NIHRDataInsights/HRCSData huggingface dataset:
Title: Covalent host targeting by thioester domains of Gram-positive pathogens
Funder: Medical Research Council

Abstract: We have identified a novel family of protein domains, containing internal thioester bonds, in dozens of surface proteins of some of the most important Gram positive human pathogens including Streptococcus pyogenes, Streptococcus pneumoniae, Clostridium perfringens and several periodontal pathogens. Internal thioesters have previously only been found in complement proteins where they form covalent bonds to the surface of pathogens. The discovery of reactive thioester bonds in bacterial surface proteins known or predicted to mediate bacterial adhesion suggests the exciting possibility of a previously unrecognised principle in host-bacteria interactions, namely the covalent attachment of bacteria to host tissue. Preliminary data confirmed the presence of thioesters in predicted thioester domains (TEDs) from S. pyogenes. Even more excitingly TEDs were found to form covalent bonds with a host protein that is known to be an important target of many Gram-positive pathogens. We will use X-ray crystallography and NMR spectroscopy to obtain high-resolution structures of TEDs from different species, providing a molecular framework to interpret TED function. Physiologically relevant TED binding partners will be identified in pull-down assays exploiting the covalent nature of TED/target complexes. The relevance of thioesters for bacterial adhesion and cell invasion will be explored using various bacterial strains. The presence of a reactive group in bacterial surface proteins opens new avenues for diagnosis and potentially also therapeutic intervention. As a first step small molecular probes will be developed that specifically and covalently label thioesters. Given the urgent need to develop new antimicrobial strategies to prevent the looming antibiotics crisis the discovery of a novel molecular virulence mechanism is an exciting development and needs to be addressed now in a concerted effort bringing together molecular and microbiological expertise as we propose.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFECTION
Title: An advanced cookstove intervention to prevent pneumonia in children under 5 years old in Malawi: a cluster randomised controlled trial
Funder: Medical Research Council

Abstract: Trial type: Prevention. Design: Village-level cluster randomised controlled trial with two arms of equal size. Interventions: Experimental - The Philips fan-assisted stove with user training (replacing open fires). Control - Continuation of traditional cooking methods (open fire). Randomisation: By matched pairs of villages using computer-based system stratified by district to trial arms in a 1:1 ratio. Target population: Children up to 4.5 years old in Malawi allowing for a minimum of 6 months data collection before a child's 5th birthday. The trial will be broadly inclusive. HIV infection will not be an exclusion criterion. Duration of treatment period and follow-up: 24 months from randomisation. Primary outcome measure: Incidence of pneumonia in children under 5 years of age diagnosed by blinded physicians or medical officers using the WHO Integrated Management of Childhood Illness (IMCI) pneumonia assessment protocol. Economic, social, qualitative measures: Analyses will be carried out to explore factors that may be relevant for scale up of the intervention in the future. Sample size and potential power of the trial: Randomisation will be at the village level with an expected average number of children per village of 85 (77 after allowing for 10% loss to follow up). The between cluster CV has been set at the conservatively high level of 0.10. The latest data from Malawi suggest that around 9% of control group children will develop pneumonia severe enough to require treatment at a healthcare facility every year. We are using a highly conservative estimate of 5% (allowing for impact of pneumococcal vaccine). A sample of 59 villages per group will give 80% power to detect a 20% reduction in risk in the intervention group from 5% to 4% (a=0.05). Consumer involvement: Villagers, local stove producers and community leaders in Blantyre and Balaka districts have been involved with the development of this trial proposal through community engagement meetings.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: INFECTION
Title: The changing endemicity and disease burden of Plasmodium falciparum in Africa since 2000
Funder: Medical Research Council

Abstract: At a time when increases in funding for malaria control in Africa have led to widespread intervention scale-up, our understanding of how malaria transmission, disease, and death may be changing remains inadequate to support evidence-based decision making and advocacy for sustained finance. The aim of this fellowship is to use the world's largest database of P. falciparum parasite rate surveys and develop novel space-time modelling approaches to assess how malaria endemicity has changed in Africa since 2000, the implications of these changes for malaria disease burdens, and their spatiotemporal association with malaria intervention coverage and efficacy. A spatiotemporal model-based geostatistical (MBG) modelling framework will be constructed that allows generation of a space-time 'cube' of predicted P. falciparum infection prevalence through time at 5x5 km resolution with appropriate uncertainty metrics, and an ensemble of biological and empirical models will be used to convert this to estimates of clinical incidence. High-resolution multi-temporal population data will then ultimately allow estimation of malaria disease burden by country by year from 2000-2015. Elaborate handling of covariates in time and space will allow assessment of the potentially complex associations between disease control efforts and evolving patterns of malaria endemicity, adjusting for contemporaneous changes in background factors such as climate and socio-demographics. Comparison of the outcome time-series of changing malaria disease burden with equivalent existing estimates of malaria mortality will provide opportunities for epidemiological triangulation and cross-refinement of both approaches. This work will utilise the world's largest database of point-located P. falciparum parasite rate surveys since 1985 augmented with more recent national malaria survey data from around twenty African countries.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFECTION
Title: A trial of the benefit of including azithromycin in the drug combination used for seasonal malaria chemoprevention in African children
Funder: Medical Research Council

Abstract: An individually randomised, placebo controlled, double-blind trial will be conducted to test the hypothesis that adding azithromycin (AZ) to the regimen of sulphadoxine/pyrimethamine (SP) and amodiaquine (AQ) used for seasonal malaria chemoprevention reduces severe morbidity in African children. Following discussions with the study communities and ethical approval, approximately 16,000 children aged 3 -59 months will be individually randomised to receive three courses of SP + AQ with either a single dose of AZ or placebo at monthly intervals during the peak malaria transmission season. Deaths, hospital admissions and clinic attendances with a febrile illness among study children will be documented. At the end of the malaria transmission season, a cross-sectional survey will be conducted in approximately 4,000 randomly selected children who will be tested for anaemia and malaria parasitaemia. Parasites will be tested for molecular markers of resistance to SP. Pneumococci, isolated from the nasopharynx before and after the intervention, will be tested for susceptibility to macrolide antibiotics. The primary end-point of the trial will be the incidence of deaths and or non-injury related hospital admissions during the four-month observation period. Approximately 100 deaths or hospital admissions are anticipated in the SP+AQ alone group. With 8,000 children in each study arm and assuming a 10% loss to follow up, the trial will have 90% power to detect a 40% reduction in deaths or hospital admissions in children who received AZ. Secondary end-points will be the incidence of malarial and non-malarial febrile illnesses and the prevalence of malaria parasitaemia and anaemia at the end of the malaria transmission season. Data will be collected using the Teleform scanning system; standard statistical analyses will be performed. A DSMB will be established to monitor progress of the trial and to approve an analysis plan.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION;6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Efficacy of mobile phone short message service (SMS) on malaria treatment adherence and post-treatment review
Funder: Medical Research Council

Abstract: The study will be conducted in three phases. In phase I, we will collect/collate primary and secondary data on mobile phone network coverage, access, cell phone ownership and use in relation to malaria risk to demonstrate the feasibility of the intervention. In addition we will develop, refine and finalize the SMS intervention as well as pilot the automated message delivery system. In phase II, we will conduct a randomized controlled trial (RCT) to assess the efficacy of the SMS intervention. In phase III, we will carry out a cost-effectiveness analysis of the intervention with respect to the primary outcomes of the intervention - adherence and post treatment review. Costs will be measured under the trial conditions, from the provider's perspective and will include costs that would be required for the Kenya ministry of health ( MoH) to expand the delivery of the intervention, if successful, to all facilities in Bondo district and nationally.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: INFECTION
Title: School-based Treatment with ACT to Reduce Transmission: Evaluation of the community impact of intermittent preventive treatment for malaria in Uganda
Funder: Medical Research Council

Abstract: We propose to evaluate the impact of intermittent preventive treatment (IPT) for malaria in Ugandan schoolchildren on indicators of health and malaria transmission in the community, using a cluster randomised design. The unit of randomisation for the trial will be a primary school. A cluster will be defined as the school plus surrounding catchment area, including households located within a 500m radius. We will select 36 primary schools in Kanungu district to participate in the study; 18 schools will be randomly assigned to receive the IPT intervention, and 18 will be assigned to standard care (no intervention). Dihydroartemisinin-piperaquine (DP), a highly effective artemisinin-based combination therapy (ACT) will be provided to eligible children attending intervention schools once a term (3 times per year) for one year. In addition, all children in the intervention and standard care schools will receive annual deworming, according to national guidelines. Outcomes will be measured using surveys of communities, schoolchildren, and mosquito vectors. Community and school surveys will be conducted at baseline and approximately two months after the third (and final) round of treatment. The primary objective of the study is to evaluate the impact of IPT for malaria, as compared with the current standard of care, on community-level indicators of malaria transmission. We will test the hypothesis that malaria transmission, as measured by the prevalence of asexual parasitaemia and the entomological inoculation rate (EIR), will be lower in communities surrounding the intervention schools, than those surrounding the standard care schools. To guide future research and implementation of the intervention, our proposal includes health service research to evaluate perceptions of the intervention and the potential feasibility of taking the programme to scale, and mathematical modelling to determine the potential impact of the intervention in other epidemiological settings.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;3.3 NUTRITION AND CHEMOPREVENTION
Health categories: INFECTION
Title: Step-down affordable treatment for chronic hepatitis B infection in Africa and India Acronym - STEP-HEP
Funder: Medical Research Council

Abstract: This is a randomised, multicentre, blinded clinical trial examining the hypothesis that in patients with chronic HBV infection and active liver inflammation, 48 weeks induction therapy with tenofovir can be followed by successful transfer to lamivudine therapy in patients with a 'normal' ALT and any relapse can be controlled by reintroduction of tenofovir. The trial will examine the safety and cost effectiveness of this induction maintenance regime as well as evaluating the value of monitoring therapy by liver function tests rather than viral load measurements.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Improving the radical cure of vivax malaria: A multicentre randomised comparison of short and long course primaquine regimens
Funder: Medical Research Council

Abstract: This is a multi-centre, open label, three-arm randomised non-inferiority trial to compare two primaquine anti-relapse regimens. The same total dose 7mg primaquine/kg will be given either over 14 or over 7 days. A control arm which receives only schizontocidal therapy without anti-relapse therapy will provide the comparison for safety, tolerability and relapse data. Once randomised into one treatment arm the subject will receive the same prescribed regimen for subsequent recurrent vivax episodes throughout the 12 months follow-up period. All potential study participants will be tested for G6PD deficiency. Patients identified as having G6PD deficiency will receive standard blood schizontocidal therapy plus 8 weeks of weekly primaquine dosing (7mg/kg total dose).


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Point-of-care viral load testing for HIV patients
Funder: Medical Research Council

Abstract: This project is part of a collaborative programme between Departments of Infectious Diseases and Bioengineering at Imperial College and DNA Electronics (DNAe, www.dnae.co.uk), a SME based in West London. The groups currently collaborate to develop point of care diagnostics for infectious diseases based on proprietary technology held by DNAe centred on a point-of-care platform for label-free nucleic acid detection during amplification. The scientific rationale behind this is that nucleic acid chain extension generates protons and thus, in the presence of a matching target, proton release can be detected during amplification using specific probes in close proximity to a pH-sensing microchip (Patent No. WO/2008/107014). The novelty of this technology lies in its reduced cost (no tagging of reagents or optics required), high-volume manufacturability (standard silicon microchips), speed (rate of primer extension), and amenability for use in a laboratory-free environment (all-electrical handheld readout instrument) for same-day results. The overarching aim of the project is to optimise LAMP-pH assay for use with a handheld pH detection device that can be manufactured cheaply, and at scale, to provide a diagnostic platform for environments without central laboratory support. The focus of this project is the development of a semi-quantitative assay for HIV-1 viral load as an application for a developed technology platform. LAMP (Loop mediated isothermal amplification) is the chosen method of amplification, an isothermal methodology generating high quantities of nucleic acid with detectable pH change. Key aspects to this project are (i) to establish an assay able to amplify low level RNA copy numbers (equivalent to <1000 copies/ml blood/serum) (ii) to optimise reaction to produce detectable pH change within 30 mins or sooner (iii) to validate the performance of the assay across reference panels of HIV


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: NTD Highlight Notice: Defining and leveraging the mechanism of action of suramin for treatment of trypanosomiasis.
Funder: Medical Research Council

Abstract: Treatment of protozoan diseases is difficult, partly due to limited local resources, resulting in a very sparse portfolio of drugs being available for some highly important diseases. African trypanosomiasis is invariably fatal unless treated; few are available, all of which have toxic side effects. Several have difficult and expensive administration regimens and resistance is highly prevalent. Further, our understanding of the modes of action of most drugs is limited. Suramin, introduced in the 1920s, represents one of the better compounds available, but is only active against early stage disease. Nevertheless, improved understanding of how suramin interacts with trypanosomes is of high value as this will uncover further potential points for therapeutic intervention. A recent genomic screen implicated a cohort of gene products in suramin sensitivity, including the surface protein ISG75, many endocytic proteins and a range of hypotheticals. This proposal emerges from multiple ongoing investigations in our laboratories, including genome-wide screening, intracellular trafficking of surface proteins, specifically ISG75, and structural biology of surface proteins. We propose to determine if ISG75 is a bona fide suramin receptor and investigate the roles of specific ubiquitin hydrolases in ISG75 trafficking and suramin sensitivity; significantly, ubiquitylation is required for internalisation of ISG75. Further, to determine if the hypothetical proteins identified by us as part of the suramin sensitivity system are involved in endocytosis/ISG75 metabolism and identify the gene products involved in suramin toxicity in insect stages of the parasite and compare with the mammalian stage. The latter two aspects are targeted at determining if there are ISG75-independent routes (ISG75 is not expressed in the insect stage). The final aim is to investigate the potential of ISG75 as a delivery system for therapeutics, using specific antibodies as targeting mechanisms


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Mapping the up-regulation of Human Endogenous Retrovirus K with respect to the development of cancer and other diseases
Funder: Medical Research Council

Abstract: Endogenous retroviruses (ERVs) differ from typical retroviruses in being inherited through the host germline and are therefore a unique combination of pathogen and selfish genetic element. Around 8% of the human genome is comprised of human ERVs (HERVs), most of which ceased replicating at least 5 million years ago. The most notable exception is the HERV-K HML-2 (HK2) lineage. Recent studies have shown that, although HERVs are replication defective and/or transcription-translation silenced in healthy subjects, in some patients (e.g. breast cancer, HIV infected, inflammatory disease) HK2 loci have been up-regulated and produce detectable viral titers in the plasma. My project will investigate: a) the disease spectrum of up-regulated HK2, b) the timeline of HK2 up-regulation compared to the timeline of the disease development and c) the infectious potential of the up-regulated HK2 loci. Why focus on HK2? My recent study suggests that ERVs are more efficient parasites to replicate within the genomes when they lose their env gene and, thus, change their life-cycle into facultative intracellular. This also suggests that env-less ERVs could be less pathogenic. HK2 however is the most recent lineage with conserved env genes. Thus, it is less likely to be well-adapted and might still carry pathogenic traits for its host. The project will follow an integrated epidemiological and experimental design split into 4 phases: a) development of robust experimental framework to study HERV up-regulation with respect to human disease, b) cross-sectional study of HK2 up-regulation with respect to disease spectrum, c) longitudinal retrospective case-control study of HK2 up-regulation and d) in depth analysis of within patient dynamics of HK2. A team of collaborators in the fields of cancer, retroviral infections and immunology from the Universities of Oxford, Harvard, Athens and Imperial College will support the successful implementation of the project.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Unravelling the molecular mechanisms regulating cell division in the malaria parasite
Funder: Medical Research Council

Abstract: Malaria is caused by unicellular parasites belonging to the genus Plasmodium. These parasites invade red blood cells and divide asexually in a developmental process termed as schizogony, causing the disease. In addition, some parasites within red blood cells arrest cell division and differentiate to form sexual gametocytes. Following ingestion by Anopheles mosquitoes, the male gametocyte undergoes rapid cell division to produce 8 male gametes in a process of microgametogenesis. Schizogony and microgametogenesis are distinct types of mitotic cell division, and both also differ from classical cell division as studied in yeast, mammalian or other cells. The molecular mechanisms that regulate cell division in the malaria parasite are not well elucidated. Our main aim in this project is to unravel the molecular pathways controlling these types of cell division and establish how they differ from classical cell division. Major molecular components regulating cell division in yeast and other eukaryotic cells are the anaphase promoting complex/cyclosome (APC/C) protein complex, its activators such as cell division proteins CDC20 and CDH1, and protein kinases and phosphatases that control the reversible phosphorylation of the complex/activators. We recently identified and partially characterized the single homologue of CDC20/CDH1 in Plasmodium, and have shown that many of the structural protein components of APC/C are not present in these parasites. In this project we aim to investigate the role of putative APC/C components and their interaction with CDC20 during malaria parasite cell division at the two stages of the life cycle. This project will primarily use the rodent malaria model P. berghei since the whole life cycle can be completed in the laboratory and it is highly amenable to experimental manipulation. We will use reverse genetics, cell biological methods such as microscopy, protein biochemistry, and proteomics approaches to achieve our goal.


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