NIHRDataInsights/HRCSData huggingface dataset:
Title: MRC AMED - INTERFERON STIMULATED DEFENCES THAT TARGET HEPATITIS B VIRUS (HBV) AND HEPATITIS D VIRUS (HDV)
Funder: Medical Research Council

Abstract: The hypothesis underlying this proposal is that there are specific interferon-induced defences that target hepatitis B virus (HBV) and hepatitis D virus (HDV) that have not yet been identified. These unidentified interferon-stimulated genes (ISGs) could play an important role in the success of interferon therapies, help define the species tropism of HBV and HDV, influence the incidence of HDV coinfection and contribute to the natural suppression of HBV/HDV (which occurs in most infected patients). To identify the ISGs that target HBV and/or HDV, we will screen over 1000 ISGs, to identify inhibitory genes, using a series of cell-culture models of HBV/HDV infection and replication. We have substantial expertise concerning the development and use of HBV/HDV infection and replication models and have used arrayed ISG-expression screening to identify ISGs targeting retroviruses, bunyaviruses and vesiculoviruses, leaving us well placed to identify and characterise ISGs inhibiting HBV/HDV. By analogy to retroviruses, we predict that anti-HBV/HDV effectors may show species dependent patterns of activity. To address this possibility, we propose to initially screen ISGs from humans and mammalian species. Moreover, we will also examine multiple mammalian orthologues of the human effectors we identify. It is possible that ISGs play an underappreciated role in defining the species-tropism of HBV/HDV. Using existing samples and data, we also plan to examine SNPs and expression levels of the identified ISGs, in patients that do and do not respond to interferon therapies. In addition, we will consider the role that expression level and polymorphism might play in the incidence of HBV coinfection. Our overall goal is to generate and disseminate knowledge about the genome-encoded antiviral defences that target HBV/HDV. This will stimulate future research in this area, and in the longer term, inform the design of prognostic/intervention strategies targeting HBV and HDV.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: A cross-sectional approach to identification & interrogation of adaptive & functional mutations affecting CCHFV replication & pathogenicity in humans
Funder: Medical Research Council

Abstract: Identification of CCHFV amino acid mutations: determine unique genetic variation in human, tick & other mammal-isolated CCHFV genome sequences -Analysis of publicly available sequences from in NCBI/EMBL/DDBJ database, identify genetic variation associated with host via bioinformatics technique and virus evolutionary analysis -Map mutations onto known structures of CCHFV proteins to predict structural and biophysical impact of amino acid substitutions on function of viral proteins by computational analysis Tracking the emergence of mutations in CCHFV human cases: examine sequence variants of CCHFV isolates from patients: -CCHFV sequencing in human patients & ticks collected in Turkey using a novel sequencing method (Oxford Nanopore MinION) -Examine genetic variations of CCHFV for intra-host single nucleotide variants (iSNVs) -Combining genetic data of CCHFV isolates with clinical outcomes of cases (fatal vs recovered), highlight genetic determinants of viral pathogenicity Experimental evaluation of identified mutations: Examine functional changes of mutations found in in silico and in vivo work -Create a library of plasmids expressing CCHFV proteins with particular single/multiple amino acid mutations predicted to induce functional changes -Establish viral entry assay using infectious particles/psuedotyped VSV bearing CCHFV envelope in a CCHFV-susceptible human cell line, evaluate infectivity via viral glycoprotein Gn/Gc with host-specific mutations & neutralizing antibody escape mutations -Develop Hazara virus infectious virus particle system into a CCHFV infectious clone to evaluate virus entry & neutralizing antibody escape mutations -Establish CCHFV minigenome in a human cell line to evaluate virus genome replication and transcription -Examine virus replication kinetics in human, non-human primate, and tick cell lines, determine virus sequences of each passage by NGS to examine emergence of genetic variations depending on the host cell species


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Elucidation of cell-autonomous immunity and host defense against vacuolar pathogens by interferon-inducible GTPases
Funder: Medical Research Council

Abstract: T. gondii is a protozoan parasite capable of infecting humans and animals. The infection in humans remains mostly asymptomatic, but can cause severe ocular acute phase disease, as well as lethal toxoplasmosis in immune-compromised individuals. T. gondii as a food-borne illness is ranked high among human infectious agents with regards to economic loss and life impairment, making it an important pathogen of both humans and animals. T. gondii resides in a membranous structure called the parasitophorous vacuole (PV) in host cells. The T. gondii PV normally avoids fusion with host acidic organelles, thereby protecting it from degradation by host cells. After infection with T. gondii, healthy mammalian hosts activate immune responses, producing interferon-g (IFN-g) to upregulate various cell-autonomous programs targeting T. gondii. So far, the Yamamoto and Frickel groups have individually and collaboratively revealed mechanisms of T. gondii control involving interferon (IFN)-inducible GTPases. IFN-inducible GTPases are recruited to the T. gondii PV membrane (PVM) resulting in its disruption and parasite death. Although recruitment and disruption of T. gondii PVM by IFN-inducible GTPases are critical in anti-T. gondii host defence and prevention of toxoplasmosis, little is known about the mechanisms by which these GTPases recognize and disrupt the T. gondii PVM. Also, our recent study demonstrates that IFN-inducible GTPases are implicated in human host cell death. However, the significance of cell death in host defence against T. gondii remains unclear. In this collaboration, we will elucidate detailed and novel aspects of IFN-inducible GTPase-mediated cell-autonomous immunity and host defence against T. gondii. Since various vacuolar pathogens such as Mycobacterium, Salmonella, Chlamydia, and Norovirus are reported to be targeted by IFN-inducible GTPases, our findings will be informative not only for toxoplasmosis, but also for bacterial and viral diseases.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Prevention of severe RSV infection by a helminth-induced serum factor that elicits antiviral monocytes?
Funder: Medical Research Council

Abstract: Respiratory syncytial virus (RSV), the main cause of viral bronchiolitis, results in hospitalisation of 2-3% of all infants and can cause life-threatening disease. With significant morbidity, RSV bronchiolitis has major health and economic implications, but specific therapy and, for most infants, affordable prevention is lacking. We previously reported that RSV titres are reduced and disease is prevented in RSV-infected mice co-infected with the gut nematode Heligmosomoides polygyrus (Hp). Our recent preliminary data suggest that Hp infection induces monopoiesis and lung monocytosis and that monocyte depletion during Hp infection ablates its anti-RSV effect. Both lung monocytosis and the RSV-protection were transferred by non-heated serum of Hp infected mice, suggesting a RSV-protective protein factor in serum, e.g. a cytokine. Here, we will test the hypothesis that Hp infection, through serum mediators, drives monopoiesis and recruitment of monocytes to the lung, which prime the lung's antiviral response, conferring protection from severe RSV infection. We will use flow cytometry, single cell and bulk RNAseq and genetically modified strains in mouse models to determine if Hp induces transcriptionally distinct monocyte populations with anti-RSV effects, and to define their kinetics. To translate murine findings, we will use RNAseq of existing blood samples from Ugandan children with/without gut helminth infection to determine if helminths also induce monocytosis and antiviral gene expression in humans. In parallel, we will use both a candidate cytokine and an open proteomics approach to identify the RSV-protective serum factor, which will be validated by quantification in serum from children with/without gut helminth infection. These translational studies will define the antiviral roles of Hp-induced monocytes in RSV infection, discover the RSV-protective serum factor and may identify these as new targets for the prevention of RSV disease.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Engaging communities to address antimicrobial resistance: Identifying contextualised and sustainable community-led solutions in low resource settings
Funder: Medical Research Council

Abstract: Antimicrobial resistance (AMR) is a major challenge to global health, food sustainability and security and socio-economic development. Multi-sectoral action that addresses human and animal health, agriculture, and the environment through a "One Health" approach is required to address the profound implications of AMR. Public awareness and/or public education on AMR is highlighted in most international guidance. However, to tackle AMR it is critically important to go beyond raising awareness and actively engage with individuals and communities globally. Community Engagement (CE) to address AMR is an under-used and under-researched strategy for addressing AMR globally, and receives little mention in global policy. We interpret CE to mean a participatory process through which equitable partnerships are developed with community stakeholders, who are enabled to identify, develop and implement community-led sustainable solutions using existing or available resources to issues that are of concern to them and to the wider global community. We will (1) develop contextualised intervention materials for community engagement that address AMR through a One Health perspective; (2) implement and evaluate an approach to CE that tackles AMR at the community level and assess: a. its effectiveness for improving knowledge, attitudes and reported behaviours in relation to AMR; b. its cost-effectiveness and the cost of scale-up; c. the extent to which it is equitable, gender sensitive and participatory; d. its potential for implementation on a national scale (Bangladesh); and e. its potential to be replicated to a different health system and community context (Nepal); (3) implement a capacity building strategy based on principles of equitable partnership; and (4) implement a robust research uptake strategy to increase the visibility of CE approaches within, and their potential impact on, the wider AMR research landscape.


Research activity codes: 4.3 INFLUENCES AND IMPACT
Health categories: INFECTION
Title: Building healthy communities in urban Brazilian slums
Funder: Medical Research Council

Abstract: We will address the urgent need for sustainable locally-developed interventions to improve multiple health outcomes linked to infectious diseases in low income cities, adopting an adaptive management approach through which an initial, evidence-based plan, developed through consensus between experts and stakeholders, is repeatedly re-assessed and, if appropriate, modified in the light of additional evidence. We will focus on potential comorbidity from infectious diseases with 3 different transmission routes and on interventions to mitigate risk. 1) Leptospirosis and enteric infections, environmentally transmitted. 2) Zika, Dengue and Chikungunya, caused by mosquito-borne pathogens. 3) Directly transmitted infections. Interventions will be chosen by the residents, facilitated by our team - either environmental (eg closing sewers) or behavioural (eg improving access to health visitors). Work will be based in 3 communities in Salvador Brazil. Biannual serosurveys will evaluate changes in incidence rates for diseases before, during and after interventions, as well as data on multiple aspects of knowledge, attitudes and practices, environmental data in public, peri-domestic, and domestic areas, the presence, extent and location of open sewers and trash accumulation, and relevant water/soil samples to quantify pathogen loads. Initially, communities will use previously- and newly-collected data as a basis for identifying interventions and relevant metrics to evaluate them. Further pre-intervention metrics will be collected during months 3-9. At the end of the first year, community-specific interventions will be implemented and further data collected. After a further 9 months the management groups will undertake an evidence-based assessment of the interventions' effectiveness, leading to a re-considered, modified, set of interventions (or a decision to maintain the status quo), followed by further data collection and ultimately to a full assessment of both interventions.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: INFECTION
Title: An inter-disciplinary approach to understanding the contribution of household flooring to disease burden in rural Kenya
Funder: Medical Research Council

Abstract: The quality and environmental context of housing provides important conduits through which social and environmental inequalities can translate into health inequity. We hypothesise that rudimentary flooring is an under-recognised contextual driver of health in poor rural communities, augmenting exposure to enteric and parasitic pathogens. This inter-disciplinary study seeks answer the question in what contexts does household flooring act as a driver of infection risk, and how can we intervene to mitigate this? We plan to work in three culturally and epidemiologically distinct settings across Kenya to evaluate enhanced flooring packages (EFPs) that include the provision of an improved floor, accompanied by a participant-informed behaviour change programme. In each site, formative research will focus on refining flooring specifications and technologies, and behaviour change needs. Participatory co-development approaches will then be used to design final intervention. Cluster randomised intervention trials will be used to assess the effects, feasibility and acceptability in each site. In total, 225 households will be randomised to receive the intervention or not. Primary outcomes include the prevalence of enteric infections, STH and tungiasis, assessed by repeat cross-sectional surveys. Secondary outcomes include incidence of gastrointestinal illness, environmental contamination and subjective wellbeing. A nested process evaluation will explore implementation fidelity and uptake, acceptability, feasibility and cost, whilst sustainability and scalability will be explored using an implementation science approach. Funders and governments still require clear policy and technical guidance on the impact and effectiveness of new transformative approaches to reducing the burden of diseases associated with poor water, sanitation and hygiene. This evaluation will be among the first to provide policy information on the potential impact of flooring improvements on community health.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: INFECTION
Title: IndiaZooRisk+: Using OneHealth approaches to understand and co-develop interventions for zoonotic diseases affecting forest communities in India
Funder: Medical Research Council

Abstract: Zoonotic diseases disproportionately affect poor tropical communities leading to loss of life, impaired livelihoods, health and welfare. Forests are a significant source of such diseases. Communities that depend on forests for food, fuel and income, incur an increased risk of being exposed to zoonotic pathogens. Social and environmental change appears to increase zoonotic diseases, but little is known on the drivers of change and how they interact. This project will (1) better understand the impacts of different drivers, such as forest degradation, land tenure, human mobility, power dynamics and knowledge systems, and seasonal ecology, on health outcomes and spread of zoonotic diseases and (2) co-develop improved interventions with affected forest communities and policy makers and practitioners from the human health, animal health and environmental sectors thereby building the capacity of local communities to be more resilient to zoonotic diseases. The research underpinning these improvements will determine (1) the contextual and biological factors that underpin vulnerability to zoonotic pathogens; (2) knowledge sharing impacts on zoonotic disease management; (3) seasonal exposure to zoonotic diseases and (4) human mobility interactions with disease ecology and integrate this understanding into predictive models and decision support tools. This project will benefit human health sector policy makers and managers understand better contextual and mobility risk factors for zoonotic diseases thanks to co-developed predictive models, targeting of surveillance and diagnostic protocols, vaccination programs and risk communication strategies at District-to-State levels. Affected communities will benefit from co-developed interventions building on traditional knowledge, increased awareness of zoonotic diseases, protection measures and health care services reducing the likelihood of death, illness or loss of income due to zoonotic disease infection.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: INFECTION
Title: Developing effective rodent control strategies to reduce disease risk in ecologically and culturally diverse rural landscapes
Funder: Medical Research Council

Abstract: Research is designed to answer whether sustainable community-based rodent management can reduce risks of disease transmission and improve overall human health and wellbeing. Multidisciplinary activities will be conducted in Tanzania and Madagascar, focus on three rodent-borne infections (leptospirosis, plague and rickettsiosis) and proceed in two stages. First we fill knowledge gaps, and deepening our existing collaborations with communities and stakeholders, allowing us to co-develop rodent control that will be holistically evaluated in the second stage. We will develop a spatially-realistic modelling tool to explore likely responses of rodent populations and rodent-borne infections to localised rodent control. Analyses of rich archived datasets and new experimental trials will be used to parameterise models and test output. In the first stage, we will work in 12 villages, where villages act as replicates, experimentally determining how rodent movements and the prevalence of RBI are impacted by control. We will also use a range of qualitative and quantitative social science to produce a deeper understanding of community practices, behaviour and understanding around relevant issues of health, hygiene and pest management, and work with stakeholders from health, agriculture and environment spheres to understand perceptions, policies and support services. In the second stage, we will conduct a comparative trial in 12 intervention - non-intervention village pairs (n=24), co-developing and trialling rodent management strategies over one year, and monitoring changes to human practices and attitudes, rodent damage, disease within the rodent population (i.e. leptospirosis, plague and rickettsiosis), human health indicators and time/financial inputs. Collaborative workshops will facilitate cross-country comparisons and high-level training to early career researchers.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: INFECTION
Title: Responding to the challenge of MERS-CoV: Development and testing of interventions to reduce risk among Bedouin populations in Southern Jordan
Funder: Medical Research Council

Abstract: Building on a successful GCRF Foundation Award, we aim to: i) Address knowledge gaps required to inform future vaccination strategies for MERS-CoV, ii) Develop and implement contextualized behavioural public health interventions to mitigate risk of MERS-CoV infection and iii) Build capacity for research, surveillance and control activities targeted at MERS-CoV. Two parallel longitudinal studies of camel owning households and their camel herds, together with an ethnographic survey, will be conducted in southern Jordan (Ma'an and Aqaba governorates). These studies will address knowledge gaps identified through the Foundation Award as important to inform future vaccination strategies such as who should be targeted for vaccination and the sociocultural issues, including vaccine acceptability, that are likely to be faced. Appropriate hygiene education interventions will be introduced as part of a randomized pilot feasibility trial in which half of the households will be randomly selected at month 18th of the project, with the other half remaining as 'control arm' during the following 6 months. Primary outcomes of the trial will be obtained from interviews on acceptability, perceived difficulty in implementing together with reported and observed behaviour related to avoiding camel oral and nasal secretions. Secondary outcomes will be based on serology in humans and camels in those having had the intervention in first half of year two compared to those who have not yet had the intervention. We will exploit opportunities for capacity building through grass-roots and higher-level workshops and engagement activities with the support of Jordan's Royal Scientific Society and US NIH. The importance , timeliness and opportunity of this project resides on the global public health threat posed by MERS-CoV, with Jordan as one of its epicenters, and the work carried out with the Foundation Award, which has generated knowledge and conditions that allow piloting of interventions.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;3.4 VACCINES
Health categories: INFECTION