NIHRDataInsights/HRCSData huggingface dataset:
Title: Understanding vector-associated parameters of arbovirus transmission
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The entomology group will act as a focus for studying the interactions between arboviruses of international importance and their arthropod vectors. These studies will range from field-based investigations that define vector capacity of arthropods under known environmental conditions for horizon scanning purposes to laboratory experimentation that will provide a detailed and fundamental understanding of vector-arbovirus interactions. Primary areas of focus in the field will include studies of dispersal, diel periodicity, host location, seasonality and overwintering capability of adult vectors and habitat association investigations of immature stages. These studies will enable the construction of arbovirus transmission and dispersal models by the mathematical biology group at IAH and also contribute to wider global studies of vector-borne disease. In the laboratory there will be a focus on defining vector competence using standardised methodologies and integrating the work of other groups at IAH and beyond to understand the genetic and immunological basis of this parameter. Projects conducted will have a global focus in part driven by collaboration with the non-vesicular reference laboratory based at IAH, as well as generating data specifically designed to produce risk assessments of arbovirus incursion into the UK. While studies are currently primarily focussed upon Culicoides biting midges and the arboviruses they transmit (not least due to recent outbreaks of bluetongue virus and Schmallenberg virus in the UK), the entomology group will also widen its remit to include studies of other biological vectors such as mosquitoes and ticks. The group will also pursue an increased focus on mechanical vectors of arboviruses as a relatively neglected area of study.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Determinants of transmission, adaptation and pathogenicity of avian influenza
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The aim of the project is to identify molecular factors that enable avian influenza (AI) viruses to establish and cause sustained infections in poultry. This project will take forward our recent studies on evolution, adaption and transmission of AI viruses mainly focusing on the analysis of the diversity of AI viruses affecting poultry and identification of genetic correlates that facilitate the sustained infection in chickens and turkeys through gaining greater transmissibility and virulence. The identified evolutionary and host-specific adaptive changes will be used to construct mutant AI viruses and their potential effects on host tropism, infectivity, replication, transmission and virulence will be assessed in different host-origin tissue culture systems and animal models including chickens, turkeys and ducks. These studies will provide foundation for the improvement of avian influenza virus control strategies by developing new advanced efficacious vaccines and highly effective diagnostic tools enabling to minimise their impact on animals, public health and world economy.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Genetic analysis of arbovirus transmission by insect vectors
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Culicoides biting midges spread a number of viruses that cause severe disease in animals, including bluetongue in ruminants, and possibly the recently emerged Schmallenberg virus. Sequencing of the Culicoides sonorensis genome has been now initiated at IAH, in collaboration with TGAC and EBI, to decipher the molecular basis of Culicoides phenotypic variation. This opens up new areas of globally significant vector-biology research, including molecular studies of vector-pathogen-host interactions, to define genetic ‘drivers’ of vector competence and transmission. Genomic DNA (and RNA) from C. sonorensis colonies at IAH and the C. sonorensis ‘KC’ cell line, is being assessed using the Illumina HiSeq2000 sequencing platform. Our collaborators at EBI will provide the first annotated genome for any Culicoides spp., that together with insects from the IAH colonies, will allow us to investigate genetic factors and molecular processes involved in orbivirus transmission, replication and vector competence. Analyses of genome-wide SNPs in multiple Culicoides spp and colony-insects bred for different traits will elucidate arthropod phylogenetic relationships and explore the underlying genetics of arthropod blood-feeding and immunology. Phenotypic differences within the colony at IAH, including sensitivity and permissive or non-permissive characteristics for virus infection/replication, will be related to genotype using current mapping strategies for identifying genetic loci involved in vector competence.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Dissection of the cellular interactions of rotavirus non-structural proteins and their role(s) in viral pathogenesis
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The aim of this project is to elucidate the role(s) of rotavirus encoded proteins, specifically the non-structural proteins found only in virus infected cells, in the process of viral pathogenesis. To do this a key technological objective of the project is the development of a helper independent gene rescue protocol for rotaviruses that will allow the exploitation of reverse genetics in dissecting the molecular mechanisms that underpin the functioning of the various non-structural proteins. Complementing the work on developing and exploiting a gene rescue protocol will be studies on two non-structural proteins (NSP1 and NSP4), already shown to be involved in regulating the innate-immune response (NSP1) and virus induced cyto-toxicity (NSP4), following their individual expression in cells transfected with cDNA copies of the relevant rotavirus genes. The long term objective of this work is to obtain a detailed understanding of the molecular mechanisms involved in viral replication and pathogenesis that is required to underpin the development of both rationally attenuated vaccines and novel chemotherapeutic interventions for these globally important medical and veterinary pathogens.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: The Tick Cell Biobank - a global collection of tick cell lines
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The Tick Cell Biobank (TCB) is a global repository for tick cell lines (TCL) derived from ixodid and argasid species of veterinary and medical importance available now and in future. As well as supplying tick cell lines on request to the UK and international research community, the TCB trains recipient scientists in cell line establishment and maintenance, characterises the cell lines including screening for endogenous viruses, and continues to derive new TCL. Establishment of TCL takes many years and requires specialised expertise and, importantly, a stable background of laboratory support, which this project provides. Since the TCB was established in 2009, the crucial role played by TCL in research into ticks and the diseases they transmit has become increasingly clear. Indeed, interest in TCL and the methods used to generate them has spread to encompass pathogens transmitted by other arthropods such as mites, fleas and lice. With environmental, social and climate change driving the emergence of new vector-borne diseases, the demand for TCL is likely to continue to increase in the future. The TCB has already been enormously successful, generating eleven new cell lines and supplying TCL to recipients in, and training young scientists from, 21 countries in five continents. TCL from the TCB have already facilitated a wide range of studies, but much remains to be done. Global research has only scratched the surface of knowledge of these economically important and biologically fascinating parasites, their microbiota and the pathogens they transmit. Continued maintenance and expansion of the TCB is essential to support this research now and for many years to come. The TCB is part of the Institute's National Capability and as such provides tick cell lines and training to other research groups in the UK and beyond as well as supporting in-house research into arbovirus groups including bunyaviruses, flaviviruses, orbiviruses and African swine fever virus.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: INFECTION
Title: Identification of genetic markers in the haemagglutinin glycoprotein critical for antigeni activity of H9N2 avian influenza viruses
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Studentship: H9N2 avian influenza (AI) viruses are endemic in poultry in many countries. They pose a serious threat to poultry and are also recognised as a threat to human health. The impact of these viruses can be minimised by efficacious vaccines and diagnostics. The efficacy of these tools is continually compromised by the emergence of antigenic variants due to genetic drift in the HA glycoprotein. Recently we identified that neither recombinant HA nor whole virus antigens belonging to two different H9N2 virus strains had antigenic cross-reactivity using chicken antisera. Consequently, a vaccine based on one strain would be unable to induce cross-protective immune responses to the other strain, despite belonging to same subtype. Similarly, reagents for serological diagnostic analysis also become redundant. Comparison of the sequence of the HA1 polypeptide of each strain revealed that there were at least 10 distinct genetic motifs between them. These finding gave us an opportunity for detailed analysis of each differing amino acid or combination of amino acid motifs that are potentially implicated in the diversity of antigenic specificity and cross-reactivity of these H9N2 viruses. A number of recombinant mutant haemagglutinin (HA) glycoproteins and AI viruses will be produced, based on the distinct amino acid variations observed between the two H9N2 viruses. These will be characterised by haemagglutination inhibition (HI), enzyme-linked immunosorbent assay (ELISA), virus neutralization (VN) tests, western blot, surface plasmon resonance (SPR) and nanoparticle tracking analysis (NTA). The outcomes will be used to establish a direct correlation between substitutions in HA that result in loss of antigenic cross-reactivity or decrease in antigen-antibody binding affinity of variant viruses. This knowledge will contribute to more efficacious vaccines and diagnostic tools to reduce the impact of influenza viruses in animals and humans.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Is PB1-F2 a virulence factor for avian influenza virus in poultry?
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Studentship; PB1-F2 is a 90 amino acid protein discovered in 2001 to be expressed from the second influenza genome segment in a +1 reading frame from the main protein PB1. Since then several different functions have been attributed to the protein including pro-apoptotic, interferon modulator, viral polymerase activity modulator and an inflammatory inducer. These functions have mostly been prescribed to the laboratory adapted influenza strain PR8 in mammalian cell lines. Recent work has shown that the PB1-F2 protein from other strains of influenza virus don’t behave in the same way. PB1-F2 is well conserved in avian influenza isolates in contrast to its frequent truncation or deletion in swine and human isolates. Therefore it stands that in the avian host PB1-F2 has an important function. Avian influenza makes frequent incursions into poultry populations resulting in economical and health burdens for farmers. In our fight to protect poultry populations from avian influenza it is important to understand any virulence factors in avian influenza strains so proper prevention and mitigation strategies can be developed. This PhD will look at several different aspects to do with PB1-F2 function in poultry to help shed some light on what it does and whether it is a virulence factor. The impact of PB1-F2 on viral replication kinetics and innate immune evasion will be investigated as well as trying to identify potentially new interactions that it may be involved in. Whilst investigating the question of PB1-F2 the PhD student will develop and use biologically relevant culture systems including immortalised chicken cell lines, primary mono-cultures, well differentiated respiratory and enteric tract cultures and ex vivo explants.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Developing genetic control methods for arthropod vectors
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Arthropod pests transmit or vector viral pathogens causing morbidity, suffering and economic harms to animals and humans. The best known such arthropod vectors may be mosquitoes, but mites and ticks, as well as other insects, are also significant disease vectors. We aim to develop new genetics-based control tools to supplement and complement existing control methods. We can use the natural propensity of the pest arthropod to seek out and mate the opposite sex as the basis for highly specific control methods targeted on the pest arthropod with minimal off-target effects. We focus on two broad approaches, aiming either (i) to reduce the numerical size of the pest population – “population suppression”, also the aim of most conventional approaches such as the use of insecticidal chemicals or (ii) to reduce the ability of the mosquito to transmit a specific pathogen, or set of pathogens. We are also exploring ways to introduce such genes into target pest populations. In each case we take a synthetic biology approach, with systematic laboratory development combined with mathematical modelling.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: INFECTION
Title: Structural Biology of pathogen:host interactions
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The primary aim of the research group is to investigate the mechanisms of pathogen:host interaction during infection/colonization at the molecular level. We use a range of structural biology techniques to understand the function of specific proteins and how they interact with their environment. Some current priorities include establishing structure/function relationships in ‘effector’ proteins from pathogens important for human/mammalian health and agriculture (e.g. Enteropathogenic E. coli (EPEC), Phytophora infestans (the Irish potato famine pathogen)), and mechanisms of pili biogenesis in Group A Streptococcus. Our primary experimental tool is structure determination by X-ray crystallography, but we also complement this with solution-based methods (circular dichroism, isothermal titration calorimetry, surface plasmon resonance, analytical ultracentrifugation, small angle X-ray scattering, spectroscopy) as appropriate. Structural data is frequently used to establish hypotheses which can then be tested, for instance, by site-directed mutagenesis and further study. We collaborate extensively with groups in Norwich, the UK and worldwide to ensure the in vivo relevance of our in vitro data. We also have an interest in developing/employing new technologies to advance throughput in protein production and structure determination to both streamline our current research projects and enhance the feasibility of establishing new projects in the Laboratory.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: More Medicines for Tuberculosis
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The More Medicines for Tuberculosis (MM4TB - EU FP7) consortium has evolved from the highly successful FP6 project, New Medicines for TB (NM4TB), which delivered a candidate drug for clinical development. Building on these foundations, MM4TB will continue to develop new drugs for TB treatment. An integrated approach will be implemented by a multidisciplinary team that combines some of Europe's leading academic TB researchers with two major pharmaceutical companies and four SMEs, all strongly committed to the discovery of anti-infective agents. MM4TB will use a tripartite screening strategy to discover new hits in libraries of natural products and synthetic compounds, while concentrating on both classical and innovative targets that have been pharmacologically validated. Whole cell screens will be conducted against Mycobacterium tuberculosis using in vitro and ex vivo models for active growth, latency and intracellular infection. Hits that are positive in two or more of these models will then be used for target identification. Targets thus selected will enter assay development, structure determination, fragment-based and rational drug design programs; functionally related targets will be found using metabolic pathway reconstruction. The role of JIC (AM lab) will be to develop M. tuberculosis gyrase as a target and establishing the mechanism of action of novel compounds that target this enzyme. This will involve biochemistry and structural methods (X-ray crystallography), carried out in collaboration with the Lawson laboratory. Medicinal chemistry, carried out in other labs in the consortium, will convert leads to molecules with drug-like properties for evaluation of efficacy in different animal models and late preclinical testing.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: The burden, determinants and outcomes of severe infections in older people in the UK
Funder: Department of Health (England)

Abstract: Infectious diseases cause considerable ill-health among older individuals. There is evidence of increasing hospital admissions for infections among older people in the UK, but the reasons for this are unclear. More work is also needed to clarify the risk factors for developing severe disease following infections. This research will quantify the burden of severe infections among UK adults aged 65 years and older, looking at the incidence of infections, antibiotic prescribing patterns, hospitalisations and death rates. We will then examine the relative importance of underlying illnesses, therapies, lifestyle and social circumstances as risk factors for hospitalisation or death following infections in older people. To do this, we will analyse anonymised linked electronic health data from general practices, hospitals and death certificates. New clinical algorithms will be developed that general practitioners can use to predict who is at higher risk of severe outcomes following infection. We will also investigate whether the risk factors among older people for developing infections and subsequent severe disease are different among those who are at higher risk of infection, such as individuals with diabetes. The results of our research should provide useful information for health planners, help clinical decision-making in general practice, contribute to the development of methods to optimise use of electronic health data for public health research and give estimates of how much disease could be avoided using existing and planned interventions (such as new vaccines and drugs).


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFECTION
Title: Development and evaluation of strategies to improve sedation quality in intensive care (DESIST) study
Funder: Chief Scientist Office (Scotland)

Abstract: The critical care work stream of the Scottish Patient Safety Programme (SPSP) focuses on reducing hospital acquired infections (HAIs) through implementation of “care bundles”. Optimising sedation practice is part of this bundle, but is proving the most difficult to implement. This is important because excessive sedation is associated with increased HAIs, longer intensive care (ICU) and hospital stay, and possibly higher mortality. We plan to develop sedation specific process and outcome measures in 8 ICUs to better describe current practice and outcomes. We will then randomise pairs of ICUs to four different combinations of sedation-related quality improvement interventions, namely: [1] enhanced education alone, [2] education plus process/outcome measure feedback, [3] education plus introduction of a new sedation monitoring technology, or [4] education, process/outcome measure feedback, and sedation monitoring technology. Our analyses will explore the relative effectiveness and interaction between these approaches using quantitative and qualitative approaches.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: INFECTION
Title: Systematic review and meta-analysis of interventions to improve antibiotic prescribing practices for hospital inpatients
Funder: Chief Scientist Office (Scotland)

Abstract: Antibiotic resistance and Clostridium difficile infection are major public health problems that are related to increasing antibiotic use. In hospitals up to a third of antibiotic use is unnecessary (e.g. prolonged surgical prophylaxis). However, at the same time there is delayed or ineffective treatment of patients with serious infections. The primary aim of this systematic review is to identify interventions that are effective in improving antibiotic prescribing to hospital inpatients by increasing effective treatment of infections while minimising excessive use. The review will will update the results of an existing review in the Cochrane Library, which includes 89 studies published up the end of 2006. Updating this review to the end of 2012 is likely to add 40 more studies. Meta-analysis will be used to synthesise evidence to answer four research questions, which will address critical gaps in the evidence that is currently in the Cochrane Library.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;7.3 MANAGEMENT AND DECISION MAKING
Health categories: INFECTION
Title: Can Vitamin D supplementation improve Hepatitis C cure rates: A multicentre randomised controlled clinical trial?
Funder: Chief Scientist Office (Scotland)

Abstract: HCV infection causes a chronic hepatitis that can lead to cirrhosis hepatocellular cancer and death. It is curable in up to 70% with a combination of interferon, ribavirin with or without a protease inhibitor. The function of the immune system also makes an important contribution to cure. Vitamin D may be important for immune function, but what level vitamin D is needed to achieve optimum function is not known and many patients with HCV have low levels of vitamin D. This trial will determine if vitamin D supplementation to raise levels into the high normal range improves the cure rate for anti-HCV treatment.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION