NIHRDataInsights/HRCSData huggingface dataset:
Title: The cellular and molecular mechanics of malaria parasite invasion of the human erythrocyte.
Funder: Wellcome Trust

Abstract: Malaria disease is initiated when merozoites, the free invasive blood-stage form of the parasite, enter circulating erythrocytes. Invasion itself is remarkably rapid, however, despite its speed, the process involves the complex coordination of several events: formation of a parasite-erythrocyte tight junction; initiation of, and force generation by, the parasite actomyosin motor; traversal of the erythrocyte membrane without it rupturing; and formation a parasitophorous vacuole. Despite recent a dvances in understanding each of these events, we still know surprisingly little about how they are coordinated and how the overall mechanics of entry are achieved. My proposed programme of research aims to address this problem from single molecule right through to whole cell levels to answer questions centered on the fundamental mechanics of invasion. What is the force potential of the invading parasite and how is motor activation achieved? How is this force transmitted to the host cell to driv e the parasite through the junction? How does the erythrocyte, the overlooked equal player in the invasion process, facilitate or respond to parasite entry? And are these processes conserved across Plasmodium species that infect humans. Each of these questions is critical for a complete understanding of malaria parasite infection. Using in vitro motor reconstitution and biochemistry, state-of-art high definition imaging, single-molecule and whole cell microscopy, along with parasite and erythroc yte-progenitor genetics, my goal is to reveal the fundamental principles that define parasite invasion, and thus identify weaknesses that can be targeted to stop it.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Spatial and temporal distribution of the N1575Y allele and his impact on the malaria vector control activities.
Funder: Wellcome Trust

Abstract: Malaria is a major cause of infant mortality in Sub-Saharan Africa. The disease is transmitted through the bite of infective mosquitoes which predominantly bite at night and inside houses. Targeting the mosquitoes using insecticide treated bednets and walls have been highly successful at reducing malaria. Recently, these interventions have been distributed across Africa on an unprecedented scale; however, this places a large selection on mosquitoes to develop insecticide resistance. This is comp ounded by the limited number of insecticides licensed for human disease insects. For example, only pyrethroids are currently available for bednets. In Burkina Faso, the major malaria mosquito, Anopheles gambiae, has developed strong resistance to pyrethroids, which target the insect sodium channel. Mutations within the sodium channel are associated with resistance and are at a high frequency in An. gambiae s.s. throughout the country. Worryingly, an additional mutation was recently described fro m West Africa which provides supplementary levels of pyrethroid resistance. Alternative insecticides are urgently required for malaria control; however, in the meantime, managing existing insecticides is crucial to preserving the efficacy of vector control tools. Information on the spread and dynamics of resistance mutations, which constitute the primary goals of this project, will greatly aid this process.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: An initiative for research in non-communicable diseases at MLW: The risk of chronic disease following severe acute malnutrition
Funder: Wellcome Trust

Abstract: MLW is strategically placed to conduct high quality laboratory, clinical and epidemiological science relevant to health in sub-Saharan Africa. The programme is embedded within a rapidly growing medical school, co-located within the largest teaching hospital in Malawi with direct access to urban and rural populations. In the next 5 years, MLW research will increase fundamental understanding of disease mechanisms and burden, test novel interventions and ensure translation into health care. The cor e programme will ensure MLW delivers the following aims: (1) Pursuit of cutting-edge research focused on health problems with a high disease burden. Research management, mentorship, development of bioinformatics expertise, and clinical and diagnostic laboratory competencies, ensuring the highest quality. (2) Provision of a research training environment for clinicians, epidemiologists and laboratory scientists. Local research infrastructure, operational and financial systems, data manageme nt and research governance support. (3) Development of globally competitive research leaders. Moving towards local leadership, embedded within the University of Malawi College of Medicine, attracting further intermediate and senior Fellows, and encouraging re-entry of trained Malawian scientists. (4) Translation of scientific advances into human health improvements. Defining national and international research agendas through policy relevant evidence; policy committee membership; research synthesis workshops; and public engagement.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);8.5 RESOURCES AND INFRASTRUCTURE (HEALTH SERVICES);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: INFECTION
Title: Eliminating malaria to counter artemisinin resistance.
Funder: Wellcome Trust

Abstract: Emerging resistance in South-East Asia to the main antimalarial drug (artemisinin) currently used across the world poses the greatest threat to current global initiatives to control and eliminate malaria. Resistance to earlier antimalarials arose from the same area and claimed millions of lives. Urgent action to contain this threat is needed, but there is no consensus on what containment measures should be undertaken. We propose a radical approach to eliminate foci of artemisinin resistance. We propose to conduct a multinational clinical and laboratory study to evaluate targeted chemo-elimination (TCE) as a strategy to eliminate artemisinin resistant Plasmodium falciparum. We will measure the impact of repeated TCE on the incidence of malaria, the size and the genetic structure of the malaria parasite population and on the transmission of malaria, and the progression of artemisinin resistance. We will develop and refine the methods of assessment and assess the acceptability, safety, ef fectiveness, costs and feasibility of TCE and thereby provide tools for scale-up if it is proved to be effective.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: INFECTION
Title: A global Chlamydia trachomatis biobank integrated with a comprehensive genome sequence database.
Funder: Wellcome Trust

Abstract: The aim of this proposal is to establish an international biobank of C. trachomatis isolates at the University of Southampton. The primary objective will be to collect 200 diverse C. trachomatis isolates of known provenance (i.e. isolation date, geographical location and a chain of evidence for passage), which will be identified from the literature. These will be purified if necessary, then typed by sequencing of ompA/other taxonomically useful genes to confirm the identity of the isolate. Phe notypic characterisation will follow. For every isolate to be included in the collection an accompanying whole genome and plasmid sequence will be generated through our collaboration with the Wellcome Trust Sanger Institute. Once characterised, live isolates and DNA will be available for purchase by members of the research community at a nominal cost. A database will be generated containing all the information on each isolate in the biobank e.g. phenotypic characterisation, genome sequence data, recommended culture conditions; this will be made available on the biobank website. We intend that the website will be a knowledgebase for chlamydia culture to encourage newcomers to field, and to support those experiencing difficulties with the techniques needed for chlamydia culture.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Investigating the natural variability in virulence of Staphylococcus aureus using whole genome sequencing
Funder: Wellcome Trust

Abstract: The bacteria Staphylococcus aureus can live harmlessly on the body surface, and is found on one in four humans. It can also cause serious infections. We have a limited understanding of why the bacteria might change from being harmlessly carried to causing disease: human and bacterial factors are both likely to play a role. This project will seek to understand what features of the bacterial genetic code (or DNA, the instructions carried in all bacteria) contribute to the development of infection. I will take a collection of bacteria found in the noses of healthy people (asymptomatic carriers), and bacteria found in people with infections, and compare the entire genetic codes of those bacteria. I will also investigate a set of individuals who have infections and are also carriers, in order to compare the genetic codes found in bacteria living on the surface to bacteria at the site of infection. I will test some of the genetic changes discovered, by comparing differences in the level s of activity in bacteria with and without those changes. This study should help us to determine how the bacterial genetic code contributes to the development of infection.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Development of an evidence based protocol in managing adults with recurrent tonsillitis.
Funder: Wellcome Trust

Abstract: ENT doctors frequently review patients with recurring tonsillitis that fail to improve with medical treatment. In 2012, 20,000 adults in the UK had their tonsils surgically removed (tonsillectomy) making it one of the 20 most commonly performed operations. Previous work shows large variation in tonsillectomy rates, but has failed to investigate the underlying causes. This unwarranted variation exposes patients to possible inequalities in care. My thesis hopes to explore the variation and help re duce it. I plan to investigate the drivers of disparity in tonsillectomy rates by studying the patterns by which 1.Patients with sore throat seek help from their GPs, 2.GPs refer patients with recurrent sore throat to ENT and 3.ENT surgeon's manage recurrent sore throat with tonsillectomy. Statistical techniques will be used to help ascertain how much variation is unwarranted. There is currently no questionnaire/tool available to evaluate the benefit from treatment for UK adults with re current tonsillitis, in a patient-centred manner. This means that comparisons of service between different health providers, or between different treatment options cannot be performed. Using standardised techniques I aim to adapt a German questionnaire/tool for use on UK adults to suit this purpose.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;7.3 MANAGEMENT AND DECISION MAKING
Health categories: INFECTION
Title: Defining protective immunity to human tuberculosis.
Funder: Wellcome Trust

Abstract: Human Mycobacterium tuberculosis (Mtb) infection results in symptomatic active disease in a minority of individuals, the remainder developing a latent infection with no clinical symptoms However, as up to a third of the worlds population is infected, the global burden of disease is still significant. As such, it is important to both identify those at greatest risk of developing active disease and also to understand how the majority are protected from it. Many studies have demonstrated that imm unity plays a key role in determining disease outcome, but the mechanisms involved remain unclear. This study compares immune responses between groups with differential risk of developing active disease: latent infection and those vaccinated with BCG are relatively protected, whereas those with previously treated active disease are at increased risk. We will look at Mtb killing in macrophages, the main cells the bacteria grow in, and measure immune responses following skin injection of purifi ed Mtb proteins, a safe technique commonly used in clinical practice. The latter approach will identify which immune components protect from active disease. Measurement of these will help calculate the risk of individuals developing active disease, and also identify desirable immune responses that future TB vaccines should elicit.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Optimisation of a series of hits against trypanosome phosphofructokinase to give a lead for treatment of the neglected disease Human African Trypanosomiasis
Funder: Wellcome Trust

Abstract: Human African Trypanosomiasis (sleeping sickness) is a neglected disease which is transmitted by tsetse flies. Without treatment death is inevitable and current drugs are poorly effective. T. brucei gets its energy from the breakdown of glucose (glycolysis) obtained from host blood for survival. The parasite proteins used for this process (so-called glycolytic enzymes) provide the parasite with its only source of energy (ATP molecules). The compounds already identified in this project have been shown to kill the parasite by specifically inhibiting glycolysis. Highthroughput screening funded by the National Institutes of Health (NIH) against one of the glycolytic enzymes (PFK) identified three chemically different families of inhibitors each capable of killing T. brucei parasites. The objective of this project is to design and synthesise related compounds to improve potency so that very low concentrations of compound (nanomolar) are needed to kill parasites. Drug molecules have a number of important criteria and should be tight binding, non-toxic, easy to synthesise, easily absorbed into the body after oral dosing, stable and specific against parasites. These properties will guide the design process to provide potent compounds that kill parasites without harming the infected people and animals.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Cell entry and innate immune recognition of enveloped viruses.
Funder: Wellcome Trust

Abstract: The goal of our research is understand at the molecular level how important viral pathogens interact with their hosts during infection. The key questions that we want to answer are: (1) How do viruses recognize their host cells? (2) How viruses deliver their genetic material into their host cells? (3) How does the hosts innate immune system detect signature chemical patterns from the viruses and mount an antiviral immune response? These are important questions because discovering basic princi ples governing virus cell-entry and virus recognition will allow us to identify new pathogen vulnerabilities and hopefully contribute to the design of novel drugs and vaccines. Our work on innate immunity may suggest new strategies for immunomodulation, which is being explored as a way to treat infectious diseases, autoimmune diseases and cancer. To answer these questions, we employ a complementary set of biophysical, biochemical and cell biological approaches. By integrating these approache s across scales-- in space and time-- we will obtain an understanding of how viruses infect their hosts in unprecedented molecular-level detail.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Generating and improving novel vaccine candidates targeting multiple stages of Malaria
Funder: Wellcome Trust

Abstract: Malaria is one of the three main killers among infectious diseases and especially children in sub-saharan Africa are affected. Although the numbers of infections could be reduced, elimination appears to be only possible if a vaccine can be found that protects from clinical malaria as well as interferes with disease transmission. I will therefore try to improve and combine current malaria vaccine candidates to meet this goal. I aim to achieve this via three different approaches. First, I will generate a number of novel particulate vaccines based on R21, a vaccine candidate developed in the Jenner Institute. R21 targets the sporozoite state of Plasmodium falciparum, but I will try to modify it to additionally induce high antibody responses to sexual-stage antigens. Second, I will try to establish a platform for displaying antigens on the surface of viral vectors to promote T-cell responses against the transgene as well as antibody responses against the incorporated surface antigens. Third, I will try to improve the immunogenicity of adenovirus based vectored vaccines by targeting them to antigen presenting cells. All these approaches, on their own or a combination of them, have the potential to significantly improve current malaria vaccine regimens


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: The Leishmania amastigote flagellum as a secretory organelle for the delivery of virulence factors
Funder: Wellcome Trust

Abstract: Leishmania are vector-borne protozoan parasites which are transmitted between mammalian hosts by the Phlebotomine sand fly. The amastigote form of the parasite resides in the hostile environment of the phagolysosome of mononuclear phagocytes where it must resist detection and degradation by the host cell. The bulbous tip of the short amastigote flagellum is often found to be intimately associated with the phagolysosome membrane, suggesting a possible role for orientation of the parasite with respect to the host cell which could be important for host-parasite interactions. The flagellum has recently been described as a secretory organelle of Chlamydomonas but such a function has not yet been assigned to the Leishmania flagellum. Electron microscopy reveals the presence of membranous structures within the phagolysosome; could these be parasite-derived? The DPhil project will investigate the role of the Leishmania flagellum as a secretory organelle for the delivery of virulence factors. Evidence will be sought for vesicle budding from the flagellar membrane. The composition of the shed material and the effect of individual factors on the host cell will be analysed. If dominant secreted factors are found knockout parasites will be generated and assessed for their ability to survive in macrophages.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: The role of nuclear export protein in influenza virus nuclear export and host adaptation
Funder: Wellcome Trust

Abstract: Influenza virus proteins all perform multiple functions in the viral lifecycle. Nuclear export protein (NEP) has been implicated in regulating switching between viral transcription and replication, viral budding as well as nuclear export. Studies have suggested that in the process of nuclear export NEP is interacting with the cellular nuclear export protein Crm1 and acting as a mediator between the viral ribonucleoproteins (RNPs) and the cellular nuclear export machinery. This project aims to explore the mechanism of influenza virus nuclear export and in particular the role of NEP in this process. Cellular and viral factors of NEP will be determined by immunoprecipitation and mass spectrometry and their interactions will subsequently be characterised in knock-down studies. Following up on current studies on the structure of influenza virus polymerase in the Fodor lab, this project will also aim to characterise the role of the 627-domain of PB2 in host adaptation. Although position 627 and several other residues in the 627-domain have long been known to be involved in host restriction, the exact mechanism of this process remains unclear. By deleting the whole domain this project aims to characterise its role in polymerase activity and how this affects host restriction.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: The roles of RNA restructuring and RNA binding proteins in regulation of gene expression during bacterial adaptation to temperature stress
Funder: Wellcome Trust

Abstract: Bacteria use complex strategies to coordinate temperature-dependent gene expression. Our goal is to understand the role of RNA structure in adaptation to temperature changes in pathogenic bacteria. Many genes encoding heat-shock and virulence factors are regulated by temperature-sensing RNA sequences (RNATs) within their mRNAs. At low temperatures, RNATs fold into structures that block ribosome access; increasing the temperature gradually shifts towards the open structure. RNATs are highly unrelated, making it difficult to identify RNATs using computational approaches. To identify novel RNATs, we will perform transcriptome-wide structure probing analyses in Escherichia coli and Clostridium difficile during cold-and heat shock, followed by a detailed characterization of candidate RNATs in vitro and in vivo. Protein-RNA interactions dictate RNA folding processes and these interactions are highly dynamic. To obtain the full spectrum of the proteins binding to mRNA during adaptive response, we will use UV cross-linking in combination with proteomics to identify proteins that bind bacterial mRNAs during early stages of stress adaptation responses. Vice versa, we will use CRAC to identify target RNAs for known RNA chaperones. The results of these studies should, for the first time, provide a global overview of RNA structure dependent gene regulation in prokaryotes.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Innate immune mechanisms and modulation during Salmonella infection
Funder: Wellcome Trust

Abstract: This work will investigate the complex host-pathogen interactions occurring during Salmonella infection with a focus on innate immune modulation. Salmonella translocates approximately 30 effector proteins into the cytosol of host immune cells to modulate its intracellular environment. The precise function, biochemical activity, kinetics of translocation and hosttargets are poorly characterized for the majority of effectors. This project aims to identify further effectors that modulate host immune signaling with a focus on NFKB signaling. This is a key pathway involved in cytokine / chemokine induction and cell death via apoptosis modulation during Salmonella infection. By studying bacterial-mediated modulation of immune signaling we hope to assign function to uncharacterized effectors as well as understand more about the functions of the host immune response.


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