NIHRDataInsights/HRCSData huggingface dataset:
Title: Tackling Histoplasmosis; a neglected disease impacting on equine health and human livelihoods.
Funder: Wellcome Trust

Abstract: Histoplasmosis is a neglected yet prevalent disease among working equids in sub-Saharan Africa where horses provide a critical source of income and draught power for transport and agriculture to millions of people. There is a lack of evidence for the mechanisms of transmission and persistence of histoplasmosis offering little rationale upon which to base disease control. This novel multidisciplinary study will combine epidemiological, ecological and community engagement approaches to investigate the dynamics of this endemic disease, and will be achieved through an international collaboration across the academic, veterinary and NGO sectors. Phase 1 comprises a prospective multi-centre cohort study, a nested case-control study, and a clinical case-series. Clinical and environmental samples will be collected along with epidemiological data to determine the contribution of environment and host factors to both susceptibility and response to the disease. Clinical samples will be analysed using serological and molecular biological techniques to determine the presence and state of infection and to characterise Histoplasma diversity. Single-cell genome sequencing will be used to define predominant and/or virulent strains. Phase 2 will involve consultation with the community and regional stakeholders to share research findings and develop and disseminate disease prevention advice facilitated by the NGO partners.

Lay abstract: Histoplasmosis, causing epizootic lymphangitis (EZL), is a severe fungal infection that occurs frequently among working horses in Sub-Saharan Africa. This disease has significant impacts on the health and welfare of horses, and on human livelihoods. This debilitating sickness leads to a reduction in the horses’ ability to pull carts for agriculture and transport, resulting in reduced income for dependent families. Little work has been done to understand how this disease is transmitted, meaning that the best methods for controlling disease are currently unknown. This research programme will investigate how this disease is transmitted in Ethiopia and The Gambia through analysing animal management information, and environmental and clinical samples. Molecular biological and statistical analyses will compare animals with and without EZL, establish the main routes for infection, whether there are particular strains of Histoplasma that are contributing to disease and whether there are similarities between Histoplasma species that infect horses and people. This project brings together an international team including experts in infectious disease, fungal pathobiology, global and population health and veterinary NGO’s. Project findings will be shared with local communities, regional clinics and laboratories that will be consulted on the design of achievable and practical prevention strategies.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Rethinking How to Understand the Burden of Antibiotic Resistant Bacteria: establishing best-practice through comparative analyses
Funder: Wellcome Trust

Abstract: This work will complement the Global Research on AntiMicrobial (GRAM) project estimating the global burden of drug resistant infections (antimicrobial resistance, AMR). The work will establish the best practice in quantifying the burden of AMR through the comparative analysis of selected data sets from the GRAM project and synthetic data generated using mechanistic models. Key goals include comparative estimates of the burden of AMR for selected data sets and evaluations of the appropriateness of different analytical approaches for different types of data and different epidemiological processes. In particular, the work will determine: i) under what circumstances the assumption that resistant infections fully replace sensitive infections with the same species is appropriate for quantifying the burden of AMR; ii) under what circumstances the contrasting assumption that resistant infections add to the burden rather than replacing sensitive infections is appropriate; and iii) under what circumstances the intermediate assumption of partial replacement is appropriate.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Infectious content: Online misinformation & vaccine confidence in UK parents
Funder: Wellcome Trust

Abstract: Infectious content: Online misinformation & vaccine confidence in UK parents This research will investigate the nature of anti-vaccination messaging disseminated on social media and its effect on vaccine confidence among UK parents.. Vaccination is among the greatest achievements in human health. Yet successes in consolidating coverage are fragile even in the UK where childhood vaccine uptake continues to decline year-on-year. Anti-vaccination messaging on social media is widely decried as a causal factor fuelling parental concerns. Academic research is running to catch up with the scale and complexity of the challenge, which warrants nuanced and context-specific understanding. Simultaneously social media users are migrating towards closed messaging platforms and visual social networks, with relatively closed APIs, which make it harder for academics to access vaccine misinformation. Research is lacking and new approaches are required. The proposed research will use a mixed-methods approach to map anti-vaccine claims and ideologies on visual platforms while recruiting focus groups of UK parents-turned-citizen-scientists to collect anonymised related content received on private messaging platforms. Research will examine ethical considerations including the right to parental choice, attitudes to mandatory vaccination, consent around the infiltration of private online spaces, and data privacy in line with GDPR.

Lay abstract: Infectious content: Fake news about vaccines and its influence on UK parents Vaccines help protect our children from catching childhood diseases like measles but some UK parents have started to doubt whether jabs are necessary or even safe. I want to understand how far parents who choose not to vaccinate their children may have been influenced by posts they've seen on social media, or on messaging apps like WhatsApp, claiming vaccines are unsafe or unnecessary. Alongside analysing vaccine-related public social media posts I'll recruit a group of UK parents to be interviewed and join discussion groups to talk about how they feel about vaccines and to share content they've seen on social media and messaging apps which may have affected their attitudes to immunisation. By better understanding these influences, I hope my research will help inform policy to provide parents with more accessible, verified information about vaccines through online channels.

Research activity codes: 3.4 VACCINES
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Generating collective solutions to reduce unnecessary antibiotic use in Vietnam
Funder: Wellcome Trust

Abstract: Antibiotic resistance in Vietnam is amongst the highest in the world, driven by high levels of antibiotic use for human and animal health. Community understanding and perceptions about antibiotics and antibiotic resistance is poor, and antibiotics are often prescribed inappropriately in healthcare settings. There is limited evidence for the effectiveness of public engagement approaches to promote appropriate antibiotic use, compared to more traditional education-based methods, or for understanding the pathways and facilitating conditions for successful behaviour change. We will facilitate community-wide change in the way people prescribe and use antibiotics for human and animal health. We will compare three different One Health approaches to change behaviour: training for human and animal health-workers; a public information campaign for communities and farmers; and participatory action research groups. Activators in communities and healthcare settings will guide groups through a four-phase action cycle similar to Wellcome’s Responsive Dialogues approach, covering: 1. Understanding the problem of antibiotic resistance; 2. Planning and implementing strategies; 3. Monitoring strategies and generating evidence; 4. Evaluating strategies and planning future actions. We will evaluate the impact on knowledge and behaviour through qualitative and quantitative methods. We will engage local researchers and policymakers through formative discussions and dissemination meetings.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: A health policy analysis of vaccine policy decisions in the Association of Southeast Asian Nations region to develop a framework to guide vaccine policy decisions: emergence of mandatory vaccine agendas, decision making process and influences.
Funder: Wellcome Trust

Abstract: Vaccine policy agendas, decision making process and influences to the decisions highly vary across countries. In recent years, mandatory vaccination policies have been introduced globally, to enforce specific vaccinations on target populations in a country. The policies pose various ethical and legal dilemmas that have been highly debated by academics, policy makers, and country citizens. Some studies have evaluated the policy impact on vaccine coverage and discussed ethics and perspectives of stakeholders. However, research has been geographically biased to Europe and United States; though the policies have been adopted globally, including among the member states of the Association of Southeast Asian Nations. Given the disparities in results and controversy of the policy, the policy decision-making on mandatory vaccinations have not been well understood. To fill this gap in research, this qualitative study will select two countries in ASEAN as cases, and apply policy theories to data collected through literature reviews and key-informant interviews. The study aims to understand the emergence of mandatory vaccinations in policy makers agenda and the actors involved, context of policy adoption and the process and influences of the policy decision. This study aims to develop a vaccine policy decision framework to guide future vaccine policies.

Lay abstract: Vaccine policy decisions and processes are not well understood. In recent years, mandatory vaccine policies have been introduced in many countries, including in Asia. These vaccine policies that take away the choice for refusing vaccines, has been controversial and highly debated. Currently, why countries choose to introduce these policies is not known. For this study, I propose to review available literature and conducted interviews with key persons involved in vaccine policies in two countries in Asia. I will use a policy framework to evaluate who decided on the mandatory vaccine policy, why they decided on the policy, how they made the decision and what influenced their decision. I aim to develop a framework which I hope will help inform future policy and position decisions on vaccinations.

Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: 3D bioprinting for enhanced biosensing, regenerative medicine and pharmaceutical manufacture
Funder: Wellcome Trust

Abstract: The GeSiM BioScaffolder 3.1 printer is a flexible 3D bio-printer with a unique piezoelectric micro-pipetting system for pico- and nano-litre spotting of cells and biomolecules, as well as pneumatically-actuated cartridges for precise printing of highly viscous materials (e.g. molten polymers) on definable coordinates within a scaffold structure or on flat surfaces. This combination of both technologies is unique and not available on competitor 3D printers. The BioScaffolder can print polymers at temperatures up to 250°C, while cells and biomolecules (e.g. enzymes, proteins) can be maintained at 37°C. This innovative approach allows struts of mechanically-stiff materials to be combined with cell-friendly materials (e.g. hydrogels) containing suspended cells in novel regenerative medicine approaches. The instrument automatically aligns print tools of different dimensions by means of a 3-axis light barrier. Struts of up to three different materials can be combined, even in a single layer. Individual cells, cell suspensions and aqueous polymer solutions can be printed onto substrates for applications in single-cell analyses, biosensing and drug delivery. Importantly, the Bioscaffolder can be interfaced with existing analytical equipment, with individual cells or solutions printed directly into instrument sample holders, or onto microfluidic chips or biosensor substrates.

Lay abstract: We will purchase a unique device that is capable of controlled printing living cells, proteins, therapeutic antibodies, as well as conventional medicines, without damaging them. In addition, this printer will be able to accurately print both water-based gels and hot plastic melts in defined 3-dimensional shapes. This device can be used in regenerative medicine applications, such as creating better implants for damaged bone or replacement joints, but also in understanding disease by printing one cell at a time for analysis, thus helping selection of optimised treatments. Moreover, a range of novel devices for enhanced delivery of medicines and vaccines can also be produced, allowing many of the current problems associated with difficult-to-deliver medicines to be overcome. This instrument will impact strongly on our research, helping deliver a step change in innovation, creating new knowledge and, of most importance, enhancing the health-related-quality-of-life of people worldwide.

Research activity codes: 1.3 CHEMICAL AND PHYSICAL SCIENCES
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Investigating the Structural Basis for Ion Channel Multimodality in novel Mechanosensitive Ion Channels
Funder: Wellcome Trust

Abstract: Channel proteins control solute flux between membrane compartments in response to physical and/or molecular stimuli. Mechanosensitive channels sense changes in lateral tension and bacteria rely on these channels to prevent cell lysis from osmotic pressure. The mechanosensitive MscS-like superfamily has six members and there is a limited understanding of their structural diversity, including unique domains. The fungal Cch1-Mid1 channel also has regions of unique sequence largely in its Mid1 subunit, which has no homologous protein outside fungi. Controversy exists over whether this calcium channel is directly mechanosensitive and/or voltage-gated. I will develop structure-function relationships in these mechanosensitive channels to understand the undefined roles of unique domains, and the structural basis for their mechanosensitivity/multimodality. I will combine Cryo-EM and PELDOR with electrophysiology and biochemical assays, to structurally and functionally characterise these systems. Due to unifying principles, microbial mechanosensitive channels are valuable models of mechanosensation in higher organisms, with the Cch1-Mid1 system providing a unique opportunity to understand mechanosensitive protein complexes. Both Cch1-Mid1 and the MscS-like channels are implicated in pathogenicity and virulence, with Cch1-Mid1 a particularly promising antifungal target for opportunistic pathogens. Structural characterisation of the channel will provide the foundation for novel antifungal development.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Understanding heterogeneity of immune cell responses through analysis of transcriptional bursting
Funder: Wellcome Trust

Abstract: The transcription of almost all genes occurs via random transitions between active and inactive gene states. The net mRNA production is determined by the frequency and size of the resulting random bursts of mRNA synthesis, making gene expression a stochastic process. As a consequence, responses of individual immune cells upon bacterial infection are highly variable, resulting in different infection outcomes. For example, only a subset of innate immune macrophages may accurately recognize and kill invading bacteria. In this project, using mathematical modelling of transcriptional bursting, inference of single-cell genomics and live-cell imaging data, I aim to understand mechanisms involved in coordination of the innate immune responses to pathogen stimulation. In particular, I will study how the foodborne Listeria monocytogenes manipulates the host cell’s gene expression and signalling responses in order to establish a successful infection. I hypothesise that modulation of transcriptional bursting characteristics is a key control mechanism that allows the host to fine-tune its response to pathogen infection, and in turn enables the pathogen to implement its infection strategy. Mechanistic understanding of transcriptional dynamics induced by bacterial infection will inform strategies to improve infection outcomes in the future.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Structural investigation into the Tol-Pal transenvelope machine and how it utilises the proton motive force
Funder: Wellcome Trust

Abstract: Antibiotic resistance is a global health issue that threatens modern medicine and how we treat bacterial infections. Investigating how bacteria live is important to fight against antibiotic resistance as it can lead to new approaches for dealing with bacterial infections, and new targets for antibiotics. The research project we are proposing aims to further our understanding of a system called Tol-Pal in a class of bacteria called Gram negatives. Tol-Pal has been shown to have a role in cell division and is important for the growth of Gram-negative bacteria. At the moment, we do not fully understand how the components of Tol-Pal work together to carry out this function. In this project we hope to use structural biology techniques to see what a complex of three of the proteins in the Tol-Pal system, TolQRA, look like. We hope that finding out what TolQRA looks like will help us to investigate the mechanism of TolQRA within the Tol-Pal system, and further our understanding of Gram-negative bacteria and how they work.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Investigations into assembly, egress and virus-host interactions of Oropouche Virus
Funder: Wellcome Trust

Abstract: Tri-segmented bunyaviruses, which includes Rift valley fever virus and Oropouche virus (OROV), are responsible for a variety of human diseases ranging from self-limiting symptoms such as acute febrile illness, to lethal encephalitis and haemorrhagic fever. OROV is the first example of a virus shown to recruit endosomal sorting complex required for transport (ESCRT) components to virus assembly sites in the Golgi, through unclear mechanisms. During this project, I will develop virus-like particle assays to determine whether ESCRT recruitment is conserved across representative tri-segmented bunyavirus families. Once this has been established, I will investigate the molecular mechanisms that drive ESCRT recruitment to sites of bunyavirus assembly. I will do this by employing a range of proteomic approaches, that will utilise exogenously expressed bunyavirus envelope glycoproteins to identify potential interaction partners that are involved in ESCRT recruitment. Finally, I will conduct experiments using live OROV in collaborative research trips to Brazil, to understand how the virus changes the proteome of the cell during infection using a variety OROV mutants. These studies will elucidate a potentially novel mechanism of ESCRT recruitment during virus assembly and provide detailed understanding of bunyavirus-host interactions. Such new insights into bunyavirus infections may aid in development of antivirals.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Determining the architecture of the HCV replication complex
Funder: Wellcome Trust

Abstract: The hepatitis C virus (HCV) infection induces an intracellular rearrangement in the host cell forming many vesicles referred to as replication organelles. In particular, double membrane vesicles (DMVs) are proposed sites for the HCV replication. The HCV polyprotein is composed of structural and non-structural proteins. Five of the non-structural proteins form the replication complex. I aim to determine the ultrastructure of the HCV replication complex by taking a multidisciplinary approach. I will use biochemical, biophysical and structural analyses, including confocal microscopy, super-resolution approaches and cryo-CLEM, to visualise how and where these non-structural proteins form the replication complex. I aim to investigate in detail whether the replication complex is formed inside the DMV or on the surface. I will also determine the topology of nascent HCV RNA which will provide extensive knowledge about HCV replication. These studies will help to explain the concerted action of non-structural proteins and their role in HCV replication.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;INFECTION
Title: Structure-Function Studies of Lipid Transporters
Funder: Wellcome Trust

Abstract: Lipid transporters are a class of membrane proteins that perform critical functions in many organisms. These proteins transport lipid molecules from one leaflet of a lipid bilayer to the other leaflet. In bacteria, lipid transporters can confer resistance to antibiotics, whereas in humans, dysregulation of lipid transporters has been implicated in a number of neurological disorders, highlighting the important role these proteins can play in health and disease. However, the mechanism of action of many of these transporters is poorly understood, in part due to the difficulties involved in the structural studies of membrane proteins. Therefore, this project aims to look at two lipid transporters that are implicated in health and disease: the bacterial Multiple Peptide Resistance Factor (MprF) and the human transporter TMEM16K. The focus in both cases will be on structural elucidation using a combination of cryo-EM and crystallography. The information obtained from these structural studies will be used in combination with biophysical assays to advance our fundamental understanding about the function of these proteins, whilst providing the groundwork that could be used to develop future novel therapeutics to target these proteins.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;INFECTION