NIHRDataInsights/HRCSData huggingface dataset:
Title: Dissecting the role of host receptor context and cytoskeletal disruption in malaria parasite invasion
Funder: Medical Research Council

Abstract: The ultimate goal of this proposal is to understand and dissect the dynamic remodelling of the host red blood cell (RBC) membrane that occurs during malaria merozoite invasion. Using novel reticulocyte phenotypes derived through in vitro erythroid culture that comprise both domain swap hybrid surface receptor proteins and modified cytoskeletal adaptor proteins we will explore the role of host proteins in this process at both the extracellular and intracellular face of the membrane. Whilst essential roles for several RBC membrane proteins have recently been reported, in many cases insight into the role that these host cell proteins actually play in the invasion process, extending beyond mere putative sites of attachment is severely or completely lacking. In vitro derived reticulocytes in which customised mutant and domain swap hybrid receptors basigin, CD55 and CD44 are expressed upon knockout backgrounds will enable us to determine the requirement for specific plasma membrane context, associations and mobility of these host receptors for successful invasion. Since extracellular attachment of the merozoite to the RBC potentiates the transient cytoskeletal disruption required for invasion we will also investigate the basis of this host remodelling event. Using site specific editing of phospho-modifiable residues on adducin and other proteins we will uncover the role of cytoskeletal adaptor associations and their regulation within the host junctional complex. Through interrogation of both the invasive susceptibility and biomechanical properties of these modified cells we will determine the nature of and degree to which existing host mechanisms for regulating cell deformability are co-opted or circumvented by the parasite and identify potential approaches to target invasion without impaired capillary deformation capacity.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: A novel pathway in the control of memory T cell function during immune responses to viral re-infection.
Funder: Medical Research Council

Abstract: Immunological memory underpins how we respond to pathogens more robustly upon re-infection, and how vaccinations work. Memory T cells are critical to these responses. However, it is poorly understood how memory T cells are regulated to promote eradication of the pathogen upon re-infection, whilst preventing over-exuberant responses that could damage the host. In new preliminary work we show that a subset of CD4+ effector memory T cells activate the cytokine TGF-beta, via the cell surface receptor integrin alphav beta8. Intriguingly this pathway appears to suppress the CD8+ T cell response during murine models of influenza re-infection and experimentally removing the pathway promoted a stronger response that increased viral clearance. This raises many important questions on how this contributes to the regulation of CD8+ T cells. In this project we will characterise the cellular and molecular mechanisms underlying this new paradigm, identify its functional importance in host immune defence, and its role in regulating responses to viral re-infection in humans. The results will provide a step-change in our understanding of how memory T cell responses are controlled during viral infection, and reveal candidate mechanisms that could be targeted to promote more effective responses to infection.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Aversion Therapy for Bacteria: Repurposing Aurodox
Funder: Medical Research Council

Abstract: There is an urgent need to develop new strategies to combat infectious disease against the background of the antimicrobial resistant (AMR) infection crisis. The World Health Organisation (WHO) has identified AMR as one of the greatest threats to global human health and we need to develop new strategies to reduce our reliance on antibiotics. The UK government has produced a five-year strategy to address AMR. In the UK, 17% of Escherichia coli strains isolated in 2009 could be categorized as multi-drug resistant (MDR), that is, resistant to at least three categories of antimicrobials. Moreover, frequently overlooked is the additional problem that some bacterial strains carry potent toxins which further complicates possible treatment with antibiotics. Enterohaemorrhagic E. coli (EHEC) strains carry Shiga toxins that are located on temperate phages. Expression of phage genes occurs when the phage lytic cycle is activated by induction of the SOS response, hence antibiotics are not recommended during these infections. We are interested in developing ways to efficiently and selectively "switch off" virulence factors central for pathogenesis. Recently we were able to add mechanistic insight to the work of Kimura et al who had shown that aurodox, a specialised metabolite produced by Streptomyces goldiniensis, blocks pathogenesis of the murine pathogen C. rodentium. We demonstrated that aurodox is able to down regulate the type III secretion system (T3SS) in EHEC. In this proposal, we will determine whether aurodox can prevent and treat infections with bacterial strains carrying the Shiga toxin, study the effect aurodox has on the host microbiome and the potential of strains to develop resistance to the compound. We will also exploit the fact we have cloned the entire aurodox biosynthetic cluster, to facilitate the generation of new derivates of aurodox. Our final aim will be to identify the specific target proteins bound by aurodox.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Genetic identification of host factors required for SARS-CoV-2 cell infection
Funder: Medical Research Council

Abstract: The unprecedented medical and economic impact of the SARS-CoV-2 pandemic represents a global challenge to the scientific community. In the absence of any vaccine or therapeutic agent, it is essential to understand how SARS-CoV-2 interacts with its host cell with the aim of identifying viral vulnerabilities for potential therapeutic intervention. Inhibitors of viral entry have been developed for HIV and HCV and represent an attractive step for therapeutic intervention. In this application we will use our expertise in CRISPR-Cas9 genome-wide forward genetic screens to identify host factors required for virus entry and infection. SARS-CoV-2 cell entry is dependent on its spike protein which mediates both binding to its cognate cell surface receptor, Ace2, and fusion of viral and cellular membranes. The Spike protein is activated by the host cell serine protease TMPRSS2 which promotes viral fusion with the cellular membrane. The role of other host cell proteins in viral entry and infection is less clear, nor do we know how the low oxygen tension of COVID19-infected lungs, affects viral infection. We have developed different models of virus entry, including internalisation of Spike fusion protein, Spike protein pseudovirus infection and, infection with live SARS-CoV-2 virus. Using these tools we will perform genome-wide forward genetic screens to identify host factors required for (i) the regulation of cell surface Ace2 expression; (ii) entry of SARS-CoV-2 into the cell and whether this is affected by low oxygen tension. (iii) Having identified the host factors required for SARS-CoV-2-mediated entry we will validate our results in the context of SARS-CoV-2 infection of primary human bronchial epithelial cells. We will characterise our hits and determine their therapeutic potential. We anticipate that the comprehensive identification of host cell factors essential for SARS-CoV-2 infection will identify targets for the development of novel antiviral agents.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: MOLECULAR BARRIERS TO THE EMERGENCE OF CORONAVIRUSES IN HUMANS
Funder: Medical Research Council

Abstract: We hypothesise that certain circulating bat coronaviruses (CoVs) could emerge in human populations with devastating consequences (similar to SARS-CoV-2). However, the existing human CoVs all appear to have emerged via transmission from possible intermediate species, rather than directly from bats, suggesting that specific molecular barriers may hinder direct zoonotic transmission from bats to humans. We therefore aim to identify both the bat CoVs with increased risk of emerging in humans, as well as genome-encoded defences that could constrain CoV cross-species transmission. By combining supervised machine learning with evolutionary and bioinformatic analyses, we will identify bat CoVs with an increased risk of emergence in humans. Six of these 'poised' bat CoVs will then be synthesised, and combined with highly pathogenic human CoVs, and seasonal human CoVs, to create a cross-species CoV test panel, on which we will focus further molecular experimentation. Previous studies have shown that genome-encoded antiviral defences can form powerful barriers to cross-species transmission of viruses, and are often encoded by interferon-stimulated genes (ISGs). We will therefore define the interferome of horseshoe bats (the reservoir of SARS-CoVs) and construct a library of ~150 horseshoe bat ISGs. These bat ISGs, along with our existing ISG libraries (human, macaque, bovine) will then be used to identify ISGs that inhibit any coronaviruses in our cross-species test panel (described above). Subsequent analyses will examine patterns of restriction of the anti-CoV ISGs in potential intermediate species, in order to identify blocks to cross-species transmission. Together, this knowledge should improve our capacity to make predictions about which CoVs are likely to make successful cross-species 'jumps', aiding surveillance of CoVs with pandemic potential. In addition, understanding how ISGs inhibit CoVs could potentially improve our understanding of SARS-CoV-2 pathogenesis.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: MICA: A bioequivalent study to WHO prequalify a new 15 mg primaquine tablet.
Funder: Medical Research Council

Abstract: Primaquine (PQ) is fundamental to eliminating malaria by blocking the transmission of Plasmodium falciparum between humans and mosquitoes and killing P. vivax liver hypnozoites to prevent relapses, the main cause of the continuing vivax burden. PQ is barely used by malaria control programmes (MCPs) for two main reasons: (i) G6PD deficiency testing, required before PQ radical cure is prescribed, is not widely available, and (ii) easy-to-use regimens of quality assured (QA) PQ tablets covering the age spectrum do not exist, thus excluding children, a key vulnerable group. Cognizant of this substantial public health gap, the WHO called for the prequalification of 2.5, 3.75 and scored 5, 7.5 & 15 mg tablets and detailed the required process. Prequalification starts with prequalifying a scored generic 15 mg tablet through a bioequivalence (BE) study that: (i) uses the international PQ reference, the Sanofi 15 mg tablet, (ii) is conducted to WHO standards and passes WHO inspection, (iii) establishes bioequivalence, and (iv) is followed by dossier submission to the WHO. Prequalifying the lower tablet strengths does not require more BE studies but is achieved by applying for biowaivers whereby these tablets are shown to be pharmaceutically equivalent (proportionality, dissolution properties) to the generic 15 mg tablet. Prequalification makes registration in malaria endemic countries easier and allows PQ bulk purchase and deployment using Global Fund money. We seek funds for the BE study to engage IPCA, the industrial partner, through a MICA which provides the necessary legal framework for the planned work. Developing QAPQ as a public good dovetails with our current work of designing evidenced-based, allometrically scaled PQ regimens for transmission blocking and radical cure and bespoke to enhance patient adherence. Thus, increasing access to QAPQ will have a significant impact on malaria elimination.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: UK-REACH: United Kingdom Research Study into Ethnicity And COVID-19 outcomes in Healthcare workers
Funder: Medical Research Council

Abstract: Healthcare workers (HCWs) from Black, Asian and Minority Ethnic (BAME) groups are disproportionately affected by COVID-19. Collaborating with the General Medical Council (GMC), Nursing and Midwifery Council (NMC) and Professional bodies/associations we will undertake a mixed-methods study with the aim of investigating if, how, and why, ethnicity affects COVID-19 clinical outcomes in HCWs. We aim to provide rapid evidence through five interlinked work packages (WP). WP1: Undertake an expedited linkage and analysis of anonymised GMC and NMC registration and NHS datasets, within a Trusted Research Environment (SAIL databank) to calculate the incidence of, and outcomes from, COVID-19 amongst HCWs. WP2: Rapidly establish a longitudinal cohort study of BAME HCWs, nested within the GMC/NMC datasets. At baseline, survey information will be collected about demographics, HCW role, interaction with COVID-19 patients, social circumstances and physical/mental well-being; baseline biological samples will be collected for genomic and serological profiling. Follow-up surveys and samples will be collected over twelve months to capture changes in survey/serological responses to forthcoming COVID-19 pandemic waves. WP3: Undertake research to understand and address legal, ethical and acceptability issues around data protection, privacy and information governance associated with the linkage of professionals' registration data and healthcare data. WP4: Undertake qualitative interviews and focus groups of BAME HCWs to understand risk perceptions, support and coping mechanisms in relation to COVID-19. WP5: Develop a multi-professional, national stakeholder group including the GMC/NMC, Royal Colleges, BAME Professionals' Associations, and BAME HCWs to facilitate rapid dissemination and translation of the research findings for HCWs/Employers/Policy-Makers.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: INFECTION
Title: COVID-NURSE. The development, testing and evaluation of a COVID-19 fundamental nursing care protocol: a randomised controlled trial
Funder: Medical Research Council

Abstract: Background: nursing care is a key determinant of patient experience and correlated with safety, clinical effectiveness, care quality, treatment outcomes and reduced overall service use. No evidence-based nursing protocols exist to address the unique challenges of nursing hospitalised patients with the SARS-CoV-2 virus. Aim: to co-create and evaluate the impact on patient experience, care quality, functional ability, treatment outcomes and costs of a nursing care protocol specifically addressing the fundamental care requirements of hospitalised patients with the SARS-CoV-2 virus not invasively ventilated. Methods: 2-stage mixed-methods programme, following revised 2020 complex interventions guidance, of: 1) rapid-review, survey, co-creation consensus development of a nursing protocol; 2) rapid-cycle cluster randomised controlled trial with embedded process and economic evaluations. Deliverables: 1.Fundamental nursing care protocol for hospitalised patients with the SARS-CoV-2 virus not invasively ventilated, with proven effectiveness on patient experience, care quality, functional ability and treatment outcomes within 9 months of project inception. 2.Feasible, acceptable and 'implementation-optimised' protocol for widespread implementation, through co-creation and changes implemented during rapid cycle trial waves. 3.Adaptable protocol designed to be generalisable for environments such as care homes, patients with other conditions requiring isolation and to global health systems via knowledge gained in a process analysis of intervention fidelity, mechanisms, contextual factors and implementation. 4.Guidelines, education materials and strategies accessible via Health Education England, the Open University's FutureLearn web platform, and experienced NHS sites acting as training hubs for other health Trusts/care homes/global health systems.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;8.2 HEALTH AND WELFARE ECONOMICS
Health categories: INFECTION
Title: Quantifying the association between COVID-19, ethnicity and mortality: A cohort study across three UK national databases
Funder: Medical Research Council

Abstract: Purpose: Early evidence suggests increased severity of COVID-19 disease amongst Black, Asian and Ethnic minority (BAME) groups. There is limited evidence from population-based cohorts at scale across the UK or internationally that quantify within BAME group differences, or examine these in relation to modifiable risk factors. Aim: To describe the prevalence of confirmed COVID-19 cases by ethnic group in a large and representative sample of UK adults, and to quantify the association between ethnicity and mortality stratified by COVID-19 infection and modifiable clinical and social risk factors (blood pressure, HbA1c level, total cholesterol, Body Mass Index, smoking status, co-morbidities, medication use, domicile and household number). Methods: A cohort study of adults registered across three large national primary care databases in England, representing over 40% of the UK population. Participant sociodemographic, deprivation, clinical and domicile characteristics will be summarised and compared by higher level ethnic group (White, Black, Asian and Mixed Other) and their subgroups. For example, the Asian subgroup includes Pakistani, Indian, Bangladeshi or Chinese while the Black subgroup includes African or Carribean, as per the 2011 census. Hazard ratios and 95% confidence intervals for all-cause mortality and COVID-19 mortality, adjusted for potentially confounding factors will be calculated using Cox's proportional hazard regression. Implication: Our findings could provide rapid evidence on patterns of COVID-19 and associated mortality across and within ethnic groups in the UK. This has the potential to inform targeted mitigation public health strategies, and could alter clinical thresholds for at-risk patients presenting with the infection.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Evidence-Based Supported Digital Intervention for Improving Wellbeing and Health of people living in Care Homes (WHELD) During COVID-19
Funder: Medical Research Council

Abstract: The 400,000 people living in care homes and those caring for them are severely impacted by the COVID-19 crisis. The residents are the frailest members of society, many with dementia, mental health/neuropsychiatric symptoms and/or concurrent physical illnesses. Providing support for these individuals is challenging for care staff who are facing a difficult, distressing and isolated work environment. We urgently need to support care staff and provide the best environment possible for care home residents. We developed a care home training intervention which improved quality of life, mental health and reduced sedative drug use across two large clinical trials in the NIHR WHELD programme. Subsequently we have evaluated and demonstrated benefits from a digital version of WHELD with virtual supervision. We will provide an adapted version of this programme to almost 1500 care homes. We will first develop specific adaptations for the COVID-19 crisis, such as peer networking and solution sharing, alongside evidence-based elements focussing on person-centred care, personalised activities, and reduction of unnecessary sedative medications. We will implement the optimized digital intervention in 160 care homes within four weeks, including virtual supervision. We will evaluate outcomes relating to staff mental health and attitudes, and resident quality of life, attainment of care goals, and use of sedative medications, and examine facilitators of and barriers to effective implementation. Building on the findings we will evaluate efficacy and cost-effectiveness in 1280 care homes using a randomized delayed start design. We will then make the programme "implementation ready" for national care home roll-out.


Research activity codes: 8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES);8.1 ORGANISATION AND DELIVERY OF SERVICES;8.2 HEALTH AND WELFARE ECONOMICS
Health categories: INFECTION
Title: TRIM: What Triage Model Is Safest And Most Effective For The Management Of 999 Callers With Suspected COVID-19? A Linked Outcome Study
Funder: Medical Research Council

Abstract: The COVID-19 epidemic in the UK has caused surges in 999 calls from people concerned about possible coronavirus symptoms including fever and shortness of breath. The London Ambulance Service, for instance, has, at times, received three times its usual number of 999 calls each day for a sustained period. The emergency ambulance service has to triage calls to decide, firstly, whether to dispatch a vehicle to attend a caller for face to face assessment, and, if attended, whether to convey the patient to hospital. This triage is key to identifying patients who need to be treated in hospital. Undertriage will result in patient harm, in this case, avoidable deaths. Overtriage will result in unnecessary conveyance to the Emergency Department, exposing patients to risk of infection, diverting resources from those in need and overburdening already pressurised services. Different models of triage are being used by services across the UK, reflecting different: priority dispatch systems (AMPDS, NHS Pathways); models of clinical advice in the ambulance call centre (paramedics, nurses, medics including GPs); response options (Emergency Medical Technician/paramedic/advanced paramedic staff; patient carrying/non-patient carrying vehicle); protocols for on scene triage to make conveyance decisions; and options for referral or call back. The lack of evidence about what model of triage works best for patients and the NHS in a pandemic situation such as COVID-19 will be filled by this linked outcome study across England, Wales and Scotland.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE;7.3 MANAGEMENT AND DECISION MAKING;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: INFECTION