NIHRDataInsights/HRCSData huggingface dataset:
Title: How does the immunomodulatory parasitic worm product ES-62 rewire bone marrow cells to increase healthspan and lifespan in obesity-accelerated ageing?
Funder: Medical Research Council

Abstract: Molecules secreted by parasitic worms are increasingly being considered as potential novel therapeutics, due to their ability to modify host inflammatory responses. One particularly well-characterised example is ES-62. Intriguingly, when tested in a C57BL/6J mouse model of obesity-accelerated ageing, in addition to its established role in suppressing inflammation, ES-62 prevented HCD-induced dysregulation of a number of physiological systems. One system that particularly interested us, due to the unexpected nature of its targeting, was the bone marrow (BM), where in male mice, ES-62-treatment prevented skewing of haematopoietic stem cells towards myeloid and megakaryocyte lineages. Furthermore, this reversal was accompanied by significant slowing of the accompanying loss of bone architecture. Overall therefore, our data suggest that ES-62 targets BM-progenitors to prevent the damaging changes in immune responses and osteoporosis that are associated with ageing. Our overarching aim is thus to employ our mouse model of obesity-accelerated ageing to determine how ES-62 achieves this. We will: 1. Identify how BM is impacted by ES-62-exposure, via characterisation of global transcriptomic (RNA-seq) and epigenetic (chromatin accessibility, DNA methylation and histone marks) landscapes using BM cells from our unique ageing mouse tissue biobank. 2. Define how ES-62-mediated changes in epigenetic and target gene signatures are linked to prevention of HCD-induced stem cell changes via assessment of a wide range of markers of ageing and consequent immune system dysfunction in recipient animals following BM transfer. 3. Determine whether transfer of ES-62-conditioned BM promotes improved health of organ systems previously shown to be protected by ES-62 and whether its rewiring effects are direct or indirect by assessing the impact of direct exposure of BM cells to ES-62 in vitro and ES-62-dependence on the microbiome, respectively.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Unravelling the impact of lateral transduction in the emergence of antibiotic resistant bacteria.
Funder: Medical Research Council

Abstract: Bacteriophage-mediated gene transfer is a major evolutionary force occurring by two well-described mechanisms: generalized and specialized transduction. We have recently discovered that Staphylococcus aureus phages engage in lateral transduction, the most powerful mode of transduction described to date. Lateral transduction converts large regions of the bacterial chromosome into "hypermobile platforms" for the high frequency transfer of any genetic element within their boundaries. Bacterial DNA is transferred at astonishingly high frequencies that are at least 1,000 times greater than any known mechanism of transduction. The observed efficiency of chromosomal DNA transfer is unprecedented, representing a paradigm shift in phage biology and in the definition of mobile genetic elements. In this project, analysing important pathogens, we will investigate whether this ground-breaking strategy of gene transfer is widespread in nature. More importantly, we will also analyse here the hypothesis that many mobile genetic elements (i.e. integrons, transposons and integrative and conjugative elements (ICEs)) encoding multiple antibiotic resistance genes, are located in the bacterial chromosome so they can be mobilised both intra- and inter-species by lateral transduction. We anticipate the results of this study will challenge basic and fundamental concepts of phage biology, which will be revisited here. Moreover, the proposed research has the potential to fundamentally re-structure our understanding of the roles of bacteriophages in bacterial evolution, including the development of antimicrobial resistance and virulence in clinical strains.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Genomic Epidemiology and Transmission of Campylobacter in Africa (GETcampy-Africa)
Funder: Medical Research Council

Abstract: Next generation sequencing (NGS) and comparative genomics approaches have considerable potential for describing the microbes associated with contamination sources, and the pathways to infection. However, this potential has been largely unmet in LMIC's, because of the significant challenges in handling the large amounts of pathogen genome data and interpreting it in the context disease epidemiology. GETCampy Africa will bring together leading researchers in enteric disease and enhance regional and international capability in genomic epidemiology and microbial source tracking in a program of capacity building, knowledge transfer and research through: 1. A co-ordinated sampling and analysis research program of surveillance and genome sequencing to investigate trends in Campylobacter infection and transmission between the environment, animals and human populations. 2. A freely accessible BIGS database of isolate genomes, containing >30K Campylobacter, genomes (and other enteropathogens) for contextualisation and linked to relevant metadata. 3. A web-accessible analysis environment, on UK/Gambia MRC-CLIMB cloud infrastructure, with instances customised for genomic epidemiology and a suit of workflows, pipelines, scripts, programs, and virtual machine images for genome analysis and source tracking. 4. A stochastic infection risk impact simulator based upon the quantitative source attribution data to model the impact of potential interventions on infection probabilities, and determine the most cost effective interventions. 5. An ambitious training and student exchange program that will include bootcamps, hackathons, and workshops, suitable for interested parties from public health scientists to undergraduate students. The GETCampy program will deliver improvements in understanding of Campylobacter epidemiology, and build capacity in NGS and bioinformatics for enteropathogen research in Africa.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: INFECTION
Title: Structural studies of viruses and their interactions with cells
Funder: Medical Research Council

Abstract: The proposal targets RNA viruses, especially the Picornaviridae, small icosahedral viruses (30nm diameter) with a +ve single stranded genome, and the Reoviridae, larger icosahedral viruses (~80nm across) with 10-12 double stranded genome segments which enter cells as intact cores forming transcription factories in the cytoplasm. Picornaviruses are responsible for a large proportion of respiratory tract infections, and also for other major epidemics, notably several million cases per year of hand-foot-and-mouth disease. Similarly, amongst the Reoviridae rotaviruses are estimated to cause several hundred million cases of gastroenteritis every year. New therapeutics are needed since there are only a rather small number of vaccines available and no licenced anti-picornavirus drugs. We propose to take advantage of, and progress, the rapid technological developments in cryo-imaging of biological samples, especially with electrons, to make a coherent programme for the integrated investigation of these viruses. In particular we will use electron tomography to visualise viruses within cells in close to atomic detail. Since the workflows are complex the duration and size of the programme award requested is essential, and there will be real synergy between the different elements of the programme, increasing productivity and impact. The programme has four aims. The first three address gaps in basic knowledge that can be filled by integrated structural studies. The fourth links fundamental knowledge to translation, including pre-competitive research into anti-virals: Aim 1 - Improve structural understanding of Reoviridae replication Aim 2 - Improve structural understanding of how picornaviruses enter cells and replicate Aim 3 - Improve structural understanding of immune responses Aim 4 - Use structure to guide anti-viral inhibitor design for drug and vaccine therapy


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFECTION
Title: Ivermectin Treatment of Livestock for Malaria Control on Sumba Island
Funder: Medical Research Council

Abstract: Novel vector control tools are urgently needed to combat residual transmission by outdoor feeding malaria vectors, and novel chemistries are needed to manage insecticide resistance. Ivermectin is used widely in human and veterinary medicine to control nematodes and ectoparasites. The blood of ivermectin-treated vertebrates is lethal to Anopheles mosquitoes. Mass ivermectin treatment of livestock (ITL) could interrupt the transmission of malaria, and clear livestock of nematodes improving health, weight gains, and economic benefit to their owners. A recent meta-analysis demonstrated that ownership of livestock increases the risk of malaria in Indonesia. Sumba is one of the most underdeveloped and malaria burdened islands in Indonesia. People on Sumba keep livestock underneath their house at night, potentially increasing their risk of contracting malaria. We propose to treat livestock (cattle and pigs) with ivermectin, capture wild Anopheles after they feed on the animals, and evaluate effect on mosquito survival. Mosquito mortality data will be coupled with blood ivermectin concentrations to assess ivermectin susceptibility of Anopheles species on Sumba. We will engage the surrounding community to demonstrate the potential benefits of ITL to thwart malaria. Small group meetings will be conducted to assess community, public health worker, and government officials' perspective on malaria and this novel vector control tool in order to enhance compliance with ITL. There are at least ten potential Anopheles species incriminated in malaria transmission on Sumba, and very little is known about their feeding preferences. We will use both human and livestock baited traps to characterize the feeding behavior of Anopheles on Sumba to gain a better understanding about how effective ITL could be on Sumba. If effective, then this intervention could be reproduced throughout Indonesia and other areas of the world to eliminate malaria.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: INFECTION
Title: MICA: Radio+ TB trial development: Determining the optimal regimen for bacteriologically negative, radiographically apparent TB diagnosed usingnewtest
Funder: Medical Research Council

Abstract: Obj 1+2 - How these two tests are optimally combined to predict TB? From a completed South African household contact study, 518 baseline chest X-rays will be analysed with three CAD packages with 48 prevalent and incident (by culture and Xpert) as reference standards. By ROC analysis maximal sensitivity threshold scores will be identified. 250 of these participants have baseline FDG-PET/CT available and Blood RNA stored. CAD abnormality heat maps will be compared to CT component as radiological reference standard. All 250 participants will have blood tested on the TB Host Response cartridge with disease scores determined. Optimal cut off for TB Host Response test will be determined when combined with chest x-ray CAD scores to maintain sensitivity but increases positive predictive value. Obj 3 - Proportion expected to be positive in two clinical settings? a. (Active case finding) In an ongoing cohort in Zimbabwe and Mozambique, 1400 household contacts will have chest X-Ray and a single sputum Xpert, blood RNA at baseline. Blood samples from 100 with CAD above threshold matched with 100 below will have TB Host Response test run to determine proportion positive. b. (Primary care) In an ongoing cohort in Malawi, 200 presenting for TB assessment will have chest X-Ray and a single sputum Xpert, blood RNA at baseline. Blood samples from all 200 will have TB Host Response test run to determine proportion positive. Obj 4 - Patient and provider attitudes to management? Discrete choice experiments (DCE) will be designed to understand patient and provider preferences. Focus groups and existing literature will guide attributes and attribute levels for the choice set which from the basis of the DCE questionnaire. Sample size of 150. Obj 5 - Best sites for trial? We will develop a set of criteria focusing on existing screening activity/numbers and trial expertise/experience to evaluate additional/optimal sites in both clinical settings in Africa and Asia.


Research activity codes: 4.4 POPULATION SCREENING
Health categories: INFECTION
Title: Addressing the Social Determinants and Consequences of Tuberculosis (ASCOT): a pilot randomised controlled trial and process evaluation in Nepal
Funder: Medical Research Council

Abstract: BACKGROUND. Poverty drives TB rates and TB worsens poverty due to catastrophic costs of being ill and seeking care. WHO mandates ending catastrophic costs and providing social and economic (socioeconomic) support to people with TB. This has not been evaluated in low-income countries. With key stakeholders in Nepal, we designed locally-appropriate socioeconomic support packages for TB-affected households, which are ready to be tested. OBJECTIVES 1. Identify the most feasible and acceptable support package 2. Inform definitive trial design 3. Optimise future chances of funding and trial success METHODS DESIGN. An adaptive randomised-controlled pilot trial and process evaluation POPULATION. 100 people with TB registered at National TB Program (NTP) clinics in Chitwan, Mahottari, Morang, and Pyuthan districts of Nepal INTERVENTIONS. Tablet-based software will randomly allocate participants equally to: i) Standard of care (e.g. control) ii) Social Support through home-based peer-led mutual support groups to reduce stigma iii) Economic Support with monthly cash transfers to mitigate costs and meet NTP goals iv) Socioeconomic Support integrating economic and social support Interventions will be adaptive and delivered by the Nepal NGO, BNMT ACTIVITIES. Poverty and TB costs will be measured by survey. TB treatment outcomes will be extracted from NTP registers. MRC process evaluation techniques will evaluate feasibility and acceptability by qualitative focus groups and interviews with participants and project staff to examine perceptions of the interventions; and quantitative data on intervention uptake, fidelity, and costs. PRIMARY OUTCOME. Feasibility and acceptability of support packages EXPLORATORY OUTCOMES. Impact of support on TB cure and catastrophic costs APPLICATIONS. This work will ensure fundable, achievable, and impactful design of the first definitive trial of socioeconomic support for TB-affected households in Nepal.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: INFECTION
Title: MICA: Seasonal vaccination with the RTS,S/AS01 malaria vaccine given with or without seasonal malaria chemoprevention (SMC): an extension study.
Funder: Medical Research Council

Abstract: SMC is recommended until the age of 5 years. Thus, if seasonal vaccination with RTS,S/AS01E, or another malaria vaccine with a high initial efficacy but a relatively short duration of protection, is to be considered as a potential supplement or replacement for SMC, it is important to determine the efficacy of annual, seasonal vaccination in primed children until they reach the age of five years. A preliminary analysis of the efficacy and safety data obtained from the ongoing RTS,S+SMC trial by an independent expert appointed by the Gates Foundation in January 2020, at a time when study children had reached the age of three or four years, recommended that the trial should continue with all three trial groups (SMC alone, RTS,S/AS01E alone and the combination) until study children reached the age of five years and this recommendation was endorsed by the trial's Data Safety and Monitoring Board. Therefore, it is proposed that the trial should be continued, with inclusion of all three groups of children, until they reach the age of five years. Children in the SMC alone group will receive tetanus toxoid in June 2020 and 2021 together with four rounds of SMC (SP + AQ) in 2020 and 2021, those in the RTS,S/AS01E alone group will receive a booster dose of RTS,S/AS01E in June 2020 and 2021 together with four rounds of SMC placebo in 2020 and 2021 and those in the SMC + RTS,S/AS01E vaccine group will receive a booster dose of RTS,S/AS01E vaccine in June 2020 and 2021 together with four rounds of SMC (SP+AQ) in 2020 and 2021.The primary end-point for the extension study will remain the incidence of clinical episodes of malaria that are severe enough to require treatment at a health centre and which are accompanied by a positive blood film with a parasite density =>5000/microlitre. Secondary end-points will include episodes of severe malaria and the prevalence of malaria parasitaemia and anaemia. The cost of each intervention and its acceptability will be assessed.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Fluconazole plus flucytosine vs fluconazole alone for cryptococcal antigen-positive patients identified through screening: A randomised trial
Funder: Medical Research Council

Abstract: Cryptococcal meningitis (CM) remains a key driver of AIDS-related mortality resulting in ~180,000 deaths/year globally. Over 75% of deaths occur in Sub-Saharan Africa (SSA), accounting for 15%-20% of all AIDS-related deaths. Targeting cryptococcal disease in its early stages, prior to the development of meningitis, can reduce this persistently high mortality. Screening patients with low CD4 counts using a simple point-of-care test to detect cryptococcal antigen (CrAg) and treatment of CrAg-positive patients in advance of severe disease represents a practical and cost-effective approach to reducing mortality, with such screening programs now recommended in many SSA countries. However, recent data has shown that current pre-emptive treatment with fluconazole alone may be suboptimal with a significant number of patients going on to develop meningitis and die. Testing of more effective antifungal regimens is thus urgently required. A combined treatment of fluconazole and flucytosine was shown to be safe and effective in a recent Phase III trial of those with symptomatic meningitis, with mortality halved compared to historic cohorts treated with fluconazole alone. The EFFECT trial is a Phase III, multi-centre, pragmatic open-label, 1:1 randomised treatment trial embedded into existing screening programs in South Africa and Tanzania. It will compare 6-month all-cause mortality between those treated with fluconazole alone (1200 mg/day, control arm, current recommended treatment) versus a combined regimen of fluconazole (1200 mg/day) plus flucytosine (25 mg/kg qds, intervention arm) for 2 weeks. In total, 600 participants will be recruited over a 2.5-year period and followed-up to 6 months. The trial will also assess progression to cryptococcal meningitis, tolerability and safety, and cost effectiveness. A safe and potent oral treatment regimen, which could be administered to outpatients, could have a major impact on survival, driving down AIDS-related mortality.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Optimising Vancomycin Dosing for C. difficile Infection (OVID-CDI)
Funder: Medical Research Council

Abstract: C. difficile infection (CDI) is a major cause of nosocomial diarrhoea, with recurrent disease (rCDI) occurring in ~25% of cases. CDI arises as a result of antimicrobial-mediated gut dysbiosis, which is exacerbated by antibiotics directed at C. difficile, leading to this high rCDI rate. CDI treatments are limited to metronidazole (MET), vancomycin (VAN) and fidaxomicin (FDX), but, as MET efficacy is inferior, guidelines favour VAN and FDX. FDX is associated with lower rCDI risk, due to its narrow spectrum and relative sparing of gut microbiota (unlike current VAN), but is expensive, meaning VAN remains the main therapeutic option. The standard dosage of oral VAN (125 mg qds) achieves high faecal concentrations (>1000mg/kg), yet its MIC for almost all C. difficile isolates is <2mg/L. VAN killing kinetic data suggest limited additional benefit beyond 2xMIC. So, it is possible that a substantially reduced VAN dosage could still be effective at inhibiting C. difficile, while markedly reducing impact on the microbiota, potentially reducing rCDI rates. While FDX and newer CDI antimicrobials have undergone dosage-ranging studies, VAN has not. The significant expertise in clinically-reflective CDI gut models at Leeds allows us to perform in vitro studies to evaluate the effects of new, reduced VAN dosages/schedules on C. difficile, gut microbiota, resistance selection/development and rCDI risk. We will perform in vitro killing kinetic studies on prevalent C. difficile ribotypes and representatives of key gut microbial populations. These will inform a series of gut models testing dose/frequency/duration, each with rCDI risk, to optimise a CDI VAN dosage regimen. This will be compared with FDX, & extended dosage FDX, current alternatives to standard VAN therapy for CDI. We will co-develop a clinical trial alongside this grant to test the optimised VAN regimen beyond this application.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Developing anti-plasmid compounds to combat drug resistant infections
Funder: Medical Research Council

Abstract: Antimicrobial resistance (AMR) poses a threat to human and animal health. Developing and introducing new antimicrobials to the clinic has proven difficult, and resistance to new antimicrobials is highly likely. Therefore, new approaches are needed to reduce AMR prevalence. One reason AMR is increasing is that bacteria share plasmids, many of which are self-transmissible and can carry multiple resistance genes. The aim of this project is to characterise FDA-approved drugs and natural product compounds that inhibit the transmission/persistence of AMR plasmids. I constructed a fluorescence-based reporter system using global AMR plasmids carrying extended spectrum beta-lactamase (blaCTX-M-14) and carbapenemase (blaKPC) genes, which confer resistance to some of our 'last line of defence' antibiotics. These plasmids are located in uropathogenic E. coli and K. pneumoniae, respectively. Using this system, I identified (a) non-antibiotic FDA approved drugs and (b) natural product compounds which inhibit plasmids. In this project, we will determine their range of activity by testing on clinical isolates containing AMR plasmids (UK and China). We will characterise their mechanism of action and determine how they inhibit transmission/persistence. We will then test them in an in vivo mouse model of gut inflammatory infection the natural mouse pathogen Citrobacter rodentium. This will enable us to determine compounds efficacy in vivo (by measuring both transmission/conjugation and persistence) and impact upon the microbiome. This project will characterise new ways to reduce AMR plasmid prevalence in the intestine. Furthermore, it will broaden our understanding of the complex biology surrounding plasmid dynamics. In the long term, my research will contribute to understanding AMR transmission and reducing global AMR levels.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION