NIHRDataInsights/HRCSData huggingface dataset:
Title: The population genetics and co-adaptation of trypanosomes with tsetse flies.
Funder: Wellcome Trust

Abstract: We propose to test the theory that host and parasite populations should locally adapted to each others presence, using combined field and laboratory studies in a biological system where the knowledge is potentially of practical relevance; the ability of tsetse flies to transmit trypanosome parasites. These findings will have implications for disease epidemiology and vector control strategies. If, for example, there is co-adaptation between vector and parasite locally, once such vector population s of tsetse flies are controlled, it is conceivable that re-invasions from other locations would not substantially increase the disease transmission rate because they would be poor transmitters. To undertake this study, we will sample tsetse flies and trypanosomes from different site sin Kenya, we will compare them genetically to see how different they are and then experimentally compare the ability of different tsetse populations to transmit different trypanosomes.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Comparative transcriptomics of blood stream and procyclic form of Trypanosoma brucei and investigation of its mRNA methyl cap structure and function
Funder: Wellcome Trust

Abstract: In Human African trypanosomiasis (HAT), the causative parasite Trypanosoma brucei (T. brucei) undergoes a transition between the Tsetse fly vector (procyclic form) and mammalian host (blood stream form) (1). A better understanding of the disease transmission cycle is imperative for the development of new therapeutic targets because substantial changes in protein expression occur when the parasite transitions from one stage to the next. This proposed project's overarching question asks is the T. brucei proteome substantially controlled at the level of mRNA selection by ribosomes; and if so, what is the mechanism of this selection. Aim 1: Perform RNAseq (in collaboration with the Wellcome Trust Sanger Institute) of total polA+ and polyribosomal RNA purified from blood stream form (bsf) and procyclic form (pcf) T. brucei followed by bioinformatic analysis comparing the transcript profiles. Aim 2: Correlate transcriptome data with proteomic analysis, using the SILAC method, of global protein expression levels in bsf and pcf T. brucei. mRNA processing in eukaryotic cells involves the addition of the 7-methylguanosine cap (methyl cap) to the first nucleotide of the 5' end of the transcript. Since the methyl cap is essential for gene expression in all eukaryotes investigated we will investigate whether it is essential in trypanosomses and whether the enzymes that catalyze formation of the methyl cap are potential drug targets. In the vast majority of eukaryotes methyl cap formation is catalysed by a single guanylyltransferase and a single methyltransferase. Trypanosomes are highly unusual in that they have an additional guanylyltransferase and methyltransferase on a single polypeptide (2). Aim 3: Our approach is to knock out the single methyltransferase and the bifunctional methyltransfere/guanylyltransferase and determine the effect on cell viability. If either enzyme is required for cell viability, it will be pursued further as a drug target with the drug discovery unit. The effect of methyltransferase knock-out on transcript stability, splicing, and translation will also be investigated to determine the effect of the methyl cap in trypanosomes.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Characterisation of host-pathogen interactions involving mucosally transmittted HIV 1 founder viruses.
Funder: Wellcome Trust

Abstract: The spread of HIV continues relentlessly, and all attempts at prevention by vaccination to date have failed. In particular, we know very little about the earliest events in infection that may hold the key to designing effective interventions allowing prevention of infection and vaccination. Recently researchers have shown that of the millions of viruses in sperm only a single virus is transmitted. Furthermore the viruses that transmit are different to the ones that don t. We propose to reveal th e biological characteristics of these so called founder viruses and understand on a genetic level why only one virus is transmitted in the majority of cases. We will explore whether these viruses have greater ability to infect certain key cells in vaginal and penile lining, or whether they transmit more efficiently from these cells to the T cells. The T cells are a type of white blood cell where most HIV replication occurs, and destruction of these cells leads to immune collapse and AIDS. Arme d with a working model for successful transmission we can design more effective strategies to improve barriers to infection and design vaccines to reduce the transmission rate to zero.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Interactome analysis of the structure of the trypanosome nuclear lamina and other complexes.
Funder: Wellcome Trust

Abstract: Defining function and the role of proteins in biological processes requires information at many levels. Genome sequences facilitate a parts list. A level of functional definition is possible by gene knockdown or knockout strategies. In the African trypanosome these approaches are powerful, but a complete definition of function requires determining the physiological context in which specific proteins operate. Protein interactions cannot at present be reliably predicted by in silico approaches, an d direct evidence is essential. It is proposed to use a new set of techniques to examine protein-protein interactions in trypanosomes. Using a GFP-tagged version of the protein (integrated at the endogenous gene locus), coupled with a supercooled ball mill procedure at -186&#730;C to generate a fine grindate, protein complexes have been isolated in high yield from total trypanosome cells. It is proposed to use this technology to explore how generally applicable the technique will be by focusin g on several complexes involved in intracellular transport. Proteins will be identified by MS/MS. If, as anticipated, the method is general, this will provide a powerful addition to the analytic methodology available for study of trypanosomes and potentially other (pathogenic) protists.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Wellcome Trust-Vietnam Initiative on Zoonotic Infections WT-VIZIONS
Funder: Wellcome Trust

Abstract: Our focus will be on viral infections in Vietnam with special emphasis on zoonotic viruses: these are relatively under-studied and viruses of animal origin are the dominant source of emerging infectious diseases in humans. WT-VIZIONS: 1. Establish a model consortium focused on an integrated approach to human and animal health in a country at the epicenter of emerging infectious diseases. 2. Quantify the epidemiology and burden of disease (focus on viral zoonoses) in i) patients hospitalized w ith one of four clinical syndromes; ii) infections in a cohort of high risk individuals occupationally exposed to animals; with targeted sampling from domestic animals and wildlife in association with (i)/(ii). 3. Elucidate the origin, nature, and burden of infectious diseases of unknown origin in the human study populations; 4. Characterize genetic diversity within virus populations on either side of the species-barrier to understand cross-species transmission and disease emergence; 5. Ident ify socio-demographic, environmental and behavioural drivers for disease emergence; 6. Provide a platform and resource for complimentary research on human and animal pathogens, and nonviral zoonoses. The results will inform the design of surveillance for infectious disease, and the opportunity to conduct detailed investigations of outbreaks, especially zoonotic diseases, occurring during the study period.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFECTION
Title: Characterizing Spirality in Campylobacter jejuni.
Funder: Wellcome Trust

Abstract: The aim of this project is to gather more information about the spiral structure of Campylobacter jejuni. The specific aims are to identify and characterize genes and gene products necessary for C. jejuni spirality and confirm the importance of spiral structure in pathogenicity.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Study of carbamate and organophosphate resistance in Anopheles gambiae, the main malaria vector in West Africa.
Funder: Wellcome Trust

Abstract: Increasingly carbamates and organophosphates insecticides are suggested as alternatives to pyrethroids insecticides due to the high resistance levels recorded to pyrethroids particularly in the main malaria vector from West Africa. The resistance to these insecticides is bolstered by the occurrence of a new duplication phenomenon. In recognition of the importance to preserve the effectiveness of vector control based on insecticides, it needs to provide useful information on the resistance to org anophosphate and carbamate. The development of improved tools to detect and monitor these resistance mechanisms are relevant, that is our goal, here, we will: -Develop by 2013 diagnostic tools to detect the duplication phenomenon in natural populations of malaria vector using news innovative techniques of molecular biology. -Monitor these resistance mechanisms in the field mosquitoes in seven West African countries up to 2014 by using available and developed diagnostic tools. -Better under stand the metabolic resistance; another resistance mechanism against carbamates/organophosphates using new analyses tools based on whole genome of the vector. If funded, this fellowship will necessary increase the research capacity of young research team at IRSP which will assist technically the NMCP in Benin. Furthermore this proposal will be a baseline for a strong collaboration between LSTM and IRSP.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Activation of the endoplasmic reticulum stress sensor IRE1 by lipid perturbations during flavivirus infections.
Funder: Wellcome Trust

Abstract: Inside the infected cell, flaviviruses usurp the endoplasmic reticulum. They use the host cell machinery associated with the endoplasmic reticulum for the synthesis and maturation of viral proteins. In addition, flaviviruses trigger specific membrane rearrangements leading to the formation of a web of membranes derived from the endoplasmic reticulum. This membranous web is critical for the flavivirus life cycle, as it represents a platform where the viral genome replicates and where the viral pa rticle is assembled. How flaviviruses trigger the formation of this membranous web is currently unknown. We hypothesize that the cellular enzyme IRE1 is involved in this process. Indeed, flaviviruses have been shown to activate IRE1 and IRE1 regulates endoplasmic membrane synthesis. We will study the mechanisms by which flaviviruses activate IRE1. Specifically, we will test the contribution of the recently indentified Q-site of IRE1 to flavivirus-induced activation. Finally, with the objective o f developing new antiviral treatments, we will test the ability of Q-site ligands to modulate IRE1 activity. As IRE1 activation could be crucial for the flavivirus-induced membrane rearrangements, Q-site ligands could inhibit the replication of flaviviruses causing major health problems to humans and animals.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: The impact of microbial translocation and immune activation on the health of Zimbabwean children.
Funder: Wellcome Trust

Abstract: Usually, bacteria living harmlessly in the gut are separated from the bloodstream by an intact gut wall. However, damage to this barrier allows bugs to enter the bloodstream (a process called microbial translocation; MT), where they over-stimulate the immune system (so-called immune activation; IA). This study will investigate whether MT and IA cause ill-health in African children and whether preventing MT/IA improves health. 1) Growth: IA may waste energy, resulting in poor growth. Increa sing food intake in African children only improves growth a little. We will investigate the theory that improving sanitation helps growth by reducing MT/IA. To do this, we will compare gut wall damage and MT/IA between children with standard sanitation and improved sanitation. We will see whether children with improved sanitation grow better by 18 months of age. 2) HIV infection: Over half of babies infected with HIV die by age 2, but the reasons why are not well understood. In adults, the H IV virus damages the gut wall and allows MT/IA to occur, which increases the risk of dying. We will see whether the same is true in children, and whether an inexpensive antibiotic called cotrimoxazole can reduce MT/IA, by killing gut bacteria, and improve survival.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: In silico rational design of novel inhibitors to Hepatitis C virus (HCV) non-structural proteins
Funder: Wellcome Trust

Abstract: Around 3% of the world population is currently infected with hepatitis C virus (HCV). Chronic infection will develop in 85% of cases and is a prerequisite to liver cirrhosis and hepatocellular carcinoma1-3. Response rates and toleration to current treatments vary between the viral genotypes, placing an emphasis on identifying novel ways to treat infection. Several viral polymerase and protease inhibitors are currently in clinical trials2,4, though the inaccuracy of the viral polymerase leads to rapid development of resistance mutations5, suggesting a combination therapy approach may be required. This project will utilise available structural information, virtual high-throughput screening (vHTS) and rational drug design to identify and optimise novel inhibitor compounds targeted to the viral protease NS2, and to other non-structural proteins involved in viral replication such as NS5A. Identified active compounds will be purchased or synthesised, analysed and optimised to produce new anti-virals against both existing and novel viral protein targets. This project will involve a combination of structural biology, virtual high-throughput screening, rational drug design and chemical synthesis, and as such will take advantage of the interdisciplinary nature of the Astbury Centre at Leeds University.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Quantitative proteomic analysis of latent human cytomegalovirus infection
Funder: Wellcome Trust

Abstract: Following primary infection, HCMV typically establishes a latent infection in monocytes under the control of a healthy immune system. Little is known about the intracellular pathways manipulated by HCMV to maintain latency, or the phenotype of latently infected cells. I will: (i) identify cell surface targets of individual HCMV latency genes (ii) enrich ex vivo latently infected monocytes to characterise the most important biochemical pathways altered by latent HCMV infection. I have developed a new technique ?plasma membrane profiling? (PMP) to enrich plasma membrane (PM) proteins for proteomic analysis. I will employ the functional proteomics approach SILAC (Stable Isotope Labelling by Amino acids in Cell culture), to perform semi-quantitative analysis on plasma membrane proteins enriched by PMP. Using this approach I will determine how latent HCMV infection alters the cell surface proteome by analysing transduced cell lines expressing individual HCMV latency genes, and an in vitro model of latency. I shall use the markers I identify to enrich latently-infected ex vivo CD34+ monocytes. In addition, I will characterise biochemical pathways altered by latent HCMV infection in these cells using ?KAYAK? (Kinase ActivitY Assay for Kinome profiling), a novel proteomic technique. Candidate proteomic ?hits? will be biochemically characterised.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Defining mechanisms driving immunopathology in Tuberculosis-HIV Co-infection.
Funder: Wellcome Trust

Abstract: TB is a leading cause of death and disability worldwide, especially in Africa. It primarily infects the lungs, causing extensive tissue damage, commonly affecting HIV-infected patients. When HIV is treated, TB symptoms and tissue damage frequently worsens, especially early during TB treatment. This can cause death or serious lung damage and also places a burden on healthcare in the developing world. The cause of tissue destruction in TB-HIV infection is unknown. Our previous work implicates the body's own cells in causing damage to the lungs while trying to fight the infection. We will try to understand these processes using state-of-the-art technology working in an area of very high rates of HIV-TB. We will study patients with TB-HIV and healthy patients and measure immune cells and lung-damaging mediators in their sputum and blood. We will follow patients over time during their TB and HIV treatment, observing changes in the mediators. We will also study blood cells from patie nts that we isolate in the laboratory. This project will aim to determine how the body damages the lungs, which may lead to new treatments to stop this damage and reduce death from infection.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Wellcome Trust Clinical PhD Programme, University of Liverpool 'Innate immunity in cryptococcal disease and immune reconstrustion inflammatory syndrome'
Funder: Wellcome Trust

Abstract: Cryptococcal meningitis (CM) and cryptococcal immune reconstitution inflammatory syndrome (IRIS) are a significant cause of morbidity and mortality in patients with HIV/AIDS in Africa.Immune response appears crucial in the development and outcome of both conditions however the exact pathophysiology remains poorly understood.It is hypothesised that inappropriate monocyte/macrophage activation is relevant. This study aims to address two aspects of cryptococcal disease. Firstly it will examine the role of monocyte and macrophage activation during cryptococcal meningitis,assessing whether an alternatively activated phenotype results in reducedfungal clearance, increased risk of IRIS, and death. The second aspect assessesmonocyte and macrophage activation following the introduction of anti-retroviral therapy,to examine whether IRIS corresponds with a switch to a classically activated state. This will be achievedusing a prospective cohort study design, recruiting 100 patients with CM and following them for 6 months. Blood monocyte and CSF monocyte/macrophage activation status will be assessed using flow cytometry and whole blood antigen stimulation. Additional indirect information will be determined by analysing cytokine profiles and soluble markers of monocyte/macrophage activation status in CSF and blood.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Recognition and evasion of Human cytomegalovirus by natural killer cells.
Funder: Wellcome Trust

Abstract: Human cytomegalovirus (HCMV) can cause serious disease in people whose immune system is suppressed. Natural Killer cells (NK) are part of our immune system whose role is to kill cells that are infected by a virus, such as HCMV. HCMV has the ability to remain in the body after initial infection (latency) and to reactivate and produce virus. HCMV has co-evolved with humans for millions of years and has acquired genes that allow it to evade cells of the immune system such as NK cells. Our researc h is aimed at determining how the virus inactivates NK cells. Also it is not known if latent virus can be seen by NK cells and, if not, what mechanisms prevent recognition. The viral state of latency allows the virus to persist in humans for life. If we understood how the virus evades the immune system when it is latent it would allow us to develop strategies to target these cells that harbour virus.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Transcription & post-transcriptional processing in the Plasmodium chloroplast
Funder: Wellcome Trust

Abstract: The parasite that causes malaria is one of the world's biggest killers, responsible for a million deaths a year. Recent work has shown that, surprisingly, the killer parasite, Plasmodium, comes from an evolutionary lineage of photosynthetic organisms Its closest relatives are dinoflagellate algae. Reflecting this ancestry, Plasmodium has a chloroplast, the subcellular compartment responsible for photosynthesis in plants and algae. The Plasmodium chloroplast is no longer photosynthetic, but stil l has other biochemical functions that are essential for the cell. Because the animals that can catch malaria do not have chloroplasts, it is a very exciting target for new drugs to kill Plasmodium. Like plant and algal chloroplasts, the Plasmodium chloroplast contains a small amount of DNA. Making the proteins it encodes is essential for the parasite's function, but little research has been done on the biochemical details of this. However, our experience of the equivalent process in plants and algae allowed us to identify Plasmodium proteins that are likely to be important in it. We want to find out if these proteins are located in the chloroplast, as predicted, and test their function. In the long term, this may help us develop new drugs to treat malaria.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFECTION
Title: The structural dynamics of modular polyketide synthases.
Funder: Wellcome Trust

Abstract: Disease in humans can be both caused and cured by polyketides, natural products generated by microbes. Polyketide molecules are constructed by linking together a series of simple building blocks into long chains within huge factory enzymes, known as polyketide synthases (PKSs). Each step in the assembly line is assigned to an independently folded portion (or domain) of the long PKS protein molecule, with every domain performing a specific task before the growing substrate chain is passed along t o the next work station. In these systems, acyl carrier protein domains (ACPs) behave like conveyor belts, shuttling their polyketide cargo chain between the active sites of each enzyme component in turn. Crucial aspects of PKS function will remain a mystery until the properties of ACP domains are understood in detail. To assemble a realistic picture of the behaviour of ACPs in their native context, we will examine the interactions between fragments from DEBS, the PKS factory about which most is known. We will then make our conclusions more general by studying the PKS responsible for producing mycolactone, a toxin that suppresses the immune system and causes Buruli ulcer, a neglected tropical disease.


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