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Surrey, United Kingdom

Agency: GTR | Branch: BBSRC | Program: | Phase: Research Grant | Award Amount: 529.33K | Year: 2015

The Immuno Polymorphism Database (IPD) (https://www.ebi.ac.uk/ipd/) is a set of specialist databases that contain curated sequence datasets of polymorphic immune genes. Developed and maintained by the Anthony Nolan, these databases help save the lives of people with blood cancer by matching donors major histocompatibility complex (MHC; (also known as HLA in humans) to prevent rejection. One of these databases is IPD-MHC, a repository of non-human MHC genes that includes the major farmed animals species; cattle, sheep, pigs, trout and salmon. All these species exhibit high degrees of variation within their MHC genes. This diversity differentially influences how the adaptive and innate immune systems respond to pathogens and vaccines. Therefore a greater understanding of this diversity and the tools to analyse it offer a significant advance to our broad capability to examine immune function in these fundamental food producing species. Since the first release in 2003, IPD-MHC has become the central source of curated and annotated comparative MHC data and nomenclature globally. The website now receives nearly 250 visitors every day and over 500 sequences were submitted in 2013 from all over the world. However, this success has created problems. The database and website have never been specifically funded. IPD-MHC has existed as an in kind project that the research community and bioinformaticians at Antony Nolan have considered important enough to create and continue. The demands that the level of traffic has created mean that this model is no longer sustainable. Indeed, there is already a chronic lack of development and this data repository is in danger of becoming redundant. This proposal will support a dedicated IPD-MHC bioinformatician located at Anthony Nolan to work alongside the other IPD bioinformaticians. Their role will be to unify the individual species websites, incorporate the extensive chicken MHC data as a key farmed animal and create one streamlined data submission processes. Once this is in place, the capability of IPD-MHC will be significantly enhanced to accept a greater range of data and an expanded suite of analysis tools will be imbedded to allow advanced analysis for non-bioinformaticians. IPD-MHC still has overwhelming support from the research community, Anthony Nolan and the offer of free infrastructure from the European Bioinformatics Institute. This project is aimed at securing this central resource and expertise in the UK, to benefit this important UK research community and reach out to the rest of the world as part of the global food security agenda.

Agency: GTR | Branch: BBSRC | Program: | Phase: Intramural | Award Amount: 78.00K | Year: 2016

This research aims to define the viral attributes that influence novel H7N9 avian influenza virus to transmit from chickens to human and cause severe diseases and mortality in humans. This novel H7N9 virus contained internal gene cassette from H9N2 viruses enzootic in poultry. The proposed research will investigate: - how internal genes of H7N9 derived from H9N2 virus impact on virus virulence and transmission in avian and mammalian species; - what are the molecular signatures in the internal gene segments of H7N9 virus that make virus more virulent in humans; - what would be the potential consequences to poultry if H7N9 further reassort with currently prevalent novel H9N2 genotypes carrying internal genes of high pathogenicity H7N3 and H5N1 viruses; - what are the consequences on poultry for virus spill over from human to poultry (are the acquired adaptive genetic changes maintained?) These questions will be address by achieving following specific objectives: 1. To defining the influence of internal gene segments of H7N9 virus derived from H9N2 (Beijing-like lineage) on pathogenicity and transmission in avian and mammalian hosts. 2. To identify the molecular signatures that make H7N9 viruses more transmissible and virulent in humans 3. To examine the potential of H7N9 virus reasserting with contemporary circulating novel H9N2 genotypes containing internal genes of HPAI H7N3 and H5N1 viruses 4. To examine the susceptibility of birds to mammalian adapted H7N9

Agency: GTR | Branch: BBSRC | Program: | Phase: Research Grant | Award Amount: 414.56K | Year: 2016

Culicoides biting midges (Diptera: Ceratopogonidae) are currently the most important biological vectors of livestock arboviruses in Europe. Outbreaks of bluetongue virus (BTV) and Schmallenberg virus (SBV) continue to have a significant economic impact through clinical disease and the imposition of animal trade movement restrictions. At least three Culicoides-borne viruses recently identified in Europe possess an unknown origin, hence future outbreaks involving described or undescribed strains or species of Culicoides-borne viruses have a high potential of occurring in the future. These viruses could include further incursions of known arboviruses (including additional species of Culicoides-borne arboviruses such as African horse sickness or Epizootic Haemorhagic Disease Virus) or as yet undescribed species with an unknown pathogenicity to livestock or humans. In this project we will dissect Culicoides vector-arbovirus relationships across multiple ecosystems and species and in unprecedented detail to provide data useful for both defining risk of incursion and subsequent spread. Using newly developed methods to blood-feed Culicoides viruses of epidemiological interest, we will assess barriers associated with vector competence that may underlie restrictions to arbovirus movement in Europe. The fundamental genetic drivers determining vector competence in Culicoides will then be explored using genomic techniques to identify panels of candidate genes influencing this process. Following identification, comparative genomics will identify species specific differences in panels which will be examined across ecosystems in Northern and Southern Europe. In addition, we will also examine the virome of European Culicoides of veterinary importance as a potential influence on vector competence and as a means of understanding how viral diversity within populations can be used to infer risk of outbreak. Using metagenomic analyses we will examine viromes from Culicoides populations across the participating countries that have already been the subject of targeted sampling for surveillance purposes. We expect this to reveal for the first time the true diversity of viruses present within Culicoides and to begin to untangle their role in the epidemiology of pathogenic virus transmission, opening a new field of research for animal virus vectors.

Agency: GTR | Branch: BBSRC | Program: | Phase: Research Grant | Award Amount: 4.45M | Year: 2014

Swine influenza attracts considerable attention because of the threat of zoonotic infections causing human pandemics. During the pandemic, a fear that viruses emerging from pigs may infect people resulted in the widespread destruction of animals in some countries and trade bans. Consequently, the insidious effects of this highly prevalent virus on the health and welfare of pig populations, estimated to increase the cost of production by £7 per finished pig, have not been given due regard. The primary disease caused by influenza virus in usually mild, but results in greater susceptibility to secondary infections. Vaccination will be a key control measure for influenza in pigs to improve general herd health. Through our studies we will develop a more detailed understanding of the dynamics of virus transmission and the consequences of transmission and vaccination in driving viral evolution. During these studies we will also define a range of parameters, for example local and systemic immune responses and sites of virus replication, which are associated with the onset and cessation of transmission. We need to know if current and proposed novel vaccines not only prevent clinical signs but also stop viruses being transmitted unnoticed. Furthermore, if viruses can be transmitted unnoticed are they changing because of the immune response in the population? To answer these questions we need to understand virus transmission in detail and how the viruses change when they pass between animals. We can then apply this new knowledge to population wide models of disease spread to predict the efficiency of any proposed control measures. This knowledge will also inform the design of novel vaccines. Vaccination against influenza in pigs is not routinely performed in Europe mainly for two reasons: the cost benefit of vaccination has not been clearly demonstrated and it is not clear that the available vaccines will protect against the strains currently circulating in the pig populaion. The most striking example of the latter is that current vaccines do not include pandemic H1N1 influenza virus antigen. These studies will provide essential evidence to design control programmes for influenza in pigs, most notably: i) finding out how efficient are the current prophylactic methods at controlling the spread of infection; ii) what level of immunity is required in a population to prevent the spread of infection and the evolution of new strains of virus and iii) determine whether new, broadly cross protective vaccines are more effective at controlling influenza infections in swine to enhance animal health and livestock production. Importantly, this type of information is not available for any natural mammalian hosts of influenza viruses, including humans and horses. Therefore, the results of our studies will have a broad impact on influenza control measures.

Agency: GTR | Branch: BBSRC | Program: | Phase: Research Grant | Award Amount: 416.19K | Year: 2016

White blood cells are a key part of the bodys immune system to combat infections by viruses, bacteria and other pathogens. Our research is focused on a type of white blood cells called T cells. There are different types of T cells with distinct functional abilities, for example, killer T cells recognize and lyse cancer cells or infected cells, while suppressor T cells dampen immunity and suppress inflammatory responses. Many pathogens have learned to co-exist with the host by manipulating suppressor T cells to their advantage and thus they can escape immune control. We know very little about suppressor T cells in chicken, because we do not have specific and stable markers to identify these cells in chickens. A novel chicken suppressor T cell subpopulation has been recently identified, by our group, based on the expression of a suppressive molecule called TGF-beta. We have demonstrated that these cells may be involved in the pathogenesis of an economically important infectious disease called Mareks disease in chickens. Similar to humans, many animals including chickens develop cancer with the distinction that cancers in animals are mainly induced by viruses. Mareks disease (MD) is a common disease of chickens, causing transformation of the infected T cells and tumour growth in various tissues and eventually death. Our data show that cancer cells resemble the recently identified suppressor T cells and Marek disease infection increases the number of the suppressor T cells in the birds. We propose to determine whether the recently identified suppressor T cells are the precursor of cancer cells and if these cells are specifically targeted by the virus. We will also explore whether differences in molecular signature of the recently identified suppressor T cells can explain the susceptibility to MDV infection.

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