NIHRDataInsights/HRCSData huggingface dataset:
Title: Informing strategies for malaria eradication: a combined epidemiological and economics approach
Funder: Wellcome Trust

Abstract: The last decade has witnessed substantial declines in the global burden of malaria; however, in recent years progress has stalled. We aim to combine a mathematical modelling framework with economic analyses to gain insight into the optimal global, regional and country strategies to achieve the ultimate aim of malaria eradication. Specifically: 1. What is the optimal strategy to achieve malaria eradication? Should resources initially focus on high burden countries, elimination countries or a balance between these? How does this change as burden and transmission decline? How do competing aims in the short-term (e.g. the need to reduce morbidity and mortality) hamper achieving longer-term eradication aims? 2. What is the trade-off between country priorities and regional and global strategies? How do competing national priorities determine regional and global success? What degree of international cooperation is needed and at what scale? What are the economic benefits and costs of co-operation to countries? 3. How are strategies influenced by the wider political economy? How do competing priorities influencing national decision makers impact wider eradication efforts? How does weak governance and political constraints in national and international decision-making reduce the effectiveness of strategies?

Lay abstract: Malaria deaths have fallen by 60% since 2000 but just under half a million deaths continue to occur each year, mostly in children in sub-Saharan Africa. Malaria is a preventable disease - we have tools such as bed nets to prevent infection and if quickly treated, deaths can be avoided. However, financial resources are limited. The aim of our research is to understand the optimal way to move towards eradicating this disease taking into account the distribution of the disease, the tools and funds available, and the way in which the wider political environment influences the decisions that individuals and governments make. To do this we will combine computer simulation models with economic and political theories to compare and contrast different strategies. By working closely with global public health agencies such as WHO and The Global Fund we expect that our work will inform future policies and funding allocations.

Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: INFECTION
Title: Small but mighty: Investigate how c-di-AMP contributes to osmotic regulation, amino acid metabolism, respiration and beta-lactam resistance in Staphylococcus aureus
Funder: Wellcome Trust

Abstract: The signalling nucleotide c-di-AMP is intimately linked to osmotic regulation and essential for the growth of Staphylococcus aureus under standard conditions. However, the molecular mechanisms behind this are currently not understood. Osmolarity in bacteria is regulated through the intracellular levels of potassium, osmolytes and amino acids. c-di-AMP directly or indirectly regulates the uptake and synthesis of all three compounds and the mechanisms behind this will be investigated in this work. Furthermore, we have recently discovered that c-di-AMP is dispensable when S. aureus is grown under anaerobic conditions, suggesting that fundamental cellular processes that are controlled by c-di-AMP are regulated differently during anaerobic growth. Here, we will address how c-di-AMP contributes to the osmotic regulation in bacteria, how this affects their ability to cope with cell wall-targeting antibiotics and how fundamental processes such as osmolyte uptake and amino acid utilization are altered under low oxygen conditions, which S. aureus encounters during infection. As nucleotide signalling molecules have critical functions that allow bacteria to adapt rapidly to changing conditions, these studies will provide important insight into the survival of this pathogen in the environment as well as on changes occurring when it transitions to growth in a human host.

Lay abstract: Staphylococcus aureus is an important human pathogen that can cause severe and sometimes lethal infections. Infections are becoming more and more difficult to treat due to the emergence of antibiotic resistant strains. S. aureus is a "hardy" organism that can grow under very harsh conditions outside and inside the host. For this, the bacterium must sense and adapt rapidly to changes in the environment. Small nucleotide molecules, so called signalling nucleotides, are key components in allowing S. aureus to rapidly adapt. As part of this work we will study the function of one such signalling nucleotide, namely c-di-AMP. Previously, we have shown that c-di-AMP is important for the growth of S. aureus and also for its resistance to antibiotics. As part of this work, we will investigate why c-di-AMP is required for bacterial growth and how this molecule contributes to antibiotic resistance in S. aureus.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Defining Oocyst Wall Biogenesis and Function in Cryptosporidium Transmission
Funder: Wellcome Trust

Abstract: Cryptosporidiosis is the second leading cause of severe diarrhoeal disease in young children (estimated 79,000 years of life lost). There is no vaccine and the only approved drug is not effective for young children or immunocompromised patients. Cryptosporidium parasites are transmitted as a spore-like “oocyst” and due to their resistance to chemical disinfection (chlorination) are often water borne. There are no genetic markers or reagents available to study Cryptosporidium transmission. I propose to analyse Cryptosporidium transmission by defining the molecular mechanisms of oocyst formation using a mutagenic toolkit I developed. • First, we need to identify the components of the oocyst wall. We will use Mass Spectrometry to create the first comprehensive list of oocyst wall components and will use conditional mutagenesis to analyse their function in oocyst formation and transmission. • Second, it is critical to understand how oocyst-related genes, including Cryptosporidium Oocyst Wall Proteins (COWPs) impact transmission. We will create reporter strains to confirm expression and evaluate their function in transmission. Biochemical analysis of COWPs will reveal how their inter/intramolecular interactions contribute to oocyst structure. • Finally, regulation of the process of oocyst development is completely unknown. We will develop high-content imaging assays to screen for pharmacological inhibitors of oocyst formation.

Lay abstract: Diarrhoeal disease is responsible for 10% of the deaths of children under five years old worldwide; Cryptosporidium is the second leading cause. There is no vaccine and the only therapeutic provides no benefit to young children and immunocompromised patients, those most in danger. We require a better understanding of Cryptosporidium biology to enable drug discovery for this important parasite. I will implement a biochemical and genetic approach to investigate transmission and identify potential therapeutic targets. Cryptosporidium are water borne parasites that are transmitted in a hardy "oocyst" shell. This shell renders them resistant to common, low-cost water treatment (chlorination). Very little is known regarding how Cryptosporidium build this shell. New genetic tools that I developed allow us to study this process for the first time. By manipulating parasite genes, we can understand their role in oocyst formation and transmission. Understanding Cryptosporidium transmission may illuminate new targets for desperately needed therapeutics.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Parasite offence or host defence? The roles of biological rhythms in malaria infection
Funder: Wellcome Trust

Abstract: For several centuries, the species of malaria parasite infecting a patient was diagnosed by the regularity of fever (every 1, 2, or 3 days). Fever results from the synchronous bursting of malaria parasites in the host’s blood when they release their progeny to infect new red blood cells and cause the symptoms of malaria. Despite such ancient knowledge, why parasites that exclusively live within the bodies of other organisms, have a daily rhythm is unknown. I have shown that the survival and transmission of malaria parasites depends on coordinating their developmental rhythm with the circadian rhythm of their host. I will integrate evolutionary ecology, chronobiology, and parasitology to explain how parasite rhythms are generated, why daily rhythms matter for parasite fitness, and open up novel avenues for disease control. This includes the development of drugs to disrupt parasite rhythms, harnessing circadian systems to enhance immune responses, or precisely timing drug administration to make treatment more effective. Growing evidence that the daily rhythms of malaria parasites can confer tolerance to antimalarial drugs, and that the use of bed nets is changing the biting time of the mosquitoes that transmit malaria, makes understanding how and why parasites exhibit daily rhythms increasingly urgent.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: How do people get multi-drug resistant tuberculosis?
Funder: Wellcome Trust

Abstract: Recent data suggests that most isoniazid resistant strains have been circulating for decades. The global diagnostic focus on rifampicin resistance has meant that isoniazid mono-resistant strains are systematically being treated with first-line therapy. With MDR-TB incidence rising despite overall TB incidence falling, the concern is that we are selecting for rifampicin resistance. The alternative explanation, that MDR-TB is transmitting more successfully, seems unlikely, but possible. The hypothesis I will test is that most isoniazid resistance is acquired through transmission whereas most rifampicin resistance evolves de novoin patients with undiagnosed, pre-existing isoniazid resistance. I will investigate the following research questions in Vietnam: (i) What is the proportion of transmitted versus newly evolved MDR-TB? (ii) What is the prevalence of isoniazid resistance among patients never previously exposed to the drug, and what proportion of patients with unsuccessful treatment outcomes evolve isoniazid resistance? (iii) What is the risk of evolving rifampicin resistance by treating isoniazid resistant strains with first-line drugs? What proportion of patients who evolve rifampicin resistance after exposure to first-line drugs also evolved isoniazid resistance? (iv) Do host genotype and variable anti-tuberculosis drug pharmacokinetics contribute to evolving drug resistance? The findings will inform policy on diagnostics, treatment protocols and disease control.

Lay abstract: Multi-Drug resistance tuberculosis (MDR-TB) is defined as resistance to the two most important TB antibiotics, isoniazid and rifampicin. It is harder to treat and patient outcomes are much worse. Unfortunately, MDR-TB rates are rising as drug-susceptible TB rates are falling. It remains unclear why. I plan to investigate whether people get MDR-TB from other infected patients, or whether drug-resistance more commonly evolves within patients after they are exposed to antibiotics. To do this I will determine the DNA sequence of all MDR-TB strains in Ho Chi Minh City, Vietnam, and build a family tree from these data to determine which strains are related through transmission. I will also focus on patients who aren’t cured by antibiotics or get disease a second time, asking whether their treatment failed because they were given too few effective antibiotics, or the wrong dose of antibiotics, and whether this in turn led to resistance.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: COVID-19 consortium Healthcare worker Bioresource: Immune Protection and Pathogenesis in SARS-CoV-2 (COVID-HCW Study)
Funder: Barts Charity

Abstract: We cannot ventilate our way out of a pandemic. Nor will RCTs for infected patients deliver alone. Perhaps 97% of subjects do not need hospitalisation. Research is currently focused on the 3% with severe disease. Many questions remain including the factors behind the broad clinical spectrum of SARS-CoV2, earliest risk predictors and persistence of immune protection. To understand these we need serial sampling of healthy subjects before and after infection, with analysis of host genetics, baseline immunity, presence of neutralising antibodies and the earliest proteomic, transcriptomic immune and cellular changes of infection alongside studying the timecourse of immunity and viral transmission chains. No single research group can address these: collaborative work is needed, with shared samples and data. We therefore designed the HealthCare Workers Bioresource: an observational cohort study recruiting healthcare workers with high COVID-19 exposure, with serial data collection and sampling for 16 weeks (including in convalesence) and at 6 and 12 month follow-up. Baseline sampling (plasma, serum, PBMC isolation, RNA, alongside nasal swab RNA PCR and data entry. Samples will undergo aliquoting and distribution fo collaborative science (30+ groups @100mcl). The datalake includes SNP analysis, transcriptomics, and the proteome. Around 10 additional groups are involved, from multiple organisations. To outrun exponential growth, speed was essential. We are in follow-up month 2 - initial n=400 cohort was finished in March, 15 days after initial idea, with all permissions, but without funding. We manufacture our own swabs. Porton Down is using serum for serological testing. Baseline, week 1 and 2 swab PCR is done and data is being collated. We will aim to expand to n=1000 at NHS Nightingale and Royal Free, with franchised studies in Sydney and Capetown.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFECTION
Title: Permissivity and reprogramming during HIV-1 infection of T cells
Funder: Wellcome Trust

Abstract: I aim to understand the molecular and cellular mechanisms regulating HIV-1 replication and spread in T-cells and how the virus manipulates cells to create a permissive niche. HIV-1 most efficiently disseminates between T-cells by cell-cell spread (CCS) that dominates infection. We have recently discovered CCS triggers target T-cells to become vastly more susceptible to infection, allowing HIV-1 to replicate in resting T-cells that are usually non-permissive for infection. By using CCS infection to bypass the need to mitogenically stimulate target T-cells (a process which drastically changes T-cell biology), we have discovered HIV-1 transcriptionally and phenotypically reprogrammes T-cells to induce a tissue-residency-like phenotype via Vpr, revealing new consequences of HIV-1 infection. Our key goals are now to: 1. Determine how CCS drives HIV-1 replication in resting T-cells, defining key viral and cellular factors and mechanisms. 2. Determine how HIV-1 navigates innate immune defences to infect resting T-cells, how this shapes permissivity, and how sensing operates in T-cells. 3. Dissect how HIV-1 reprogrammes T-cells, Vpr mechanism and the consequences for T-cell fate and function. Our work will advance mechanistic understanding of how HIV-1 manipulates its most important target cell to drive replication and persistence, uncover exciting new biology and inform future therapeutic innovation towards cure.

Lay abstract: HIV-1 remains an enormous global health challenge. HIV-1 replicates in immune cells called CD4+ T-cells and uses a process of cell-to-cell spread (CCS) to transmit infection rapidly from one cell to another. We have recently discovered that when HIV-1 spreads by CCS it manipulates T-cells to make them better targets for the virus, allowing HIV-1 to infect and replicate in resting T-cells that are usually resistant to infection. This also reprogrammes the cell, leading to intriguing changes to T-cell biology and function. Our goals are now to understand how HIV-1 CCS alters T-cells to make them more permissive for viral replication, how HIV-1 changes the biology of the T-cells it infects, and the consequences for viral pathogenesis and persistence. By gaining greater understanding how HIV-1 manipulates the cells it infects, we aim to inform the development new drugs to combat HIV-1, eradicate the virus and ultimately achieve a cure.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Mechanism of cell-to-cell transmission of flaviviruses
Funder: Wellcome Trust

Abstract: This proposal will investigate the mechanism of cell-to-cell transmission and spread of flaviviruses using Dengue and Zika as model systems. We will therefore address a longstanding debate on how they exit from infected cells, and preferentially spread into specific cell types. Dengue and Zika are the two most prevalent flaviviruses worldwide, sharing significant overlap in their genome architecture and biology. Dengue infects >50 million people annually, causing severe pathologies. Zika too has emerged as a global threat with recent outbreaks linked to serious neuro-developmental complications in children and Guillain Barré syndrome in adults. no vaccines or therapeutics exist for these viruses, and our current understanding on mechanisms of their transmission and spread is severely limited. Viral infections spread by overcoming multiple barriers to move from cell to cell. Viral progenies can move across extracellular space either as free particles via fluid phase diffusion, within vesicles, or by cell-cell contacts. To understand transmission, we will therefore address: (i) characteristics of the extracellular virus populations, (ii) whether multiple transmission routes exist (iii) whether the viral envelope is the primary determinant of transmissibility. This proposal builds on our previously published and ongoing studies on viral manipulation of autophagy for assembly and spread.

Lay abstract: In this study we will determine how flaviviruses, in particular Dengue and Zika, which share significant similarities are transmitted between cells and spread into specific tissues. Dengue and Zika viruses have huge health implications - Dengue alone infects >50 million people worldwide annually; Zika is a closely related emerging virus that causes severe neurological damage in new-borns and adults. How they spread into specific organs in infected individuals is not understood. Our proposal aims to address this gap in knowledge. We will determine exactly how virus progeny particles are released from infected cells and transported into neighbouring recipient cells. We will identify the host genes that are involved in this process. We will also address which viral protein determines virus transmissibility. The mechanism of transmission of virus particles dictates spread, tissue tropism and pathogenesis. We will therefore add critical information on how to target this process and block disease progression.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Real-time modelling for forecasts during infectious disease outbreaks
Funder: Wellcome Trust

Abstract: Local and international public health bodies often face difficult decisions during infectious disease outbreaks. Limits on human resources or logistics, for example in the speed and scale of vaccine production and delivery, require prioritisation of areas or population groups when rolling out an intervention. It is now possible to collect a wealth of epidemiological, genetic, spatial and behavioural data during an outbreak and make it available immediately for analysis. It remains an open question how these data are best combined for forecasts that can inform decision making. My fellowship aims to systematically investigate and improve the predictive capabilities of mathematical models during outbreaks. In particular, I will develop methods to combine different data sources in order to analyse an outbreak in real time. By testing these methods on a range of recent epidemic datasets, I will assess the predictive capabilities of models using different amounts and types of data. A particular focus will be on translating forecasts into recommendations for decisions, and on how the accuracy of forecasts affects the quality of these decisions. All the work will be conducted with the aim of generating a computational platform that is readily deployable in an outbreak situation for meaningful decision support.

Lay abstract: Forecasts based on computer models using data collected in real time, are now used throughout society, from weather/climate to air-traffic control. Real-time forecasts during infectious disease outbreaks have the potential to inform the public health response. I aim to understand the ability of mathematical models to generate accurate forecasts, and use this to develop methods and software that can be deployed routinely during outbreaks. I will use state-of-the art methods for Bayesian inference on past and current infectious disease outbreaks to determine how to produce the most accurate forecasts. I will also study how the quality of forecasts affects the public health decisions that follow from them, and how this can be used to assess the reliability of recommendations that are based on forecasts. Lastly, I will investigate key gaps in data collection and what additional information would lead to better forecasts.

Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFECTION
Title: The bacterial cell wall in life and death
Funder: Wellcome Trust

Abstract: The bacterial cell wall is essential for viability. The synthesis of its major structural polymer, peptidoglycan, is the target of crucial antibiotics such as penicillin and vancomycin. The wall also forms the interface between pathogenic bacteria and their host. Despite this importance, we do not understand how the wall is able to maintain life and yet be dynamic to permit growth and division, how the wall allows appropriate interaction with the environment or even how antibiotics kill bacteria. We will address these fundamentally important areas, using our considerable interdisciplinary expertise and founded on a wealth of preliminary data, focusing on the human pathogen Staphylococcus aureus as our primary target organism. We aim to: 1. Determine the molecular architecture and dynamics of the wall in the living cell by developing and applying our world leading microscopy approaches and novel chemical probes. 2. Build on the framework of our architectural information to understand how the wall is maintained and how it acts as the environmental interface. 3. Develop our understanding of the cell wall to elucidate the simple underlying principles that govern bacterial growth and how these are perturbed by antibiotics, explaining why some antibiotics are bactericidal and others bacteriostatic.

Lay abstract: The bacterial cell wall is essential for bacterial life and its synthesis is the target of crucial antibiotics such as penicillin and vancomycin. Here we will determine the structure and function of the cell wall to elucidate not only how it permits cell growth but also how antibiotics lead to death. We will use the infamous "superbug" Staphylococcus aureus as our target organism to address key fundamental questions of bacterial life and death. Our primary goals are: 1. To determine the molecular structure of the cell wall and how it changes during growth, at a resolution never previously achieved in any organism, using our world leading microscopy approaches. 2. To use this information to then establish how the cell wall acts as the interface between a cell and its environment. 3. To bring together our findings to elucidate the basic mechanisms underpinning growth and the action of antibiotics across bacteria.

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