NIHRDataInsights/HRCSData huggingface dataset:
Title: DETECTIVE: Dissemination and resistance mechanisms of carbapenem-resistant Gram-negative bacilli
Funder: Medical Research Council

Abstract: The proposed research to be conducted by the network will be organised around three independent but inter-connected projects: 1) Investigate the reservoirs and routes of transmission of carbapenem resistant K. pneumoniae 2) Investigate the community carriage dynamics of carbapenem resistant E. coli leading to the continuous introduction of strains into hospitals and subsequent infections. 3) Investigate the reservoirs and routes of transmission of carbapenem resistant Acinetobacter baumannii. Each project will implement a deep sampling protocol where all ICU patients in our three partner hospitals, the ICU environment and ICU staff will be sampled for carriage of carbapenem resistant strains in our three target pathogens. All isolates will be genome sequenced by our partner hospitals using Illumina sequencing platforms. Data will be collated and analysed via dedicated CLIMB servers to allow us to investigate connected networks of these AMR pathogens in the Chinese clinical setting, and model transmission and dissemination routes. We will also implement the MinIon platform in the partner hospitals allowing us to develop real-time genomic epidemiology of AMR pathogens within the Chinese hospitals. And we will utilise the extensive data set we produce to perform a GWAS investigation of uncharacterised genetic loci which enhance MIC levels to carbapenem drugs beyond know carbapenemase enzymes.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Strategies to reduce the burden of antibiotic resistance in China
Funder: Medical Research Council

Abstract: WP1 will develop and optimise a digital intervention to reduce unnecessary antibiotic prescribing in lower level health facilities drawing on theory, evidence and our own effective interventions. We will use participatory co-design, qualitative research with up to 60 clinicians and patients and a feasibility trial to ensure all elements of the intervention are acceptable and feasible. A cluster randomised controlled trial will then compare the intervention with usual care in 55 practices and 1642 patient consultations. The primary outcome will be reduced antibiotic usage, with non-inferiority in clinical outcomes. WP2 comprises six linked studies in three representative areas of East China, to gather evidence on and analyse the inter-relationships between antibiotic use, occurrence and transmission of ABR in the environment, animals and humans. The studies will include assessment of antibiotic exposure in population cohorts from survey and urine (n = 3,300) and identification of types and frequencies of ABR genes in humans and food animals; analysis of antibiotic residues and ABR genes in the aquatic environment, including wastewater; mixed methods research into drivers and practices associated with antibiotic use (600 families); and analysis of the national policy context (with expert and stakeholder input) to propose strategies and systems for optimising and monitoring antibiotics use. WP3 will estimate the health and economic burden of ABR in China and the cost effectiveness of different antibiotic-reducing interventions. The analysis will draw on national surveillance data, published literature, a prospective observational cohort study in 50 representative hospitals to determine rates of infection, resistance, length of stay, mortality and cost and findings from WP1 and WP2. A decision analysis model will be developed to determine the costs and health effects of antibiotic exposure, resistant infection and different prescribing interventions.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: CHNUK: Integrated platforms from science to policy in response to antibacterial resistance
Funder: Medical Research Council

Abstract: We will Bring together China and UK science and policy groups with industry, government advisors and funders, forming hubs to support platforms for fundamental and translational AMR discovery research targeting 'old' and 'new' essential processes, virulence and resistance mechanisms. Develop new scientific methods and associated software platforms to combine high throughput natural product discovery with rapid chemical progression of fragment compounds from 'hit' to 'lead'. Establish a China UK discovery pipeline from target to translation, with the combined natural product and fragment based lead discovery being a key element of our broad activities in AMR and allied fields. Map capabilities and develop policy positions to influence funding and practice that will develop and strengthen the pipeline of AMR discovery R&D in China. Enable substantive exchange programs to train and inform, across the wider breadth of disciples, the next generation of AMR researchers. This will Develop a robust research pipeline of AMR policy and discovery between China and the UK Develop new capabilities and platforms at major national infrastructure investments (UK and Shanghai synchrotrons), automating high throughput structure determination at Shanghai with technology from the UK, driving the speed of hit chemical progression, and further pushing its bounds of productivity. Develop a new generation of skilled and interconnected AMR researchers in China with a wide breadth of understanding and deep specialist training in 'state of the art' techniques Develop new policy positions that will help influence and sustain AMR discovery funding, development and deployment in China.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: INFECTION
Title: LY256: A novel and potent antibiotic for treating Clostridium difficile infection
Funder: Medical Research Council

Abstract: Clostridium difficile infection (CDI) is the most common cause of hospital-acquired infection, with high rates of morbidity and mortality in elderly patients. The infection is invariably due to broad-spectrum antibiotic-induced dysbiosis of the gut microbiome. Treatments with the front-line antibiotics, metronidazole and vancomycin, are of major concerns, primarily due to their lack of C. difficile selectivity and low gut concentrations. Recurrent CDI occurs in 20-30% of the patients, after which the rate increases to 40-65%. The recently introduced fidaxomicin has limited effectiveness in preventing recurrent CDI, particularly CDI caused by the hypervirulent strain, NAP1/BI/027. Faecal microbiota transplantation (FMT) is the only approved treatment for patients with multiple recurrent CDI. Thus, there is a real unmet need for new targeted-spectrum antibiotics that prevent relapse of CDI. We have recently discovered a pre-clinical lead compound, LY256 that showed selective and potent in vitro and in vivo activity against several C. difficile strains. In two different small animal (hamster and mouse) models of CDI, orally administered LY256 2.5-5.0 mg/kg BID for 5 days was efficacious in treating CDI. In the present proposal, we have outlined a robust translation pathway for early-stage pre-clinical development of LY256 for the treatment of CDI. The project will generate new product specific IP covering: methods of large scale manufacture of LY256, effective orally administered doses for treatment of both primary and recurrent CDI, and the potentially disruptive adjunct therapy by combining chemo- and microbiome/biologic approaches which would result in additional market exclusivity.


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Converting natural product leads into structure- and ligand-based drug discovery campaigns against leishmaniasis and Chagas' disease
Funder: Medical Research Council

Abstract: The development of new drugs for the treatment of kinetoplastid diseases is hampered by a lack of validated drug targets, and insufficient understanding of basic parasite biology. Here, we intend to leverage the more diverse chemistry available in natural product (NP) compounds active against Leishmania donovani and/or Trypanosoma cruzi to elucidate the MoA and enable initiation of novel structure based small molecule drug discovery programmes. Our approach to defining MoA utilizes a combination of established and novel techniques. These include: 1. High-throughput genetics: We will utilise our genome-wide RNAi library (RITseq) in T. brucei alongside our genome-scale overexpression libraries in T. brucei, L. donovani and T. cruzi. These global knock-down and overexpression methodologies enable us to rapidly assess virtually every gene in the parasite genome for their potential role(s) in resistance to the compounds we are screening. Specifically, we will identify genes, that when their levels are modulated (up or down), can confer compound resistance. We will also generate cell-lines that are resistant to our NPs in vitro. The resulting drug-resistant clones will be assessed by whole-genome sequencing to identify genomic changes responsible for resistance. 2. Cellular: We have developed a number of genetically modified parasite cell lines that enable us to report on specific cell and organellar functions (proteasome, glycosome) affected by our NPs. We also use a number of established reagents, e.g. MitoTracker, redox-active reporters. In a broad sense, these cell-based approaches provide an early and broad indication of the potential MoA our NPs. 3. Chemical proteomics: Our sophisticated mass spectrometry-based quantitative proteomics techniques allow us to directly identify proteins that selectively bind to bioactive compounds. Specific approaches that will be utilized include thermal shift proteomics (CETSA) and SILAC-facilitated pulldowns.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: UK-Brazil Joint Centre for Arbovirus Discovery, Diagnosis, Genomics and Epidemiology (CADDE)
Funder: Medical Research Council

Abstract: 1. What is the genetic diversity of Brazilian arboviruses? We will develop rapid cost-effective sequencing protocols (specific & untargeted) for Brazilian arboviruses and apply them to human, vector & animal samples from 5 established cohorts. We will test hypotheses of associations between arbovirus genetic diversity and key phenotypes, e.g. (1) Are there viral mutations linked to Zika-associated microcephaly cases? (2) What is the epidemiological impact of ZIKV sexual transmission? (3) Are there viral genomic signatures of sylvatic vs urban YFV transmission cycles? (4) Are there genomic signatures associated with disease severity or vector specificity for Brazilian arboviruses? 2. Why do arbovirus epidemics spread & persist? To better understand local arbovirus transmission in São Paulo and how this relates to wider virus spread , we will investigate factors driving the spread and persistence of transmission in vector, human and non-human primate populations. We will determine when and where is transmission risk for arbovirus infection is highest, and whether risk zones vary under different scenarios. 3. Can we quantify mobility and anticipate transmission? Prevention and control measures are hindered by poor understanding of how human, vector and reservoir species mobility contributes to arbovirus spatial spread. Through geospatial modelling we will identify hotspots of transmission in São Paulo and Brazil, with the aim of anticipating arbovirus dissemination. We will develop a platform for real-time arbovirus detection and epidemiological analysis. 4. How do we develop a precision public health model for Brazil? We propose that precise public health inventions are possible through the integration of data from multiple data sources. Specifically we will combine primary surveillance data with rapid analysis systems to track and predict disease distributions. Crucially we will develop Brazilian technical expertise and capacity to act upon this information.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: 'SPIICA' - the Sao Paulo-Imperial College Immune Correlates in Arbovirus Infection Network
Funder: Medical Research Council

Abstract: We here build on successful links between infection and immunity researchers in Sao Paulo and Imperial College, established under previous Newton funding. Our aim is to extend this grouping into a Joint Centre Partnership, seeking to establish the immune correlates governing differential disease outcome after exposure to Chikungunya virus (CHIKV). Among arboviruses, CHIKV is of concern for its ability to cause chronic, arthritis-like joint disease, which can persist for years. From murine models, it is believed the polyarthralgia is driven by immunopathology rather than virus per se. This emphasises the need for a clearer understanding of the immune correlates in human patients. This understanding is a prerequisite both for ensuring that any vaccine strategy promotes protection rather than immunopathology and also that we have a toolkit to map the effects of any vaccine trial. We will recruit a CHIKV patient cohort, 90 patients in each of four groups, across 3 seasons at 6 clinical centres in Brazil. Each patient will be evaluated clinically and followed longitudinally, giving sequential blood samples. Samples will be evaluated using an arsenal of analyses, across labs in the two countries. We will conduct detailed studies of serological correlates, mapped at the level of CHIKV antigens and antibody isotype, also encompassing generation of and characterisation of exemplar human neutralizing monoclonal antibodies. We will undertake multi-parameter flow cytometry of innate and adaptive immune subsets. The response of each patient group will be characterised at the level of cytokine arrays and RNAseq transcriptomic biosignature. We will conduct T cell epitope mapping using CHIKV peptide libraries. We will also investigate metabolic consequences of CHIKV infection across the patient groups. We aim to build an improved rationale explaining the different outcomes following infection thus favouring vaccines offering protection without immunopathogenesis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: INFECTION
Title: Bridging epigenetics, metabolism and cell cycle in pathogenic trypanosomatids
Funder: Medical Research Council

Abstract: This programme of research will create a network of researchers studying the regulation of gene expression in the kinetoplastid protozoa, allowing us to dissect the processes that link metabolism, epigenetic change to chromatin, gene expression and cell differentiation. This will give insights into the processes that enable these organisms to enter a quiescent state that protects them from both immunological and chemotherapeutic intervention, and also provide novel targets against which to develop new drugs. Specifically, we aim to characterise the range and extent of post-translational modifications to proteins (specifically histones) involved in chromatin formation in Trypanosoma cruzi and Leishmania infantum and L. mexicana cells undergoing passage through the life cycle and in response to metabolic pertubations. This will involve the isolation of chromatin from different parasite lifecycle stages, and isolation of the individual proteins of the complex (using immunopreciptation methodologies with antibodies specific for the trypanosomatid histones, and BioID approaches to identify neighbouring members of the complex). Proteomic approaches will determine the repertoire of proteins involved. Post-translational modifications (PTMs) on individual proteins will be assessed using specific antibodies and also mass spectrometry of digested proteins to seek mass changes consistent with different PTMs. The abundance of individual metabolites in cells at different cell/lifecycle stages will be determined using LC-MS based untargeted metabolomics. CRISPR/cas9 approaches will allow rapid knockout of non-essential enzymes producing metabolites implicated in PTM, and use of different metabolic substrates will also be used to modulate their abundance to asses impact on epigenetic change and gene transcription by RNAseq. Cell culture techniques will assess life cycle progression in mutants


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Cathelicidins As Novel Therapeutic Antivirals For Dengue Infection
Funder: Medical Research Council

Abstract: Characterisation of the antiviral and immunomodulatory activity of the cathelicidin family of host defence peptides in Dengue infection may represent a novel approach that would inform the development of highly effective antiviral therapeutics. This study will characterise the impact of dengue infection on cathelicidin expression in vitro and in samples from patients diagnosed with mild or severe dengue fever, associating cathelicidin status with inflammatory markers and disease severity. Given that dengue virus is known to utilise autophagy induction to facilitate replication, and that cathelicidins are known to have the potential to induce apoptosis in infected cells, we aim to assess whether cathelicidin treatment can shift the balance from autophagy to apoptosis in dengue infected cells, as a way of halting viral replication and facilitating infected cell clearance. We will also use in vivo and in vitro models of dengue infection to provide a comparative assessment of the potential for exogenous peptide treatment, and upregulation of endogenous peptide, to be used as adjunct therapeutic approaches for dengue infection. Key Research Deliverables 1. This study will provide a full translational characterisation of the impact of dengue infection on cathelicidin expression, in vitro and will assess cathelicidin and inflammatory status in patients diagnosed with mild or severe dengue fever. 2. We will provide a mechanistic characterisation of the immunomodulatory roles of cathelicidins in the context of the modulation of cell autophagy/apoptosis pathways in dengue infection. 3. We will provide in vitro and in vivo characterisation of the potential for either exogenous cathelicidin treatment, or vitamin D/butyrate mediated endogenous cathelicidin production to be used as an adjunct therapeutic approach for dengue infection.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Pathogen exchange at the human wildlife interface - a comprehensive molecular study on vector-borne disease in rural Sulawesi.
Funder: Medical Research Council

Abstract: Vector-borne pathogen entry into the human population from macaque monkeys is on-going in Southeast Asia, currently the best-known example is zoonotic malaria. The UK PI was co-investigator on ground breaking research in Malaysian Borneo that uncovered the entry of Plasmodium knowlesi, a malaria parasite of Southeast Asian macaques, into the human population. Sulawesi has seven unique macaque species that most probably radiated from Borneo in the middle Pleistocene. The macaques of Borneo have up to five Plasmodium species and it is not known if any of those species traveled with the macaques to Sulawesi. Using field-appropriate sampling, downstream genetics, genomics and bioinformatics the applicants propose to investigate, for the first time, vector-borne pathogen transmission, particularly but not limited to malaria transmission, within and between the unique Sulawesi macaque species and remote rural populations. A comprehensive set of pathogen DNA fingerprints from mosquito vectors, macaque hosts and the human population will be produced to capture vector-borne pathogen transmission at each remote study site in Sulawesi. The expected outcomes are to: 1) describe the clinical impact and molecular fingerprint of vector-borne pathogens transmitted within remote rural populations in Sulawesi; 2) identify mosquito vector species and the pathogen genotypes they transmit between humans at each location; 3) catalogue mosquito vectors that feed on, and vector-borne pathogens harboured by, macaque troops that overlap with humans at each location; 4)compare pathogen genetic fingerprints generated from mosquito vectors, macaque and human hosts to determine pathogen crossover events between hosts, particularly zoonotic crossover from macaque monkeys to humans. The outputs will inform location-specific strategies to pre-empt emerging vector-borne zoonoses.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Improving diagnosis of brain infections in Indonesia using novel and established molecular diagnostic tools.
Funder: Medical Research Council

Abstract: Brain infections, such as meningitis and encephalitis, remain a significant cause of morbidity and mortality in Indonesia and the UK, with considerable costs to families, health care and society. In Liverpool, we have developed a novel host-transcript based blood test: TRanscripts to Identify bacterial Meningitis or TRIM test. It uses host transcripts in the blood. The test exhibits high sensitivity (100%), specificity (90%) in distinguishing patients with bacterial meningitis from the mimics (meningism or viral meningitis). The test offers to help clinicians' rule-out bacterial infection and decide appropriate treatment. In partnership with Universitas Gadjah Mada (UGM), Indonesia, our preliminary results indicate the TRIM test maintains high accuracy (100%) in distinguishing bacterial meningo-encephalitis from clinical mimics among child and adult patients. In addition, at UGM, we have increased pathogen detection among suspected meningo-encephalitis cases by 31% (from 11 to 42%) via introduction of systematic testing of cerebrospinal fluid (CSF) using pathogen-specific PCR and pathogen directed antibody ELISA testing. In this three year study, we will validate TRIM test accuracy in a large number of suspected Indonesian meningo-encephalitis patients (n=694), recruited through hospitals linked to UGM and Universitas of Indonesia (UI). Alongside, we will continue systematic CSF testing at UGM, and extend to patients recruited through UI. To further improve pathogen detection, we will perform next-generation sequencing on PCR negative CSF samples, at the Eijkman Institute. Identified pathogen sequences will be used to refine pathogen-specific PCR. This study will assess and implement novel and established diagnostic tools among Indonesian brain infection patients. In the longer-term, these tools will support more appropriate treatment of these patients, strengthen local research capacity and collaboration between UK and Indonesia.


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