NIHRDataInsights/HRCSData huggingface dataset:
Title: Host and Viral Determinants of Interferon Resistance During HIV-1 Transmission
Funder: Medical Research Council

Abstract: The hypothesis underlying this proposal is that transmitted/founder (TF) HIV-1 is more interferon resistant than other HIV-1 genetic variants, and that specific interferon (IFN)-stimulated genes (ISGs) underlie this phenomenon. We will identify and characterise ISGs that limit HIV-1 transmission and define how TF viruses avoid this inhibition. The most important restriction factors targeting HIV-1, such as APOBEC3G, TRIM5, tetherin and SAMHD1, were identified using cell lines. However, TF HIV-1 interferon resistance is typically only revealed in primary cell systems. In our preliminary experiments, we unexpectedly observed that TF viruses can exhibit striking IFN resistance in cell lines. Thus, this important phenotype is now amenable to investigation using more tractable experimental systems. To probe the determinants of TF HIV-1 IFN resistance, we will perform fine mapping using chimeric viruses comprised of our already identified IFN sensitive and IFN resistant infectious molecular clones (IMCs). We will also expand this approach to other IFN-phenotypes using chimeric IMCs, and will use in vitro evolution to identify additional viral IFN sensitivity/resistance determinants. Importantly, we will validate our observations using primary cells and patient sequence data. To identify the ISGs resisted by TF HIV-1, we will screen over 500 individual human ISGs to identify genes that inhibit HIV-1. Using matched TF and chronic control (CC) IMCs, we will uncover anti-HIV-1 ISGs that are resisted by TF HIV-1. We have substantial expertise with ISG screens and have previously studied restriction factors inhibiting multiple stages of the HIV-1 lifecycle, leaving us well placed to characterise how these ISGs inhibit HIV-1. Our ultimate goal is to generate and disseminate important knowledge illuminating HIV-1 transmission. This will stimulate further research in this area, and in the long term, inform the design of intervention strategies targeting TF HIV-1.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Molecular Dissection of England's Scarlet Fever Upsurge 2015-2016 and Impact on Invasive Infections
Funder: Medical Research Council

Abstract: Background: Surges of scarlet fever have historically been associated with increased invasive group A streptococcal (iGAS) infection. Major surges of scarlet fever were reported in 2014-2016. Although no increase in iGAS was detected in 2014, in 2016, rates of iGAS rose markedly during the peak weeks of scarlet fever activity. In contrast to 2014, one dominant lineage of GAS emerged in 2015 among throat isolates. This type of GAS was also the leading cause of invasive disease, strongly suggesting that the two events were linked. Aims: We will determine if the emergent lineage is better suited to causing outbreaks of pharyngeal infections or iGAS, and determine if differences observed could be linked to the specific genetic changes that distinguish this lineage from other strains. Scientific approach: Genome-sequenced strains representative of the emergent lineage and those that are closely related but not within the emergent lineage will be subject to the following comparisons A. Fitness to cause nasopharyngeal infection 1. Adhesion to matrix proteins and human tonsil 2. Survival in the mucosal environment 3. Expression of virulence factors associated with pharyngeal infection. 4. Transcriptomic differences on human tonsil. 5. Longevity of carriage in the nasopharynx and transmission B. Fitness to cause invasive infection or adverse outcome 1. Surviving human immune responses 2. Surviving during soft tissue infection 3. Linkage of iGAS genomic data to demographic, severity, and mortality data. 4. Genomic analysis of throat and iGAS strains to determine similarity. C. What is the molecular basis for differences in lineage success? 1. Can mutation of the SNP that distinguish the lineage alter its phenotype and reduce fitness? 2. Can introduction of the same SNP to other strains confer increased fitness? The work will provide definitive information about the new lineage and data regarding the variant genes identified therein


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Targeting airborne bacterial infection: Studies on patient- and laboratory-generated mycobacterium tuberculosis aerosols.
Funder: Medical Research Council

Abstract: We recently established methods to obtain transcriptome profiles from TB patients' cough aerosol samples. These will be used here to elucidate the biological properties of Mtb that support its airborne transmission. As Mtb's survival depends on aerosol transfer from TB cases to contacts, interventions directed to this phase have major potential to impact on the global annual incidence of 9 million cases. Our strategy is to sample cough aerosols produced by newly diagnosed TB patients in Pretoria and model these in vitro in contained aerosol chamber (Goldberg drum) studies. Use of CASS aerosol sampling, which has been shown to categorize patients associated with high and low risks of household transmission, will link our results to infectivity. We will test our hypothesis that the properties of Mtb in early aerosols (<30s post cough) are distinct from those in sputum and that this reflects a selective aerosolisation process. The drum studies will allow us to determine transcriptional adaptations of Mtb to the aerosol environment over extended times (up to 4h) and to screen for genes supporting aerosol transfer by use of an established Mtb transposon mutant library. These studies will be underpinned by nucleotide sequencing and will provide transcriptome, relative mutant frequencies and microbiomic profiles as required. Both patient and lab studies will be used to evaluate the potential contribution to transmission of Mtb cells incapable of forming colonies on primary culture. High numbers of these growth factor dependent cells have been demonstrated by us in sputum and in preliminary aerosol studies. The two sampling systems will be subjected to computational fluid dynamics modelling to assess internal airflows and the impact on sampling efficiency. Combining these methods our biological results will enable us to develop a case-centred model of infectivity and focus on identifying and exploiting vulnerabilities of Mtb transmission amenable to intervention.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Bioengineering to combat the tuberculosis pandemic
Funder: Medical Research Council

Abstract: Innovative cross-disciplinary platforms are required to address infectious diseases prevalent in resource limited settings. Tuberculosis (TB) kills more than any other infection and is becoming increasingly resistant to antibiotics. In Southampton, we have developed a three-dimensional bioelectrospray cell culture system to study the host-pathogen interaction and have published and unpublished data demonstrating that events more faithfully mimic events in vivo. At the Africa Health Research Institute in Durban, parallel research themes have developed expertise in the ex vivo analysis of clinical samples and microfluidics, centred within a unique laboratory infrastructure. This project will combine these complementary approaches to deliver a collaborative interdisciplinary network built on strengths of each institution and prove the potential of advanced cell culture modelling to address diseases affecting the world's poorest. We will introduce the 3-D bioelectrospray system to the AHRI laboratories and utilise it to interrogate host immune response ex vivo from patients using primary lung cells. We will combine microspheres with a microfluidic sorter to systematically characterise granulomas containing TB infection from those with progression. We will utilise sequence data from granulomas removed at surgery for TB to transduce cells and characterise protective versus pathological host immune responses. Finally, we will combine microspheres with advanced microfluidic system to permit pharmacodynamic and physiological modelling of the peri-granuloma environment to develop more efficacious antibiotic combinations. This work will demonstrate the transformative potential of the model to study infectious diseases in resource poor settings and can equally be applied to diverse infections characterised by a prolonged host-pathogen interaction. It will initiate a collaboratory network to develop these findings towards novel interventions to control the TB pandemic.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFECTION
Title: m-Africa: Building mobile phone-connected diagnostics and online care pathways to support HIV prevention and management in decentralised settings.
Funder: Medical Research Council

Abstract: Undiagnosed and untreated HIV can have devastating consequences for the individual and populations, leading to increased morbidity, mortality, and transmission. South Africa has a forward looking mHealth strategy to deliver improved HIV health services but this emerging field is still in its infancy, with currently no safe and acceptable online care pathways and very limited knowledge of the usability and performance of devices in care pathways in low and middle income countries. With this Foundation Award we will assess facilitators and barriers to implementation of new mobile phone-connected diagnostics and online care pathways into the KwaZulu Natal health system for HIV prevention, diagnosis and clinical management. We will use mixed-method studies using qualitative (key informant interviews, focus groups) and quantitative methods (AHRI household survey of 100,000 residents) to: (i) map current HIV diagnostic capability and needs; (ii) explore smartphone/mobile phone and digital capability among service providers and users; (iii) explore ways mobile technologies are used and viewed; (iv) explore the acceptability and feasibility of integrating new diagnostics into a range of models, including health worker-led testing and self-tests. In parallel we will develop a range of innovative smartphone connected diagnostic tests, benchmark their performance to gold-standard tests (e.g. sensitivity, specificity, speed, cost compared ot laboratory ELISAs and PCR) and run small scale pilots of their usability in primary care and home settings. Technologies at our disposal span from apps to interpret commercial HIV tests to early stage assays utilizing advanced nanomaterials to detect p24 in acute infections and viral load. We will engage with a broad range of stakeholders to ensure we develop solutions allied to their needs. This work is pivotal to building a fit-for-purpose integrated mHealth diagnostic, prevention and clinical platform for HIV prevention in LMICs.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: INFECTION
Title: SEARCH: SouthEast Asian Research Collaborative in Hepatitis
Funder: Medical Research Council

Abstract: Novel interferon free treatments for hepatitis C have the potential to cure hepatitis C (HCV) and substantially reduce the resulting mortality from liver cancer and end stage liver disease. The WHO has set ambitious targets to treat 80% of those with active infection (over 70 million people) by 2030. However, access to new treatments is very limited , particularly by price. Vietnam (a low middle income country) has the 9th highest number of deaths attributed to viral hepatitis. An estimated 1 million people are infected with HCV in Vietnam, where the epidemic in Vietnam is unusually characterised by a prevalent circulating viral genotype (6), only seen at high levels in SE Asia. The proposed work will study a new interferon free treatment combination, sofosbuvir (NS5B inhibitor) and ravidasvir (NS5a inhibitor). The optimum duration of therapy for sofosbuvir/ravidasvir is not known and there is very little data with this or any treatment combination in genotype 6 HCV infection (the only Phase III study completed was done in genotype 4 infection). It is likely that many patients can be cured with treatments shorter than the licensed durations, with the potential to significantly reduce treatment costs and complexity of care. The work proposed will carry out two studies to evaluate the optimum duration of therapy (i) 60 patients (30 genotype 1, 30 genotype 6). Those whose virus is undetectable (<500 IU/ml) within 48 hours of starting treatment will receive 4 weeks of treatment; others will receive 6 weeks of therapy. All those failing treatment will receive 12 weeks of therapy (ii) in 43 cirrhotics with genotype 6 , patients achieving undetectable (<500 IU/ml) virus in blood at 2 weeks will received 12 weeks, all others 24 weeks. The studies will include full genome sequencing of isolates, pharmacokinetic studies of interactions in HIV drugs and collection of health economic data to inform clinical practice and policy in the scale up of the novel therapies


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: The Dynamics of Filovirus Infection in bats in Ghana
Funder: Medical Research Council

Abstract: We aim to determine how filoviruses (e.g. Ebola, Marburg) persist in bat populations in Ghana. We will continue to study bat species, initially Rousettus aegyptiacus and Epomophorus gambianus, but also potentially Epomops franqueti and Hypsignathus monstrosus, in roosts where there is pre-existing evidence of infection. We will use highly sensitive and specific PCR based detection to characterise the variability of filoviruses in Ghanaian bats, using specifically collected samples. We will then develop specific pseudotyped virus neutralisation assays to demonstrate and test for bat antibody responses to these detected viruses. We will sample infected bat roosts longitudinally over the course of the grant to allow determination of the patterns of filovirus infection within them. Building on mathematical modelling frameworks, we will estimate transmission rates within these colonies and determine whether viruses persist in small populations, or whether they rely on transmission between roosts or amongst different species of bats. The work will be delivered through collaboration between UK based and Ghanaian scientists, with a strong capacity building focus. Dr Osbourne Quaye, the Ghanaian virologist leading the programme there, has already benefitted from a visiting Cambridge-Africa fellowship programme. This programme will fully equip his laboratory for molecular virology and cell-based pseudotype virus neutralisation serological approaches and also allow for specific training in the specialist immune testing to be developed, with Dr Wright in Westminster. The field studies in Ghana will be led by Dr Richard Suu-Ire, who recently completed his PhD on bat virus infections in the University of Ghana. We will also establish collaborative links between our Ghanaian collaborators and with the University of Makeni Infectious Disease Research Laboratory, that Goodfellow helped to develop in Sierra Leone during and following the Ebola epidemic of 2013-16.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: IMPC: GPNMB in Toxoplasma gondii infection: beneficial to parasite or host?
Funder: Medical Research Council

Abstract: Toxoplasma gondii is a parasite that infects around 30% of the global human population. It is acquired following consumption of contaminated water or produce, or meat from infected animals. The parasite travels from the intestine to the brain, where it forms cysts that persist for the lifetime of the infected individual. In many cases T. gondii causes only mild flu-like illness during the acute phase of the disease, but infection can also have severe health consequences. For example, reactivation of cysts in the brains of people whose immune systems are compromised can result in severe encephalitis and death. Spontaneous abortion, still birth and severe birth defects can occur if the infection is caught during pregnancy and transmitted to the foetus, and ocular disease can occur in both congenitally infected infants and otherwise healthy adults. Treatment for toxoplasmosis is available, but it can cause severe side effects and is ineffective against brain cysts. Thus, the development of novel treatments is an important research goal. T. gondii is an intracellular parasite, and actively invades cells in its mammalian hosts. Once it has infected a host cell, it is capable of changing the behaviour of that cell by changing the levels of specific host cell proteins. This allows the parasite to (1) enhance host cell migration and use host cells as a dedicated shuttle service to reach the brain, and (2) to protect itself by turning down the host immune response and ensuring that the host cell in which it resides does not die. The purpose of this project is to understand which host proteins T. gondii targets to achieve this. We may then be able to design novel therapies for toxoplasmosis, that are directed against these host proteins, and prevent T. gondii from using them for its own benefit. We have recently discovered that T. gondii infection results in increased levels of a protein, GPNMB, in the infected host cell. This protein has previously been shown to play roles in cell migration and regulation of immune responses. We therefore hypothesise that T. gondii is using this protein to modify host cell migration to spread through its host and/or to dampen the immune response. We will test this by assessing immune responses, and the formation of brain cysts with following T. gondii infection in the absences or presence of the GPNMB gene. We will also determine whether GPNMB enhances host cell migration following T. gondii infection. Ultimately, these experiments will allow us to identify if GPNMB may be a good target for novel therapies. GPNMB is already being investigated as a drug target in cancer, and it may be possible to adapt these novel therapeutics for control of T. gondii infection.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: AMR Rapid Diagnostic Tests - AMR-RDT
Funder: Medical Research Council

Abstract: Antimicrobial Resistance (AMR) has become a global threat and rapid diagnostics are urgently needed to tackle this challenge. To identify barriers to the development, implementation and use of rapid diagnostics and propose a roadmap to future solutions we are launching AMR Rapid Diagnostic Tests (AMR-RDT) as a multi-sectoral, multi-stakeholder and interdisciplinary working group with global reach. It brings together over 50 key individuals and organisations from 15 countries worldwide that are active in the field of diagnostics and antimicrobial resistance. This unprecedented body of expertise and the access it brings to national and international institutions, and networks will amplify the reach and implementation of the working group's outputs. AMR-RDT will concentrate on five overarching topics: Need & Target Product Profiles, Technologies, Development Roadmaps, Business Models, and Behavioural Change. The working group will focus on human healthcare but also recognises the importance of One Health aspects. AMR-RDT is funded as a one-year project by the UK Medical Research Council under the frame of the Joint Planning Initiative on AMR (JPIAMR) and is coordinated by Till Bachmann at the University of Edinburgh.


Research activity codes: 4.3 INFLUENCES AND IMPACT;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: INFECTION
Title: Novel Bayesian methods for comparing and evaluating infectious disease models in the light of partially observed data.
Funder: Medical Research Council

Abstract: Modern computational statistical methods, such as Markov chain Monte Carlo (MCMC), have revolutionised our ability to perform parameter inference for infectious disease models from partially observed data. This project will translate these advances into improvements in methodology for model comparison and model evaluation. In a Bayesian framework, effective estimation of the marginal likelihood or model evidence is the key requirement to be able to perform model comparisons. This research project will develop importance sampling techniques that efficiently exploit the hierarchical structure of epidemic models to calculate the model evidence from partially observed data. In pilot work using discrete time models and small populations, this approach proved to be an order of magnitude more efficient than the leading alternatives. Important outcomes will be a computationally scalable version of this approach to large populations and a comparison with generic methods. Effective model evaluation methods for epidemics are an essential requirement if policy recommendations are to be underpinned by data. This project will extend the recent concept of Bayesian latent residuals to enable the concept of influential data to be defined for partially observed epidemics. Furthermore a direct link will be established between individual data and the posterior distribution by reweighting samples from the posterior. Together these approaches to quantifying the influence of single observations, individuals or time periods will provide a better understanding of how infectious disease model predictions depend on data. To ensure that the proposed methodology remains relevant to epidemiologists, applications in emerging data, emerging diseases and determining the seasonal drivers of infection will be pursued. Specific examples (pneumococcal infection, pandemic influenza and soil transmitted helminths) will illustrate the research and enable us to disseminate our results widely.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: INFECTION