NIHRDataInsights/HRCSData huggingface dataset:
Title: Developing novel phylodynamic modelling methods for forecasting infectious disease outbreak detection and transmission dynamics
Funder: Wellcome Trust

Abstract: Phylodynamic methods utilising genetic and epidemiological data, such as contact-tracing, hot-spot identification and modelling of strain-specific transmission dynamics, can provide a useful way for forecasting infectious disease outbreaks and transmission dynamics of interest. However, information from epidemiological investigations and genome sequences are rarely utilised together in current gold-standard methods used for outbreak assessment (2). We propose to develop novel phylodynamic methods for real-time outbreak detection of RNA-viruses (Sars-CovV-2, Influenza) using contact-tracing and predicted hotspot identification, as well as further developing understanding of transmission dynamics at the strain-specific level in a sustained outbreak over time. Sars-CoV-2 sequence data is sourced from COG-UK and linked to epidemiological patient data from PHE (3). Influenza sequence data is sourced from PHE, including strain-specific samples for Influenza A and B, and linked to epidemiological patient data from 2015 to present (4). Methods will be developed into publicly available R packages for application in future RNA-virus outbreaks. We aim to advance methods for incorporating genome sequence data into real-time forecasting of outbreak detection (5–8). Additionally, by increasing understanding of strain-specific transmission dynamics, we will advance understanding of seasonal infectious disease transmission at local, community and national level, and inform annual vaccine development in the UK (9).


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFECTION
Title: Dissection of the function of the Plasmodium falciparum protein families EBL and RH during erythrocyte invasion.
Funder: Wellcome Trust

Abstract: Plasmodium falciparum causes >90% of malaria mortality, killing over 400,000 people annually. To multiply, P. falciparum parasites must invade human erythrocytes. Invasion begins with attachment of the parasite to the erythrocyte, followed by reorientation to position the parasite to invade. These early steps depend on two families of membrane proteins: Erythrocyte Binding Like proteins (EBLs) and Reticulocyte Binding Protein Homologues (RBLs). There are four members of each family in the P. falciparum genome that can individually be deleted without blocking invasion. EBLs and RBLs are therefore believed to be functionally interchangeable, but this has never been systematically investigated and all Plasmodium parasites maintain both families suggesting considerable selection pressure against loss of one family. To determine if the families have distinct roles, this project will characterise invasion of single and double protein knock-outs using advanced video microscopy tools, and visualise the localisation of proteins simultaneously using fluorescence microscopy. New antimalarial therapies are needed as P. falciparum has developed resistance to every antimalarial drug available and the only licensed malaria vaccine is <40% efficient. Invasion is essential for parasite survival, so a better understanding of the functional redundancy of ligands involved in invasion could aid development of multi-target vaccines or therapies.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Contribution of macrophages to the different clinical manifestations of cutaneous leishmaniasis caused by Leishmania aethiopica
Funder: Wellcome Trust

Abstract: Cutaneous leishmaniasis (CL) is a neglected tropical disease with about 1 million new cases per year. It is caused by parasites that are transmitted by sandflies. There are a number of different forms of the disease, ranging from small, self-healing lesions on the skin, to permanently disfiguring facial lesions. It is not well understood how the parasite can result in such a wide range of outcomes. Our aim is to gain a better understanding of the interaction between the human immune system and the parasite. We are doing this by investigating how key immune cells called macrophages interact with parasites isolated from different patients. This may reveal key differences between the different forms of CL. We are achieving this through a highly collaborative approach with experts in different fields. We hope that this research will shed light on our understanding of the diversity of CL as a disease and why some patients develop severe, life-changing lesions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Investigating Intracellular Processes in Macrophages During Candida albicans Infection
Funder: Wellcome Trust

Abstract: While most fungal infections are cleared by the immune system in healthy individuals, in immunocompromised people or in patients after invasive medical procedures these pathogens can cause life threatening systemic infections. With mortality rates around 50% our current treatments are insufficient. Thus, research to better understand these infections is required. Candida albicans is the most common human fungal pathogen and a frequent cause of hospital acquired infections. Macrophages are one of the first cells in our immune system to identify Candida and initiate an antifungal response; but how infection affects intracellular processes in macrophages is not completely understood. I intend to further investigate which intracellular processes are altered during Candida infection. In previous work, we studied the total proteins in macrophages during infection, and we found Candida infection appeared to dysregulate an oxidative stress mechanism, Nrf2/Keap1, in a novel way. We plan to further study this mechanism, as well as more broadly look for novel mechanisms of regulation. This project will contribute to understanding our immune system’s functional response to fungal infection and will bring us closer to creating new therapeutics to prevent systemic fungal infections.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Natural product inspired leads against Leishmaniasis and Chagas disease
Funder: Wellcome Trust

Abstract: Chagas disease (caused by the parasite Trypanosoma cruzi) and cutaneous and visceral leishmaniasis (caused by Leishmania spp.) are neglected tropical diseases that affect tens of millions of people worldwide. These diseases are often fatal, and treatments are limited in efficacy, exhibiting severe side-effects. A family of natural products extracted from the Brazilian plant Nectandra leucantha has been shown to have good activity against these parasites. In this project I will combine synthetic organic chemistry with cell biology to explore these synthetically accessible natural products as a potential source of new therapeutic leads, focussing on improving their pharmacological profile. I will also identify molecular targets and mechanism of action of promising compounds, using various techniques including tracking fluorescently labelled analogues and photolabile crosslinking. I will carry out genome mutation of Leishmania and selection for compound resistance, followed by genome sequencing to identify genes likely to be involved in the mechanism of action of these compounds. These studies will help to discover novel therapeutics with improved anti-parasitic activity, and their potential cellular targets.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: The Innate Immune Barriers that Constrain the Emergence of Coronaviruses into the Human Population
Funder: Wellcome Trust

Abstract: The COVID-19 pandemic has shown us the consequences of coronaviruses jumping from an animal into humans. Coronaviruses originate in bats and rodents but can also jump into humans via an intermediate species such as camels or cows. Immune defences that we inherit, such as interferon-stimulated genes (ISGs), are important in determining whether we can be successfully infected by animal viruses. However, very few ISGs that specifically inhibit coronaviruses have been identified. Our lab has built a large library of ISGs from many species including humans, monkeys and cows and we will use this to test their antiviral activity against coronaviruses found in bats as well as coronaviruses that already infect humans. Since SARS-CoV-2 is unlikely to be the last animal coronavirus to transmit to humans, learning how these ISGs protect us from coronavirus infection will strengthen our understanding of the immune barriers that hinder the cross-species transmission of coronaviruses, and help determine the risk posed by animal coronaviruses to human health.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Integrating genomic and serological surveillance for geographically targeted control of vampire bat rabies in Central America
Funder: Wellcome Trust

Abstract: Virus genome sequencing is increasingly used in outbreak control. By combining the evolutionary insights gained from sequence analyses with case data and geographic information, current transmission patterns can be mapped, and risk factors identified to model future scenarios. Vampire bat rabies (VBR) is a deadly zoonotic disease which continues to threaten human health and exerts a major economic burden via livestock mortality. Persistence of the virus is spatially dependent, dying out if unable to regularly infect new colonies. In Central America, the narrow landscape intersected by mountain ranges likely restricts the spread of the virus to specific ‘transmission corridors’, where strategic deployment of vaccination could therefore protect wider areas ahead by blocking transmission. In collaboration with the International Agricultural Health Organisation (OIRSA), we will develop sustainable regional sequencing of livestock VBR in Central America to complement national case surveillance and identify transmission corridors. Predicted transmission corridors will be verified in wild bat populations in Costa Rica with seroprevalence studies. Meanwhile, the grooming interactions of co-roosting bats will be studied using an ingestible fluorescent biomarker to explore the feasibility of using transferable wildlife vaccines in this setting. Overall, this work will deepen our understanding of VBR transmission and support preventative management.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Identification and characterization of new genes required for Type VI Secretion System mediated anti-bacterial activity
Funder: Wellcome Trust

Abstract: Bacteria typically exist in mixed communities with other microorganisms and therefore, need to compete with rival microorganisms for resources and space. The Type VI secretion system (T6SS) is a protein nanomachine that many bacteria use to fire toxic ‘effector’ proteins directly into neighbouring cells. Usually, the T6SS is used against rival bacteria, making it an important weapon by which bacteria compete with and kill each other. I aim to identify new genes which are involved in T6SS-mediated anti-bacterial activity and to determine how some of them work. The experiments will be carried out using a representative bacterial pathogen called Serratia marcescens and results should also tell us more about many other pathogens. In addition to studying the ‘attacker’ cells bearing the T6SS, we will also be investigating what happens in the ‘target’ cells on the receiving end of the toxic effectors. We will try to understand if target cells can become resistant to particular effectors, and if so, how this happens. Overall, this project will lead to a better understanding of how bacteria survive in communities, infect host organisms, and kill each other and thus, may help develop new anti-bacterial drugs and strategies in the future.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Analysis of molecular mechanisms underlying systemic salmonellosis using One Health models
Funder: Wellcome Trust

Abstract: Salmonella is a bacterial pathogen of global importance. Some types of Salmonella are specific to humans and cause typhoid, a severe systemic disease (e.g. S. Typhi). A capsule comprised of sugars on the surface of S. Typhi is believed to help it evade the immune system, but this is challenging to study in people. The same capsule (called the Vi antigen encoded by via genes) is present in some strains of Salmonella Dublin, which cause typhoid-like disease in cattle. This offers a tractable model to understand the role it plays during infection. My research will involve creating mutations within the via genes of S. Dublin and testing how these affect interactions with immune system components in the laboratory (e.g. blood cells and serum components that kill bacteria). I will then use surgical models to study how Vi helps S. Dublin to spread from the gut to other organs and produce disease in cattle. The role of Vi has mostly been researched using mouse models and strains that naturally lack via genes but have been engineered to express them. The presence of Vi in S. Dublin offers a rare opportunity to study the role of Vi in a natural microbe-host combination.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Development of bovine lung models to assess host-pathogen interactions
Funder: Wellcome Trust

Abstract: Respiratory disease is one of the most common causes of morbidity and mortality in cattle, representing not only a serious threat to animal welfare but also an important loss from an economical point of view in the livestock industry. The entry mechanisms of most of the pathogens involved together with immune response of the lungs, especially in young animals, are not clearly understood. The major method of investigation of the pathogens' interaction with the lungs is the in vivo approach as, to date, there is no suitable lung model able to mimic both the epithelial and immune system functions at the same time. The aim of this project is evaluation of the models that are currently available, in particular regarding their similarity with ex-vivo lung tissues, and to improve these models to include immune cells. Additionally, the detailed study of ex-vivo tissues will allow a better understanding of the basic physiological and immunological composition of the bovine lungs which is currently not exhaustive. The knowledge gained from both ex-vivo and currently used in vitro studies will lead to the development of appropriate, complex, 3D models such as organoids that can replace animal use in bovine respiratory system research.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Investigating Human Host Factors Involved in Coronavirus Infection in the Search for Antivirals
Funder: Wellcome Trust

Abstract: SARS-CoV-2 is the virus that causes COVID-19 in humans and has resulted in a global pandemic since March 2020. Viruses are small pathogens that need to find, bind and enter host cells to replicate and assemble new virus particles that are then released to infect neighbouring cells or other hosts. This project aims to find parts of the human cell (known as host factors) that are involved in SARS-CoV-2 infection. I will continue research from a large experiment which will identify host factors that either help or hinder the virus. We can then use drugs to either inhibit that which helps the virus (pro-viral factors), or promote that which fights the virus (anti-viral factors) to develop antiviral therapies for the treatment of COVID-19. Drugs with potential antiviral activity in cell models may then be moved to preclinical mouse models to test if they work against SARS-CoV-2 infection and are safe. I will also assess if any drug targets are translatable to other coronavirus infections. Finding drugs that act against a broad range of coronaviruses may be important in the event of a new, infectious coronavirus outbreak in future.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Molecular mechanisms for productive invasion of the human liver by Plasmodium sporozoites
Funder: Wellcome Trust

Abstract: Malaria is initiated by infected mosquitos that bite mammals and deposit Plasmodium parasites in their skin. The parasites then reach their livers via the bloodstream and invade liver cells. Inside these hepatocytes, the parasites differentiate and become capable of infecting red blood cells, which causes typical symptoms of malaria. Previous research have implicated the role of multiple host surface proteins for liver invasion as well as parasite proteins that interact with the mammalian receptors.My research aims to determine which proteins are necessary for liver invasion at a molecular level. I will produce mammalian and parasite proteins and confirm interactions between them. For that purpose, I will use techniques that either detect the binding of proteins or a change in molecular weight upon protein binding. Next, I will employ methods that elucidate structures of host and Plasmodium proteins. To accomplish that, I will subject protein complexes to X-ray and electron beams and analyse the resulting data. Finally, I will use cellular assays to demonstrate the necessity of confirmed protein-protein interactions for the liver invasion. My research will help explaining the molecular basis of liver invasion by Plasmodium parasites potentially paving the way for a novel strategy of malaria vaccine development.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Host heterogeneity in disease transmission: Immune regulation and heritable genetic variation in pathogen acquisition and spread
Funder: Wellcome Trust

Abstract: Individuals vary widely in their ability to acquire and transmit pathogens, making it challenging to predict and manage the spread of infection. It is therefore key to understand the drivers of variation in the behavioural, physiological, and immune traits that contribute to pathogen transmission. The fruit fly, Drosophila melanogaster is a genetically tractable model system for infection, immunity and behaviour and is therefore ideal to investigate how individual host heterogeneity scales up to population disease dynamics. My first aim will ask how the innate immune system regulates avoidance behaviours and pathogen shedding, using existing loss-of-function mutants to investigate the crosstalk between immunity, behaviour and pathogen shedding. My second aim will be to measure the broad sense heritability in these traits. This will quantify the genetic contribution to each phase of pathogen acquisition and spread. Finally, I will investigate evolutionary trade-offs underlying super-spreading hosts. Using a large outbred fly population, I will continuously select on standing genetic variation to create fly populations with extreme shedding phenotypes. I will then test how experimental evolution for these extremes has affected the correlated evolution of other behavioural and immune traits. Altogether, this project will aim to answer the question: “what makes a super-spreader?”


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Providing the scientific evidence and tools for reaching 2021-2030 NTD Roadmap goal of eliminating schistosomiasis as a public health problem in Africa
Funder: Wellcome Trust

Abstract: The World Health Organization (WHO) defines neglected tropical diseases (NTDs) as those which are neglected by research and funding, and disproportionately infect poor and marginalised communities. One such NTD is schistosomiasis, a waterborne parasitic disease which infects over 250 million people worldwide, and is second only to malaria in terms of socioeconomic burden. In the new NTD roadmap 2020-2030, the WHO aims to eliminate schistosomiasis as a public health problem by 2030. Preventive chemotherapy has been a pillar of intervention strategy for many years in endemic countries of Africa, but some regions do not respond as expected, with persistent high prevalence of schistosomiasis. In this PHD I aim to investigate factors which could be maintaining these persistent hotspots, and therefore hindering the goal of elimination. I will investigate whether using preventive chemotherapy at a defined time in the transmission pattern of S.haematobium would reduce prevalence and reinfection. I will also carry out a survey of attitudes and practices involving WASH in Zimbabwe with a focus on COVID-19 and its effects on endemic schistosomiasis. Finally, I will explore genetic differences in parasite populations, post treatment in persistent and non-persistent regions, allowing an investigation into parasite susceptibility to treatment.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: INFECTION
Title: Investigating the conservation, function and vaccine potential of DBLepsilon and DBLzeta domains of Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1)
Funder: Wellcome Trust

Abstract: Every year, the malaria-causing agent Plasmodium falciparum results in over 400,000 deaths and 200 million clinical cases in humans. These outcomes have negative socio-economic implications in malaria-endemic regions of the world and thus require urgent interventions such as vaccines. During infection, P. falciparum attacks and multiplies in human red blood cells. Of importance, the parasite alters the infected red blood cell surface by expressing its own proteins. These P. falciparum derived proteins mediate binding to various tissues, uninfected red blood cells and serum proteins – leading to severe disease outcomes. Interestingly, preliminary evidence suggests that P. falciparum derived proteins (known as DBLepsilon and DBLzeta) that bind to serum proteins are conserved across the global P. falciparum population. This offers the possibility of developing a vaccine against severe malaria. In this study, I will be exploring these serum-binding P. falciparum proteins by examining their conservation and function. I will also produce antibodies from these proteins and test for activity against diverse P. falciparum samples. This study will provide insight into the viability of the serum-binding P. falciparum derived proteins as potential vaccine candidates for protection against severe malaria.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Investigating the host-pathogen genetic interactions of Plasmodium falciparum, the causative agent of human malaria
Funder: Wellcome Trust

Abstract: Malaria is a substantial public health problem responsible for approximately 409,000 deaths every year according to the World Health Organisation. Despite decades of research and significant financial investment an effective malaria vaccine is yet to be developed. Malaria parasites continually evolve to counteract human resistance traits and understanding how malaria parasites are changing could lead to the development of more effective vaccines and antimalarial drugs. I aim to use a combination of human and malaria genome sequencing to dissect host-parasite genetic interactions. I plan to expand existing datasets by sequencing ancient parasite DNA samples and to use the modern technique of single cell sequencing to enable in depth, highly powered analysis of malaria parasite genome evolution and function.


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