NIHRDataInsights/HRCSData huggingface dataset:
Title: Spatiotemporal dynamics of arbovirus transmission: implications for disease control and elimination
Funder: Wellcome Trust

Abstract: This project will better characterise the transmission dynamics of dengue, Chikungunya and Zika viruses, their persistence in the global human population and use the insights gained to refine assessments of the potential impact of interventions. I will develop evidence-synthesis models linking multiple streams of surveillance data to estimate spatiotemporal variations in the reproduction number of Chikungunya and Zika viruses from the recent epidemics in Colombia and Brazil and use age-stratified dengue incidence data to estimate the transmission intensity of dengue. Analyses of geospatial correlation between transmission intensity estimates of the arboviruses will provide insight into transmission similarities and potential immune-mediated interactions. Using advanced inferential techniques, I will characterise climate-dependent entomological and epidemiological parameters, which will be used to produce global dynamic maps of arbovirus transmission intensity. I will then add spatial structure to the dynamical models of arbovirus transmission to explore the extent to which seasonality, immune-mediated interactions, human movement and zoonotic reintroduction determine arbovirus persistence and the feasibility of elimination. Analyses of clinical trial data will provide insights into the immunogenicity, efficacy and mode of action of the Takeda dengue vaccine and inform the targeting and optimisation of vaccination alone and in combination with other interventions in specific locations.

Lay abstract: Every year, hundreds of millions of people are infected by mosquito-borne dengue, Chikungunya, and Zika viruses. New promising vaccines, drugs and other interventions (e.g. making mosquitoes resistant to infection) are in advanced development, but to make best use of these we need to improve our understanding of how these infections are transmitted. We do not yet fully understand how and why transmission varies from place to place and is affected by climate. My research will address these knowledge gaps and will assess how different interventions might reduce or stop disease transmission. I will use mathematics and statistics to analyse case data collected in Latin America to better understand how seasonal changes in climate affect transmission and thus the geographic spread of epidemics and to predict the impact of vaccination alone and in combination with other interventions. This research will inform policymakers on how to best use interventions to prevent disease.

Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Preparing for disease X, the next pathogenic respiratory viruses: the development of cross-reactive nanobodies for diagnosis, prophylaxis and treatment of coronavirus infections.
Funder: Wellcome Trust

Abstract: We will address the urgent and unmet need within the biomedical community for effective agents to combat the existing threat from coronaviruses and to be prepared for those that will arise in the future. We will also deliver a pipeline that will be applicable to other high threat respiratory viruses (Disease X). We propose to build a nanobody screening strategy that targets cross-reactivity from which we anticipate identifying (pan)-coronavirus binders. The pipeline will combine nanobody technology, structural biology and virology making use of the Diamond synchrotron at Harwell for X-ray data collection and the CL3 facilities in Oxford and Liverpool for handling live viruses. Together the results will enable the structure-activity relationships of anti-coronavirus nanobodies to be determined providing information that will guide sequence changes to increase nanobody binding and counter the effects of virus escape mutants or natural variants on virus detection and neutralisation. The demonstration of in vivo potency to SARS-CoV-2 and other than coronaviruses(cross therapeutic) is a key aim of the proposal and we will test any new potent neutralising nanobodies in an appropriate disease model.

Lay abstract: Respiratory viruses are the most frequent causes of human disease worldwide and owing to the nature of transmission, have the potential for spreading rapidly. SARS-CoV-2, a virus that reached 27 countries within a matter of weeks, highlights how the emergence of a novel respiratory virus can quickly lead to a global pandemic. We propose to build a multi-disciplinary pipeline to generate, identify, characterise and test nanobodies, for the rapid diagnosis and treatment of newly emergent pathogenic respiratory viruses. Nanobodies are small single domain antibodies that can be used to produce highly potent agents for detecting and blocking viral infection. By understanding how and where they bind to viruses we will learn how to improve their activity. Overall, we aim to produce reagents that will have immediate use in coronavirus outbreaks and also establish a pipeline ready for Disease X, the very serious threat that unknown viruses pose to human health.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS;5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: INFECTION
Title: Iron in Toxoplasma gondii: sensing, acquisition and use of critical nutrient in an obligate parasite
Funder: Wellcome Trust

Abstract: The battle for iron is crucial in pathogenesis. The obligate intracellular parasite Toxoplasma gondii requires iron however little is known about iron in this parasite. My goals in this project are to determine mechanisms for sensing, acquisition and usage of iron by the parasite. Using a combination of biochemical and genetic techniques I will determine the source of parasite iron and how it modulates the iron acquisition in the host. To investigate if the parasite can respond to iron, I performed RNAseq on parasites grown under high iron or with iron removed and determined genes transcriptionally regulated by iron, including several genes with predicted roles in iron transport and metabolism. Although several iron-related genes have been predicted in Toxoplasma, none have been studied and it is likely that other, more divergent, genes exist. To find novel genes required for survival under low and high iron conditions, I will perform genome-wide pooled CRISPR screens. Genes with changing phenotype scores across different iron conditions will be characterised through genetic and biochemical assays to understand their function in parasite pathogenesis. This project seeks to use novel chemical and genetic strategies to understand and characterise the interactions between iron and Toxoplasma gondii.

Lay abstract: Iron is central to life: almost every cell requires iron to produce energy. All cells use intricate mechanisms to sense, acquire and store iron until it is needed, but pathogens face an extra hurdle as they must subvert iron from the host. I am interested in how the parasite Toxoplasma gondii is able to sense and acquire iron from the host. I will use a number of genetic and biochemical techniques to study these processes. I will determine how the parasite responds to changes in iron concentration and investigate how this is regulated. By deleting every gene in the parasite a pooled fashion, I will investigate how the parasite changes iron metabolism in the host and find novel parasite genes required for iron transport, storage and use. These studies will determine how Toxoplasma uses an essential element, teaching us about parasite biology and giving us new strategies to prevent disease.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: The Global War Against the Rat and the Epistemic Emergence of Zoonosis
Funder: Wellcome Trust

Abstract: The project will draw the global history of a foundational but historically neglected process in the development of scientific approaches of zoonosis: the global war against the rat (1898-1948). The project will examine the scientific study of the rat and the public health practices developed and deployed for its control and eradication in the wake of understanding its role in the transmission of infectious diseases. It will explore the synergies between knowledge acquired through scientific studies of the rat, with knowledge acquired during the development and application of practical, public health measures of vector-control: rat-proofing, rat-catching and rat-poisoning. By examining for the first time the epistemological, architectural, social, and chemical histories of rat control from a global, comparative perspective, the project will engage in an analysis of how new forms of epidemiological knowledge and reasoning arose centred on the epistemic object of the rat. The project will address two key research questions: 1. In which ways did the global war against the rat contribute to the emergence, development and consolidation of zoonosis as a scientific category? 2. What was the role of the global war against the rat in establishing animal-human contact as a pivot of epidemiological reasoning and public health intervention?

Lay abstract: Rats carry deadly diseases like plague and murine typhus. When this was discovered at the turn of the nineteenth century, it led to a global war again rats. This project will for the first time examine the global history of the scientific study of the rat and of the public health practices developed and deployed for its control in the wake of understanding its role in the transmission of infectious diseases. It will explore how knowledge acquired through scientific studies of the rat and knowledge acquired during the development and application of practical, public health measures of vector-control (rat-proofing, rat-catching, and rat-poisoning) contributed to our understanding of the way in which diseases harboured by animals are transmitted to humans, and of the role that different forms of animal-human contact play in this process of animal to human infection known as zoonosis, a key driver of global health risk today.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Divide and conquer: disrupting bacterial biofilms with cyclic dipeptides
Funder: Wellcome Trust

Abstract: By 2050 10 million lives could be claimed a year by drug resistant infections. We must develop new strategies for antimicrobial drugs. Often in infections bacteria form biofilms, requiring concentrations of antibiotics up to 1000 fold higher to be treated. Cyclic dipeptides are molecules produced by organisms in all domains of life, and their function is unknown. They can inhibit bacterial growth and/or biofilm formation, albeit by undetermined mechanisms. The majority of the biological effects caused by cyclic dipeptides are inter-species and in some instances inter-kingdom, mediating host pathogen interactions. I will study enzymes from gram-positive and gram-negative bacteria involved in the production of different cyclic dipeptides. I will characterise each enzyme biochemically and structurally and determine their substrate scope. I will produce novel molecules, which will be used to disrupt growth and biofilm formation in Pseudomonas aeruginosa and Staphylococcus aureus growing alone and in bacterial co-cultures. I will combine genetic and chemoproteomic approaches to determine the molecular targets of cyclic dipeptides in P. aeruginosa and S. aureus. I will validate targets using bacterial mutants and biochemical assays. The identification of molecular targets of cyclic dipeptides will unveil crucial pathways for inter-species interactions and identify novel antimicrobial targets and molecules.

Lay abstract: By 2050 one person will die every three seconds from antibiotic resistant bacterial infections. We need to develop new drugs to combat antibiotic resistance. Many bacteria grow by sticking to a surface in structures called biofilms. Some bacteria are completely resistant to antibiotics when in biofilms. Cyclic dipeptides are molecules that can disrupt bacterial growth and biofilm formation. They are common in nature but their biological function is unknown. I will study the enzymes that make these molecules, how they are affecting bacteria and how this information can be used to our favour. Then, I will manipulate these enzymes into making new molecules of my choosing, to be tested for antimicrobial activity. I will focus on disrupting growth and biofilm formation in two organisms that cause infections in humans. This project will increase our knowledge of bacterial infections and teach us new ways to inhibit bacterial growth and/or biofilm formation.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Identification of genomic components that predict transmission of the malaria parasite in different vector species
Funder: Wellcome Trust

Abstract: The malaria parasite (Plasmodium falciparum) has a complex life cycle in which it must transit through multiple environments in a vertebrate host and mosquito vector. Transmission begins with ingestion of an infectious blood meal by one of 40 potential Anopheles mosquito species capable of transmitting the disease. This initiates the most extreme population bottleneck in the life cycle in which the parasite must rapidly undergo fertilisation, develop into an invasive form and transit through the midgut epithelium. The overarching goal of this proposal is to understand how this transmission through the mosquito vector drives selection on the parasite. I hypothesise that parasites have adapted to their local vector community composition, and this shapes their ability to infect sympatric and allopatric vector species. Using large-scale transmissibility assays and single-cell RNA-sequencing, I will identify genomic and transcriptomic vector-dependent signatures of transmission. I will then generate allelic-replacement parasites to unambiguously attribute phenotypic variation in species-specific transmission to specific loci in the parasite. Comprehensively understanding how vector communities shape parasite populations will guide future interventions and vector control programs by providing information that will allow for strategies to be locally tailored based on parasite genomic-surveillance and entomological surveys.

Lay abstract: Background: Malaria is caused by a unicellular parasite that is transmitted by mosquitoes in the genus Anopheles. The goal of my work is to understand how parasites have locally adapted to different Anopheles mosquito species in order to predict global patterns of transmission. Approach: I will address this question in the laboratory by tracking parasites, collected from patients around the world, as they infect geographically diverse mosquito species. Using single-cell genomics and CRISPR to modify the parasite’s genome, I will be able to understand how specific variants of the parasite’s genetic code determine whether a parasite can be transmitted by some mosquito species but not by others. Impact: My work will provide a global view of the genetic basis of Anopheles species-dependent transmission dynamics. Understanding how local adaptation shapes the malaria parasite is fundamental to public health because treatment or intervention for one parasite strain might be ineffective for another.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: What makes a virus an intestinal pathogen?
Funder: Wellcome Trust

Abstract: Enteric viruses are a major cause of mortality and morbidity in the young, the elderly, and the immunocompromised. Even after decades of research, it is still poorly understood why these viruses replicate particularly in the gastrointestinal tract and what triggers virus dissemination beyond the gut. Despite their worldwide prevalence, and recently emerged neuropathogenic strains, astroviruses represent one of the least studied groups of human RNA viruses, mainly due to difficulties with culturing and molecular manipulations. My research will focus on understanding the molecular determinants of astrovirus infection – starting with basic replication mechanisms and moving towards physiologically relevant translational outputs. Key goals include: 1. Characterisation of the viral RNA structure and replication strategy to understand their role during virus infection. 2. Functional dissection of the astrovirus polyprotein processing strategy and its role in virus infection. 3. Identification and assessing the importance of gut-specific determinants in virus infection. 4. Identification of the molecular mechanisms responsible for neurovirulence. Elucidation of the fundamental molecular biology of astroviruses underpins an understanding of their pathogenesis, both in the gut and in the central nervous system. It will also facilitate the development of vaccines and antiviral therapies, addressing an unmet need for young children in developing countries.

Lay abstract: Enteric viruses are the commonest causes of gastroenteritis worldwide. There are several virus families that cause human enteric diseases, resulting in severe diarrhoea with various potential complications, including spread to the central nervous system. Despite decades of research, it is still poorly understood why these viruses replicate particularly in the gastrointestinal tract and what triggers virus dissemination beyond the gut. I will address these questions using a range of cutting-edge molecular virology and human organoid techniques. I will investigate one of the least studied, but nonetheless highly prevalent and often underdiagnosed groups of human RNA viruses – the astroviruses. The group includes recently emerged strains that are neuropathogenic in children, elderly and the immunocompromised. My work will elucidate the fundamental molecular biology of astroviruses, contributing vital knowledge that will underpin an improved understanding of their pathogenesis and the development of effective vaccines and antiviral therapies.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Hitting a moving target: genomic and metabolic approaches to improve anthelmintic use in evolving helminth populations
Funder: Wellcome Trust

Abstract: Parasitic helminths cause debilitating disease in animals and humans. Treatment and control relies on a limited number of anthelmintic drugs, but anthelmintic resistance is widespread in veterinary species and a growing concern in humans, where mass drug administration with the same few compounds is underway. There are a paucity of resources invested in anthelmintic drug discovery and anthelmintic resistance. Therefore, a key question is how to best use currently available drugs for sustainable helminth control. I will use new genomic resources and newly validated crossing techniques for parasitic helminths to identify the genetic mechanisms of resistance to moxidectin, an important and widely used anthelmintic in the veterinary field, which was approved for control of onchocerciasis (river blindness) in 2018. I will investigate side-resistance to a related drug, ivermectin, and assess putative factors that promote multi-drug resistance. Newly recognised metabolic effects, which may play a role in ivermectin and moxidectin mode of action and synergy with other anthelmintics, will be explored with metabolomics. This research will provide tools to optimise the sustainability of helminth control strategies in animals, improve surveillance of emerging resistance in humans and provide a better understanding of drug mode of action to inform rational combination therapy.

Lay abstract: Parasitic worms of veterinary and medical importance are treated and controlled with a limited number of anthelmintic drugs. However, we do not know how some of the most important drugs work. Further, the widespread development of anthelmintic resistance in parasitic worms - analogous to antibiotic resistance in bacteria - threatens food security and raises concerns about reliance on the same drugs to control related parasites in humans. I will use new metabolic and genetic techniques to study drug activity and resistance to important anthelmintics in animal and human health. Initial work will focus on Haemonchus contortus (the barber’s pole worm), an economically important gastrointestinal worm of sheep and a close relative of the human hookworms. I will also use the cattle filarial worm Onchocerca ochengi as a model for human onchocerciasis (river blindness). My aim is to develop much-needed tools to optimise strategies for control and eradication of parasitic disease.

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Connecting causes and immune consequences of infection-induced metabolic change
Funder: Wellcome Trust

Abstract: This research proposal focuses on metabolic changes driven by the immune response to bacterial infection in the model system Drosophila melanogaster. We will use in vivo genetic manipulations, experimental and computational analysis of gene expression, and experimental metabolomics to address two overarching biological questions. First, how does immune activation drive metabolic change? Second, how do these metabolic changes aid or impede the realised immune response and host survival? The proposal contains three aims directed at these questions. In the first aim, we use whole-animal metabolomics to identify metabolite level changes driven by different infections. In the second aim, we identify signals and transcriptional regulators responsible for the concerted regulation of metabolic enzymes during infection, and connect these signals and regulators with their downstream immunometabolic consequences. In the third aim, we target specific metabolites for analysis, using in vivo genetics to determine which immune-driven metabolic changes have important effects on realised immunity and tolerance of infection. Key goals: we will &bull; identify the metabolite changes resulting from different bacterial infections &bull; establish how these changes are driven by innate immune detection and signalling &bull; connect specific metabolite changes with their effects on infection tolerance and immune function in vivo.

Lay abstract: All animals experience metabolic changes when they have infections. These changes can be terribly debilitating: the slow wasting caused by tuberculosis was the origin of its historical name, “consumption”, while people who have blood infections can lose 10% or more of their body weight in a matter of weeks. These metabolic changes are caused by activation of the immune response, but we still don’t understand how immune responses cause metabolic change, and—more importantly—we don’t understand why immune responses cause metabolic change. We believe that some of the metabolic changes driven by infections must be beneficial during some infections, but we don’t know how or why. If we understood these metabolic changes better, we might be able to make therapies that would inhibit damaging changes to metabolism while allowing those changes that promote a healthy immune response. We will address these problems by studying the response to infections in a fruit-fly. We will identify the metabolic molecules that are changed by infection, we will determine how these changes are connected with the activation of the immune response, and we will establish which of these changes are important in fighting infection or helping the fly survive and which are not.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION