NIHRDataInsights/HRCSData huggingface dataset:
Title: Analytical methodology to perform genome-wide association studies in bacteria
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Genome-wide association studies (GWAS) aim at discovering the genetic basis for a phenotypic trait of interest. GWAS have been hugely popular and successful in human genetics, but not yet so in bacterial genetics. This is because the GWAS methods used by human geneticists are not directly applicable to bacteria, due to important differences in recombination, population structure and genome plasticity. We propose to develop novel methodology specifically designed to perform GWAS in bacteria, which will account for these differences. The new method will compare a sample of genomes to determine the genetic elements and events that may be causing a phenotype of interest. The method will by applied to simulated datasets, in which the existence or not of causative links between genotypes and phenotypes is known exactly. These simulations will be used to guide the development of the method by providing a benchmark for the optimisation of the results. They will also reveal the strengths and weaknesses of the final method, under a variety of conditions. The methodology will be applied to two state-of-the-art datasets in Campylobacter jejuni and Escherichia coli, each of which consists of about a thousand genomes. These two applications should reveal interesting new mechanisms, for example about the adaptation of Campylobacter to different hosts or about the differences between environmental and clinical E. coli. These applications will also ensure that the method is generally applicable to the large genomic datasets that are increasingly becoming available. The methodology will be made available via the internet as a software package called BassoMapper which will be free and open source. BassoMapper will be developed so that it does not require bioinformatics or statistical expertise to be used. This will guarantee that the new methodology is available for microbiologists to apply it to a wide variety of systems


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFECTION
Title: A new framework to study the impact of antimicrobials on the within-host dynamics of bacterial infections.
Funder: Biotechnology and Biological Sciences Research Council

Abstract: We will exploit the tractability, relevance and broad applicability of the murine model of Salmonella infections to understand and quantify the effects of different antibiotics on the dynamics of growth, spread, persistence and relapse of bacterial infections, in vivo, in order to optimize and rationalise the treatment of infectious diseases. We will develop a novel framework based on a coherent multidisciplinary strategy that integrates experimental biology and mathematical modelling, with the support of pharmacokinetic-pharmacodynamic (PK/PD) testing and modelling. We will compare and contrast the effects of four antibiotics, each representative of a mode of action and belonging to different classes of commonly used drugs. We shall use: i) gentamicin which poorly penetrates phagocytes; ii) ciprofloxacin which efficiently penetrates inside cells; iii) ampicillin which acts only on replicating bacteria; iv) chloramphenicol which is bacteriostatic. We shall monitor the reciprocal impact of pathogen behaviour and antimicrobial treatment by high-resolution in vivo analysis of numerical and spatial fluctuations of molecularly tagged Salmonella subpopulations within infected tissues. The work will explore: a) the relationship between bacterial location, growth, death and spread in vivo and the action of antimicrobials; b) the effect of bactericidal vs bacteriostatic drugs on infection dynamics; c) the basis, in terms of host-pathogen infection dynamics, of the establishment of persistent infections post-antimicrobial treatment and subsequent relapse; d) the applicability of modelling frameworks to predict the effects of combined multidrug treatments and to select the most efficient combinations of drugs. The work will create translatable conceptual advances as well as mathematical and PK/PD models to rationally tailor drug development, choice and optimised treatment regimens to the biological features of infection processes.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: A nanoparticle diagnostic for the detection and discrimination of human and avian influenza virus
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Commision a report that will cover: 1. A market assessment, for influenza-directed rapid diagnostic technologies, including an analysis of critical factors in market penetration. 2. A comparative analysis of our ligands and detection system versus existing detection systems and, in as far as possible, other systems currently in development. 3. A review of sensor/detection technology platforms, to determine if the gold nanoparticle-based detection is the optimal system for rapid diagnostic readout using our bespoke ligands. 4. A list of companies active in the rapid diagnostics space, with technology platforms appropriate for the deployment of the flu ligands and/or nanoparticle conjugates. 5. Recommendations for appropriate routes to market, with an associated SWOT analysis. 6. A development plan, setting out critical goals and performance parameters that will have to be met to validate the technology and bring it to market.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Rescuing Antibiotics from Bacterial Resistance
Funder: Biotechnology and Biological Sciences Research Council

Abstract: 1. To collect experimental data to inform subsequent decisions on experimental and intellectual property strategies. 2. To identify the sub-set of antibiotics that elicits indole pulse signalling from their target bacteria. 3. To assess the effect of tryptophanase inhibitors on E. coli sensitivity to indole pulse-generating antibiotics in the presence of indole at low (persistent signalling) levels. 4. To collect preliminary data on selective inhibition of indole pulse signalling under conditions that allow persistent signalling to continue.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Pathogen-Host Interactions Database: PHI Database
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Food Security is one of the BBSRCs three nominated strategic research priorities. Global demand for food is rising because of population growth, increasing affluence and changing diets. In a typical cropping year in each field yield losses through infections caused by pathogenic microbes are rarely below 5% and are more typically around 10-15%. As the intensification of cereal and non-cereal crops increases globally, the losses to these important providers of global calories through biotic stresses is set to increase. In summary, the development of a suite of novel sustainable solutions to control pathogens must occur within the next 10 years to meet global food demands. _x000D__x000D_Available since 2005 at www.PHI-base.org, this database contains expertly curated molecular and biological information on pathogenicity, virulence and effector genes experimentally proven to affect the outcome of pathogen-host interactions. Information is also given on the target sites of some anti-infective chemistries. This phenomics resource currently contains highly curated information for 1065 genes, 1335 interactions and 97 pathogenic species. Included are fungal, oomycete and bacterial pathogens which infect animal, plant, fish or other hosts. Access to PHI-base is free and our most frequent users are based in the UK, Europe, USA, China and Australia. Use of curated data from PHI-base has been cited in 53 peer reviewed papers. _x000D__x000D_This National Capabilities project aims to keep the PHI-base database up-to-date, by ensuring that its content remains current and extensible. This involves database management, maintenance of the underlying infrastructure and user-interface, as well as the regular uploading of new contents. The backlog of relevant non-curated papers will be kept to a minimum by outsourcing this activity to a curation company which we have trained and by involving ~50 species experts in the community to nominate missing papers for curation then checking entries prior to upload.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: INFECTION
Title: The impact of host genetic variation on susceptibility and pathology
Funder: Biotechnology and Biological Sciences Research Council

Abstract: In this theme, we aim to pursue genetic variation underlying disease prevalence. By combining resistance data with genome mapping techniques we are able to define loci associated with resistance to a very wide range of infections in production animals. Genetic variation can impact upon every stage of infection from initial entry to the nature and resolution of pathology and subsequent memory responses. Each pathogen-host combination offers new challenges. Targets for study are prioritised on the basis of economic importance/impact and clear evidence of heritable resistance. The aim in each study is to link genotype to phenotype (e.g. variation in an innate immune response; difference in resistance to a pathogen) in a predictive manner. We will focus on (1) poultry infection by Salmonella and Campylobacter as sources of human infection. Some S. enterica serovars as well as avian pathogenic E. coli (APEC) also threaten poultry welfare and exert a substantial economic and welfare burden owing to their ability to migrate to systemic sites, causing fowl typhoid or colibacillosis respectively. (2) Mycobacterial infections of cattle and sheep.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Rational selection of targets for control of bacterial pathogens of food-producing animals
Funder: Biotechnology and Biological Sciences Research Council

Abstract: This project brings together scientists with expertise in diverse animal models and bacterial genetics to identify factors important for colonisation, host-specificity and pathogenesis. Although complete and partial genome sequences exist for the pathogens under study, the role of the encoded products in persistence, pathogenesis and protection needs to be evaluated. High-resolution comparative genomics and high-throughput in vivo and in vitro screens have identified bacterial determinants which are predicted to be important for these processes. We aim to determine how they function and examine their effect on innate and/or acquired responses in naïve or resistant hosts. The work will be integrated with studies on pathogen recognition (theme 1) and resistance (theme 2) and be exploited to develop and refine intervention strategies.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Mechanistic understanding of virus pathogenesis and resistance
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Endemic and exotic virus diseases pose a major threat to the livestock industry worldwide and in the case of potential zoonoses impinge on wider human welfare. Understanding mechanisms of virus pathogenesis in mammals and birds has major implications for identifying strategies that can translate to the clinic. We will i) exploit Roslin’s expertise in post genomic technologies to identify new viruses of veterinary importance, ii) map the viral genes associated with disruption of the innate immune response (PRRSV, influenza virus), iii) investigate the role of small non-coding RNA in beta- and gamma-herpesvirus infection and iv) explore the epidemiology and aetiology of newly discovered viruses.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: The influence of dual infections on viral load and disease severity
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Endemic and exotic virus diseases are threats to food security and, in some cases, potential zoonoses. Laboratory studies of virus pathogenesis rely on infection of “clean” animals. In nature, however, secondary infections or underlying persistent infections are likely to play a major role in determining the outcome of infection. Understanding how viruses and other pathogens interact within target species and disease transmitting vectors may lead to insights into prevention of virus transmission, infection or disease.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Novel strategies to control virus infection and disease
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Endemic and exotic virus diseases are threats to food security and, in some cases, potential zoonoses. We aim to develop novel strategies to control virus infection, focussing on improving animal welfare and reducing the disease burden in food production animals. The objectives include i) development of vaccines based around pox virus and herpesvirus delivery systems; ii) exploitation of transgenesis as a means of delivering resistance genes including antiviral peptides. Preliminary studies suggest that it is possible to prevent or reduce virus transmission, infection or disease by genetic modification of mammalian/avian hosts; iii) development of the concept of a bioshield involving constitutive expression of antiviral peptides expressed by probiotic bacteria colonisation of the GI tract.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;3.4 VACCINES
Health categories: INFECTION
Title: National Capability Grant - National Avian Research Facility
Funder: Biotechnology and Biological Sciences Research Council

Abstract: This facility provides underpinning funding the National Avian Research Facility (NARF), a joint venture of The Roslin Institute (RI) and The Pirbright Institute (PI). The facility forms a national resource centre for experimental science of poultry and model avian species. The NARF, based at RI will comprise new Specified-Pathogen-Free and conventional avian facilities. This facility will provide specialist resources for avian biology research, ranging from basic developmental biology to research of direct value to the poultry breeding and production industry, and of benefit to human health through reducing food-borne zoonoses. At RI, our vision is to develop a research resource centre that will maintain and provide access to inbred and transgenic lines, transgenic and germ cell preservation technologies alongside genetic/genomic and gene expression analytical resources. This centre will be not just a unique resource centre for the UK, but a unique and world- leading centre, because of the wide range of facilities we will bring together. These resources will be available to the relevant UK research communities and also for international collaborations. NARF will benefit from input from ARK Genomics, as a centre for genomics and transcriptomics of a wide range of bird species, including inbred chicken lines, commercial poultry species and breeds and other key avian species of research interest. It will also integrate provision of other resources, for example the Chicken Gene Expression Atlas that is being developed with BBSRC funding, currently specifically to support developmental biology research. There are two components of the facility for which this NCG provides funding for: (1) support for the Transgenic Chicken Facility (TCF), including opportunities to work with the TCF to generate novel transgenic chickens and for access to material from established transgenic lines and (2) the infrastructure to maintain 8 inbred lines of chickens (although the cost of maintaining these lines will come from PI ISP/NCG funds), each of a single MHC haplotype, for studying basic immunology, vaccinology and the genetic contribution to traits of economic importance, particularly those associated with resistance and susceptibility to disease. These two aspects will also coincide in providing opportunities for generating transgenic birds in the specific genotypes of the inbred lines.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: INFECTION
Title: Viral and host immunomodulators in improved fowlpox virus recombinant vector vaccine for use in poultry against highly pathogenic avian influenza H5N1
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Recombinant Fowlpox viruses (rFWPV) are playing an important role in China in attempts to control high pathogenicity avian influenza H5N1 virus in poultry. rFWPV expressing H5 were first employed in Mexico during the campaign to control high pathogenicity H5N2, with almost a billion doses used. New recombinants, derived in China to express H5 and N1 homologous for the current panzootic, are being used in a massive vaccination campaign (some 5 billion poultry). Although rFWPV are reported to be effective in controlling disease, it is not clear how effective they are at inducing cellular immunity and controlling spread. It is likely that spread will be most effectively controlled by induction of cellular as well as improved humoral/mucosal immunity. We intend to investigate methods of (a) improving induction of humoral/mucosal immunity and (b) driving cell-mediated responses after vaccination with rFWPV. Cell-mediated immunity will probably require expression of internal and non-structural proteins (nucleoprotein will not be included as its absence is important in differential diagnosis). Coexpression of host-derived cytokines by rFWPV has been shown to affect the humoral/cellular balance of the immune response, improving vaccine efficacy in certain cases. We therefore aim to generate a spectrum of responses for each arm of the immune system by coexpression of a variety of host cytokines (and one viral cytokine) so that we can optimise the desired response. Significant improvement in efficacy may alternatively be achieved by deletion of FWPV-encoded immunomodulators that bind host cytokines, without the safety concerns attracted by expression of host cytokines. We will therefore investigate the effect of deleting two such viral immunomodulators from the rFWPV vectors. The nature of the humoral and cellular immune responses induced by the various modified recombinants will be assayed in vivo, both before and after challenge with highly pathogenic H5N1.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Characterising chicken susceptibility/ resistance markers for avian Influenza virus
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The aim is to understand genetic factors in avian influenza isolates and avian species which alter the disease phenotype, transmission parameters and potential for zoonosis. Use will be made of reverse genetics to dissect the viral genetics and the inbred chicken lines maintained by IAH to understand the role host genetics plays.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Targeted inhibition of Rift Valley Fever Virus
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Rift valley fever virus (RVFV), Bunyaviridae, is a zoonotic arbovirus that causes disease in ruminants and humans. Protection is afforded by vaccination however; current vaccines induce complications in livestock. Together with the outbreak potential, the lack of prophylaxis makes RVFV a serious public health concern. Innovative ways to create safe vaccines are needed that will induce lifelong immunity in the animal host and be non-transmissible by arthropod vectors. An upcoming field in antiviral research involves microRNAs (miRNA) which may inhibit viral replication in vitro or restrict cellular tropism for a variety of viruses. Within efforts to generate genetically modified RVFV vaccines, miRNA targets that are conserved within Aedes mosquito cell lines will be chosen for targeted inhibition of RVFV. Selection criteria for miRNAs include high copy number in each cell line and insect specificity. Constructs containing selected miRNA targets will be cloned into the SVF4 genome to establish the knockdown efficacy of virus replication in different cell lines. miRNA targets showing greatest efficacy will be cloned into the NSs region of the S-segment of RVFV, allowing for the characterization of recombinant RVFV in various mosquito and vertebrate cell lines and define the host range of these viruses in live mosquitoes.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: IAH Fellowship: Using Reverse Genetics to Investigate the Basis of Virulence and Host Range Restriction of Rotavirus
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Rotaviruses are one genus in the Reoviridae family of segmented double stranded (ds) RNA viruses Worldwide, rotaviruses are the major cause of acute viral gastroenteritis in the young of a wide range of mammals including the economically important livestock animals and humans. The acute dehydrating diarrhoea and its associated morbidity is a major cause of economic loss to the agricultural industry in livestock animals including cattle and swine, through reduced productivity. The molecular investigation of rotavirus and many other members of the Reoviridae have been hampered for over 20 years by the lack of a reverse genetics system with which to introduce specific desired mutations into the viral genome. Recently we have developed a strategy and experimental protocols which addressed this road block for the related Orbivirus genus of midge-transmitted viruses. The strategy exploits a feature believed to be common to the replication cycle of all members of the Reoviridae; initiation of the replication cycle entirely by the mRNA transcripts synthesised by the infecting particle. The transfection of permissive cells with these mRNA transcripts initiates the replication cycle and the breakthrough offered by this approach is that when these transcripts are generated from cDNA clones the system can be manipulated to make any viable variant.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION