NIHRDataInsights/HRCSData huggingface dataset:
Title: Development of recombinant BCG vaccine and complementary diagnostics for TB control in cattle.
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Control of TB in the UK is by detection of infected animals with the tuberculin skin test and culling. This is unacceptable in India. It is currently not possible to use BCG vaccine to control bovine tuberculosis because of cross-reactivity with the tuberculin test that is used to diagnose TB in cattle. This is because BCG is an attenuated strain of Mycobacterium bovis, and tuberculin is also prepared from M. bovis. IGRA-based diagnostic tests have developed for detection of TB that utilizes antigens deleted in BCG but these are not sensitive enough for bovine TB diagnosis. The key insight behind this proposal is that DIVA-based diagnostic tests and BCG-based vaccines need not be limited by the genotype of BCG strain. The first aim of this project will therefore be to develop a dcBCG deleted in additional immunodominant antigens. This will be accomplished by Tn-seq studies of persistence of BCG in cattle to identify genes that are dispensable for persistence and thereby vaccine efficacy. The deletion of BCG antigens will also be informed by proteomics analysis of tuberculin and extensive studies of immunogenicity of M. bovis antigens performed by AHVLA. We will then delete the dispensable genes from the BCG genome to generate a dcBCG strain. In parallel, we will develop an extended DIVA skin test (exDIVA) based on the current optimal set of DIVA antigens but supplemented with additional antigens deleted from dcBCG. The combination of dcBCG plus exDIVA will provide an effective vaccine for bovine tuberculosis together with a complementary cheap and effective diagnostic skin test that will be appropriate for developed countries such as the UK but particularly for developing countries such as India that are unable to implement a detection and cull control strategy. Application of this novel approach has the potential to revolutionize control of bovine TB across the world.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;3.4 VACCINES
Health categories: INFECTION
Title: Identification of the molecular basis of differential host responses to rapidly evolving Avian Influenza viruses in different avian species
Funder: Biotechnology and Biological Sciences Research Council

Abstract: We will use an integrated approach that combines virology, genomics and bioinformatics to investigate the molecular nature of differences in viral resistance between avian species and the pathogenicity of viral clades. The overall strategy is to compare groups of birds that differ in their resistance/susceptibility to clades of avian influenza viruses. Two experimental comparisons will be made. The first will compare host responses between chickens/turkeys (susceptible) vs. ducks/geese/crows/pigeons (resistant) against HPAI (H5N1 clade 2.2). Controls will be mock and LPAI (H9N2) infections. The second experiment will compare host responses between ducks/crows (susceptible) vs. geese/pigeons (resistant) against HPAI (H5N1 clade 2.3.2.1). Controls will be mock, LPAI (H9N2) and HPAI (H5N1 clade 2.2). The differential patterns of gene expression detected in these comparisons will be further investigated by network analyses to define gene expression modules. These in turn will be classified for enrichment for gene classes, gene ontology terms, KEGG pathways, etc. Dysregulation of genetic regulatory networks will be analysed from a joint analysis of the expression of gene regulators (transcription factors, cofactors, and miRNAs) and predicted targets. Using coding sequences predicted from the sequences of 48 avian genomes we will examine the rates of evolution of these genes and associate any differences between species using branch and branch-site models of evolutionary change (PAML). From a meta-analysis of results combined with other studies on avian influenza virus (RNAi, yeast2hhybrids, etc.) we will define host genes (and viral mutations in different clades) that are likely to play a role in host resistance. The expression of these genes will be confirmed by qPCR, in situ hybridisation and immunocytochemistry. The role of these genes will tested further in over-expression and knockdown studies in experimental avian cells.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Molecular epidemiology of ticks and tick-borne disease, host resistance and development of novel pathogen vaccines
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Tick-borne diseases (TBD) affect 80% of the world's cattle population, and are a significant threat to global food security. Tropical theileriosis caused by Theileria annulata is an important tick borne disease of cattle and buffalo in India, with estimated losses of $499 million per annum). Cattle and buffalo are also infected with Babesia, and the rickettsia, Anaplasma and Erlichia. Current control of TBD in India is via a combination of acaracides, anti-parasite drugs, vaccination with parasites attenuated for virulence and cross breeding for natural resistance. All these strategies have limitations such as resistance of ticks to acarcides and pathogens to drugs, delivery and production problems for vaccines and a loss of productivity in breeds resistant to disease. Moreover, animals carrying T. annulata have been associated with > 50% of production loss. Thus, new methods of control are needed if food security is to be increased, the ultimate goal being a disease free situation and full potential productivity. The proposed project will have three related aims/objectives: 1) undertake an extensive molecular epidemiological analysis of tick borne disease and model the impact of different control strategies; 2) using a systems based biology approach, investigate the nature of within and between breed resistance to infection with T. annulata and 3) investigate the impact of antigenic diversity on antigens that are candidates for a transmission blocking vaccine against tropical theileriosis in order to develop a strategy that counters the ability of the parasite to evade an immune response. All three objectives are designed to develop and improve of strategies to control TBD and reduce economic loss, in India. Such strategies will also be value to the UK since significant levels of disease in livestock in the UK are caused by tick borne pathogens: Anaplasma, Staphlycocci, B. divergens and the louping ill virus.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;3.4 VACCINES
Health categories: INFECTION
Title: Controlling enteric pathogens of poultry: Host/microbiota interactions, risk assessment and effective management interventions
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Our overarching hypothesis is that QTL controlling resistance to micro-organisms of veterinary and zoonotic importance are segregating in native Indian and modern commercial chickens. Further, we hypothesise that the composition of the commensal enteric microbiota, and thus its influence on colonisation by a panel of pathogenic micro-organisms, is also underpinned by host QTL. Finally, we hypothesise that the impact of management strategy on this dynamic system is also shaped by QTL. We will perform whole genome association (WGA) for traits including resistance to enteric colonisation by a panel of pathogens with veterinary and zoonotic relevance, as well as variation in microbiome composition, as defined by metagenomic next-generation sequencing and qPCR of the caecal microbiota. These data will also be used to investigate genetic diversity among the targeted micro-organisms, supplemented by whole genome shotgun sequencing of up to 40 cultured field isolates, informing on the occurrence of antimicrobial resistance and virulence factors. These data will support molecular epidemiological characterisation of microbial flow and development of existing mathematical models of pathogen interactions and spread within farmed chickens. Ultimately these interlinked data will be integrated into a probabilistic risk assessment of poultry management to identify optimal parameters for production using local and global commercial chicken lines. The overall aim is to identify markers (SNPs), candidate genes and eventually causative mutations for resistance/susceptibility to colonisation by specific micro-organisms The resistance-associated genotypes will inform commercial breeding programmes to reduce risk to the secure supply of safe animal protein and improve animal welfare. In a broader context these studies will develop a series of recommendations for effective and safe poultry production utilising native Indian breeds and regional production strategies.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Combined use of novel diagnostic tools and strategic vaccination to control bovine brucellosis in endemic areas
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Brucellosis imposes a vast burden on livelihoods as a result of human disease and impaired livestock productivity. Studies carried out by Guru Angad Dev Veterinary and Animal Sciences University have found seroprevalences of human brucellosis higher than 20% in selected populations in Punjab and show the need for integrated control of the disease. Control of ruminant brucellosis has been achieved with different degrees of success by applying a range of diagnostic and prophylactic tools. Researchers from The Royal Veterinary College have shown the potential impact of sustained and strategic use of existing vaccines in endemic settings and how critical it is to adapt the strategy to the level of infection and extent of animal movement. A limiting factor of vaccine-based control programs is the inability of standard diagnostic tools to differentiate between antibodies acquired as a result of natural infection or vaccination. In the proposed research we combine a detailed epidemiological study of bovine brucellosis in Punjab-including validation of novel diagnostic techniques with simulation modelling to generate evidence based on which sustainable control programs for bovine brucellosis could be designed. We will also assess incidence of human infection and economic impact of the disease through animal health economics and transactional cost economics. The results of the field studies will be used to parameterize disease transmission models and to simulate, in silico, the potential impact of different types of vaccination strategies on prevalence reduction. Field studies will also be used to evaluate conventional and novel diagnostics. Specifically, we will study a novel diagnostic strategy using assays measuring response to rLPS antigen. Overall, our work will provide evidence to inform the design and implementation of realistic and sustainable strategies for the reduction of the prevalence of bovine brucellosis and, as a result, human brucellosis, in endemic areas.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;3.4 VACCINES
Health categories: INFECTION
Title: Deciphering Klebsiella pneumoniae strategies to subvert host defences
Funder: Biotechnology and Biological Sciences Research Council

Abstract: During infection, microbial presence is continuously monitored by receptors recognizing evolutionary conserved structures. Pathogen recognition is associated with the activation of few regulators and signaling pathways that control the expression of host defence systems, chiefly the inflammatory response. Subversion of this fast-acting response is considered important for pathogen survival during the early stages of infection. This proposal aims to gain a holistic understanding of the strategies used by Klebsiella pneumoniae to counteract the activation of host defense pathways. There is scant evidence on K. pneumoniae pathogenesis at the molecular and cellular level. Therefore it is both urgent and necessary to better understand its pathophysiology to be able to design new strategies to treat Klebsiella infections. My laboratory has demonstrated that Klebsiella subverts the activation of host defence processes (receptor-mediated Klebsiella recognition, NF-kB activation) to survive in the lung. This proposal will pursue ambitious questions at the forefront of research in infection biology: (i) to decipher how Klebsiella manipulates NF-kB and IFN-dependent pathways; (ii) to determine whether Klebsiella perturbs the subcellular location of pattern recognition receptors to manipulate their function; (iii) to establish how Klebsiella takes control over host post-transcriptional modifications to alter cellular responses. By applying a multidisciplinary approach encompassing microbiology, cell biology, functional genomics, and immunology, this proposal will expand our current understanding of the strategies used by Klebsiella to survive in the lung. On top of this, this proposal will shed new light and open new avenues of research into the complexity of host-pathogen interactions. A better understanding of the host-pathogen interactions offers the potential for pharmacological intervention by targeting the host side.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: 13 Development of magnetometer immunoassay technology for the rapid and cost effective detection of endemic animal diseases and pathogens (zoonoses)
Funder: Biotechnology and Biological Sciences Research Council

Abstract: International trading of food from animal sources is very intensive. Regulations decree that the production of animal products is free from zoonoses that can affect humans. Food producers wish to avoid the costs associated with other animal diseases. Regulatory authorities wish to reduce the cost of testing, especially visual inspection at slaughterhouses. Building on solid scientific and commercial research evidence resulting from a recently completed TSB GRD-funded project, this project now aims to take MagSer (i.e.a serology test for zoonoses and animal diseases) from Proof of Principle (PoP) to a fully developed instrument and suite of assays for screening animal diseases and zoonoses. The novelty and advantage of MagSer lies in the unique combination of immuno-magnetic capture of paramagnetic particles (beads) with highly sensitive magnetometer instrumentation to detect and quantify antibodies captured on the beads. The main innovations will be the a disposable measurement technology directly applicable to the measurement of antigen specific antibodies in pig's blood and the development of a rapid, low cost and simple device that can be used at point of test to screen animals for infections and check for efficacy of vaccination. Assay development work is planned at UWE's labs with instrument and consumable development and assay integration and validation being carried out by Clarity Biosolutions Ltd. (CBL).


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Molecular epidemiology of brucellosis in northern Tanzania
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Brucellosis is one of the most widespread zoonotic diseases and is identified as one of the highest priority animal diseases in Africa. Sub-Saharan Africa has the world's fastest growing human population and highly dynamic societies undergoing rapid urbanization. Changes in connections between urban and rural populations and the supply of animal products into urban areas could significantly shift patterns of exposure to brucellosis. Effective brucellosis control requires integrated combinations of control measures, but targeted vaccination is a key tool in reducing prevalence of disease in livestock populations. However, to develop plans for the optimal use of existing vaccines we need to understand which host species are infected by which Brucella species, and which routes are most important in transmitting brucellosis to humans in different settings. This project will generate data, and tools, provide training, and establish and enhance partnerships necessary for the development of a brucellosis control program for Tanzania. The development of diagnostic capacity in Tanzanian research laboratories needed for species-level diagnosis of Brucella will enable detection and identification of the Brucella species present in different livestock and human populations. These data will enable identification of the ruminant species acting as sources of human infection and the Brucella species responsible for human disease, providing the first systematic evidence-base to guide which brucellosis vaccine is best used in different animal populations. Our team includes policy-makers in Tanzanian government who will help ensure that research findings are made directly available to those who need to know most (including vaccine producers). The project will provide the evidence-base identified by the Tanzanian government that is needed to formulate national brucellosis control policy and place Tanzania on the roadmap for progressive control of this high priority disease.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;3.4 VACCINES
Health categories: INFECTION
Title: Life on the edge: tackling human African trypanosomiasis on the edge of wilderness areas
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The zoonotic form of Human African Trypanosomiasis (HAT) is caused by Trypanosoma brucei rhodesiense transmitted by tsetse flies. At the edge of wilderness areas, domestic cattle replace natural wild hosts (such as warthog and buffalo) as the principal reservoir host. We hypothesize that this shift towards a livestock-dominated system increases community reservoir potential and risk of human disease. Combining a wealth of ecological knowledge on the Serengeti ecosystem with new empirical data and models of HAT, we will quantify the transmission of trypanosomes across the ecotone between wilderness and settled areas and identify cost-effective strategies to interrupt transmission of HAT in the Serengeti and other wildeness areas of Africa. To achieve this goal, we will:- 1: Develop novel models of the transmission of Rhodesian HAT which are spatially and temporally dynamic, thereby enabling us to model how the transmission of trypanosomes changes with the density, distribution and diversity of hosts and vectors. 2: Quantify the density, structure and feeding patterns of tsetse populations to test empirically the hypothesis that contact rates between host and vector species changes between wilderness and settled areas. 3: Identify and genotype trypanosomes from wild hosts, cattle and vectors to test empirically the hypothesis that the prevalence, population make-up and diversity of trypanosome populations changes across the ecotone and results in a greater risk of Rhodesian HAT. 4: Combine novel models (1) with empirical data (2,3) to identify 'ecologically smart' strategies to control human and animal trypanosomiasis in the Serengeti. The outputs will provide local, national and regional stakeholders with robust recommendations on cost-effective strategies to control human and animal trypanosomiasis in the wider Serengeti ecosystem and generate guidance on monitoring and managing Rhodesian HAT in wilderness areas.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFECTION
Title: The Impact of Cholesterol on Staphylococci: Cell Responses and Membrane Dynamics.
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The genus Staphylococcus comprises species that are able to colonise human skin with varying success and they are found in different sites in varying abundance. The skin lipid matrix provides key properties to the skin such as its permeability barrier due to the presence of a structured combination of fatty acids, ceramide and cholesterol that actually form an array in 1:1:1 proportions. The components of the lipid matrix contribute to antimicrobial defence, yet we have not identified the effects of each component molecule.In this study, we will examine the responses of several species of staphylococci to physiological relevant levels of cholesterol and mimicking those levels found on skin. We have identified that challenge with cholesterol results in decreased transcription of both the crt operon for biosynthesis of the eponymous carotenoid pigment of S. aureus, called staphyloxanthin, and the sigmaB-encoding gene responsible for crt operon transcription. To identify how global transcription and membrane function is affected, we will use RNA-Seq to generate the transcriptional signature of the response to staphyloxanthin and analyse changes to membrane properties resulting from reduced staphyloxanthin, which acts to control fluidity. We will characterise mutants that have lost the ability to use cholesterol for protection from antimicrobial fatty acids that increase fluidity, and test the hypothesis that cholesterol in staphylococcal membranes acts to decrease fluidity in a manner similar to its role in eukaryotes. We will also generate the transcriptional response signatures from S. epidermidis (produces no staphyloxanthin) and S. hominis (produces staphyloxanthin), because these two species are ubiquitous skin commensals in contrast to S. aureus, which resides only transiently on skin. We will also characterise experimentally evolved mutants of these species from culture in growth-limiting levels of cholesterol to identify components interacting with cholesterol.


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