlled trial comparing groups receiving the novel vaccine to a conventional vaccine group and a placebo group. Large farms in areas of high exposure risk were identified as ideal study sites, and the primary study outcome was susceptibility to disease or infection, during a six-month observation period, following a single dose of vaccine. This report provides a summary of the important issues to consider when designing a field efficacy study in livestock and proposes a study design that could be utilised for novel FMD vaccines.

James J, Smith N, Ross C S, Iqbal M, Goodbourn S E, Digard P, Barclay W S, Shelton H (2019)

The cellular localisation of avian influenza virus PB1-F2 protein alters the magnitude of IFN2 promoter and NFκB-dependent promoter antagonism in chicken cells

Journal of General Virology early view,

Abstract

The accessory protein, PB1-F2, of influenza A virus (IAV) functions in a chicken host to prolong infectious virus shedding and thus the transmission window. Here we show that this delay in virus clearance by PB1-F2 in chickens is accompanied by reduced transcript levels of type 1 interferon (IFN)-induced genes and NFκB-activated pro-inflammation cytokines. In vitro, two avian influenza isolate-derived PB1-F2 proteins, H9N2 UDL01 and H5N1 5092, exhibited the same antagonism of the IFN and pro-inflammation induction pathways seen in vivo, but to different extents. The two PB1-F2 proteins had different cellular localization in chicken cells, with H5N1 5092 being predominantly mitochondrial-associated and H9N2 UDL being cytoplasmic but not mitochondrial-localized. We hypothesized that PB1-F2 localization might influence the functionality of the protein during infection and that the protein sequence could alter cellular localization. We demonstrated that the sequence of the C-terminus of PB1-F2 determined cytoplasmic localization in chicken cells and this was linked with protein instability. Mitochondrial localization of PB1-F2 resulted in reduced antagonism of an NFκB-dependent promoter. In parallel, mitochondrial localization of PB1-F2 increased the potency of chicken IFN 2 induction antagonism. We suggest that mitochondrial localization of PB1-F2 restricts interaction with cytoplasmic-located IKKβ, reducing NFκB-responsive promoter antagonism, but enhances antagonism of the IFN2 promoter through interaction with the mitochondrial adaptor MAVS. Our study highlights the differential mechanisms by which IAV PB1-F2 protein can dampen the avian host innate signalling response.

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