NIHRDataInsights/HRCSData huggingface dataset:
Title: The impact of HIV-1 vaccination on the composition of the human antibody repertoire responses by memory B cell subsets
Funder: Wellcome Trust

Abstract: It is generally accepted that generation of long-lived neutralizing memory B cell responses will be critical for an effective vaccine against HIV-1. Successful vaccines can induce long-lived B cell memory that is maintained for decades. In contrast, HIV-1 envelope vaccination and HIV-1 infection typically induces predominantly short-lived memory B cell-dependent plasma antibodies. Recent observations have shown that vaccination or infection does not produce a homogenous population of memory cells but a constellation of subsets dependingon the kinetic time point, location, and type of infection or vaccination. This thesis is based on the premise that previous analysis of B cell repertoire responses in unsorted B cells from the blood provides an incomplete view of B cell memory development and will test the hypothesis thatthe inability to induce durable HIV responses are reflected by defects in responsiveness withinthe different B cell memory subsets. This will be accomplished through cloning and sequencing of memory B cells sorted by subset following vaccination in ongoing HIV vaccine studies. Responses will be compared and contrasted to those for tetanus. Understanding potential differential responses of these memory B cell subsets to vaccination may prove critical in the creation of novel, effective vaccines to HIV-1.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;3.4 VACCINES
Health categories: INFECTION
Title: A putative lipase as a novel toxin/effector in the Pseudomonas aeruginosa typeVI secretion system
Funder: Wellcome Trust

Abstract: The bacterial type VI secretion system (T6SS) is a macromolecular complex embedded in the cell envelope of most pathogenic Gram-negative bacteria. This secretion system is a major pathogenicity determinant and is required for Pseudomonas aeruginosa to establish chronic infections in cystic fibrosis patients. The T6SS is evolutionarily, structurally and mechanistically related to the bacteriophage tail, puncturing target cell membranes to deliver its cargo [1].The T6SS secretes toxins into both eukaryotic and prokaryotic cells in order to subvert host responses and to aid competition with other microorganisms. A limited number of T6SS effector proteins have been identified, with the majority displaying antimicrobial activities. The secretion system has no inherent mechanism of self-discrimination, therefore sister cells are only protected through the expression of immunity proteins cognate to the antibacterial effectors. Cognate antitoxins are unnecessary for antieukaryoticeffectors. The proposed research aims to characterise a putative T6SS effector from P. aeruginosa and to study its contribution to pathogenesis. Genetic and biochemical approaches along with cellular biology methods will further our understanding of the arsenal of toxins that this important bacterial pathogen has at its disposal.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Analysis of genetic diversity in millions of bacteria using genome graphs
Funder: Wellcome Trust

Abstract: In order to use sequencing to improve public health it is vital to have accurate, flexible, and statistically robust methods for understanding how a new bacterial strain relates to all previously sequenced strains. The underlying goal of this project is to develop a methodsand publicly available tools by which one can rapidly compare any isolate with the pan-genome of all known strains and then seamlessly add this strain to the pan-genome for future usersto benefit from. This will involve developing statistical and computational methods to represent genetic sequence data and known variation in a way that facilitates comparative analysis even when scaled to millions of genomes. This will also lead also to the development of associated analysis tools for epidemiological applications, classification problems (such as predicting antibiotic resistance) and association studies.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFECTION
Title: Statistical and computational methods for modelling pathogen genetic variation
Funder: Wellcome Trust

Abstract: Bacterial and parasitic genomes exhibit high levels of both diversity and structural variation which make analysis extremely challenging. We focus on P.falciparum, where the standard analysis approach of mapping reads to a reference genome leads to poor characterisations of regions with high sequencediversity or deeply diverged lineages, such as several medically important surface antigen genes. Furthermore, mixed infections are a fundamental part ofmalaria biology, and in order to build good models and ask appropriate population genetic questions, we want to be able to incorporate this. The goalof this D.Phil is to develop data structures that represents all known geneticvariation in the species in a way that preserves coordinates, and then associated statistical methods, to use all the information available about alternative haplotypes when assembling novel genomes. Concretely, as part of the MalariaGEN consortium Pf3k project to sequence 3000 P. falciparum samples and make them publicly available, we will build a population reference graph that combines heterogeneous data, including multiple reference sequences and thousands of unassembled samples. This will allow us to address many questions, such as relating to the biology of surface antigen genes, and use these graphs in association studies.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFECTION
Title: Integration of epidemiological and genetic data to reconstruct disease outbreaks in host-viral systems
Funder: Wellcome Trust

Abstract: The recent history of a virus epidemic can be more accurately reconstructed when genetic and epidemiological data are integrated, compared to focusing on either data type alone. However, current reconstructive approaches are limited, being designed for outbreaks where most cases are identified. We lack a framework capable of powerful inference when more detailed epidemiological and viral genetic data are available, but when a smaller proportion of cases is sampled. I intend to resolve this by developing general Bayesian statistical methods and applying them to host-virus systems for which both viral genetic and host behavioural data are available: hepatitis C virus (HCV) in humans, and influenza in wild birds.Accessing data obtained from collaborators from four cohorts of HCV patients, I will apply improved methods to determine factors associated with increased risk of transmitting HCV. In tandem, I will study longitudinal viral genetic diversity in a resident mute swan colony (Abbotsbury, Dorset). This will test hypotheses that influenza dynamics in long-lived birds are unlike that in the short-lived species on which almost all research focuses. Combining epidemiological and genetic sequence data will increase understanding of the dynamic behaviour of these viruses, which can be translated to improving control and surveillance measures.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFECTION
Title: Investigating impact of insecticide resistance and immune system on Plasmodium falciparum development in the major malaria vector Anopheles funestus in Cameroon
Funder: Wellcome Trust

Abstract: Resistances to anti-malarial drugs and to insecticides are presently disrupting malaria control in Africa. Therefore, novel control strategies are needed. One of these is the replacement of vector populations by non-vector ones to disrupt parasite transmission by taking advantage of observed natural refractoriness to infection in mosquitoes. This requires a good understanding of the factors impacting vectorial competence in natural populations of Anopheles and of the complex interactions between the mosquito vector and the Plasmodium parasite. If progress has been made to elucidate these interactions in An. gambiae, nothing is still known for the other major vector An. funestus. Besides, the impact of insecticide resistance on Plasmodium development in Anopheles vectors has not yet been thoroughly assessed. The present project aims to fill these important gaps in our knowledge taking advantage of progress recently achievedin the genetics, genomics and rearing of An. funestus. I plan in this project to: - Aim 1. Assess the impact of insecticide resistance on the development of P. falciparum in An. funestus, - Aim 2. Assess the molecular basis of immune response to P. falciparum infection in An. funestus - Aim 3. Study the population genetic of P. falciparum resistance genes in An.funestus.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Structural characterisation of nutrient and innate immunity factor uptake by trypanosomes.
Funder: Wellcome Trust

Abstract: Human African Trypanosomiasis is caused by the protozoan parasite Trypanosoma brucei, and is fatal if left untreated. Each trypanosome is surrounded by a surface coat of 10^8 variable surface glycoproteins (VSGs), which protect against complement-mediated lysis,and the switching of VSG expression allows evasion of the adaptive immune system. Thisproject aims to understand how the trypanosome takes up both nutrients and human immune factors in the context of the VSG coat. The project will focus on the haptoglobin-hemoglobin receptor (HpHbR), and the transferrin receptor, which allow the parasite to scavenge heme and iron respectively, in complex with human ligands. HpHbR is also involved in uptake of trypanolytic factor 1 (TLF1), a human lipoprotein particle that protects the host from numerous trypanosome species.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Targetting Pseudomonas aeruginosa with protein antibiotics
Funder: Wellcome Trust

Abstract: Bacteriocins are naturally occurring protein antibiotics produced by bacteria to kill competitors during competition for resources. Colicins are protein antibiotics specific for Escherichia coli. There has been considerable recent progress in understanding the import mechanisms of colicins. By contrast little is known about the mechanisms of action of other bacteriocins that target pathogens such as Pseudomonas aeruginosa, the primary causative cause of mortality in cystic fibrosis patients. This research has two objectives. First, to advance our understanding of how nuclease pyocins, which naturally target P. aeruginosa, bind specific outer membrane receptors using biophysicaland structural methods. Second, to exploit information on colicin-receptor complexes to computationally redesign colicins so they bind outer membrane receptors from P. aeruginosa. This aspect of the programme builds on a rotation project wherethe macromolecular modelling program Rosetta was used to redesign the receptor-binding specificity of colicin E9 towards P. aeruginosa. New designs will be tested and their success assessed by biophysical and structural methods. Uncovering how redesigned colicins and pyocins bind to P. aeruginosa outer membrane receptors will lay the foundations for a new platform technology for targeting any pathogen receptor with a bacteriocin.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Treating netting eave baffles with pirimiphos-methyl to control indoor-feeding Anopheles funestus malaria vectors at an affordable cost
Funder: Wellcome Trust

Abstract: In Zambia and all across Africa, the two main vector control interventions aimed at preventing malaria transmission are the use of long lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) [1,2,11,22,25]. In reducing abundance and infectivity of malaria vectors, these tools reduce overall transmission and protect communities [39,40], resulting in large reductions of disease burden. To sustain and improve the gains made in malaria prevention here in Zambia, we need to creatively d evelop malaria vector control strategies that are cost-effective. Pirimiphos-methyl is a new organophosphate that is very effective against malaria vectors, including those that are resistant against other insecticide classes widely used in Zambia. But applying pirimiphos-methyl to all walls and roofs in all houses in the country would be prohibitively expensive ($63M annually). To overcome this limitation, I propose to treat netting eave baffles placed around the eaves of houses to force mosqui toes into contact with targeted applications of smaller quantities of this expensive insecticide. I aim to demonstrate that eave baffles kill more malaria vectors, for longer, and at lower cost, than conventional indoor residual spraying (IRS).If proven effective, netting baffles might be adopted for malaria vector control across Zambia and in other countries.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: INFECTION
Title: Epidemiology of environmental enteropathy and intestinal microbiota amongst infants aged 0-9 months in Kilifi, Kenya.
Funder: Wellcome Trust

Abstract: Environmental Enteropathy (EE) is an abnormal inflammatory state of the lining of the small bowel, commonly found amongst children in poor countries. It is associated with impaired growth, and thought to be caused by single or repeated infections of the digestive tract. However, the roles of specific species of bacteria, virus or parasite in the development of EE are not well understood. Nor are those of other environmental exposures such as early complementary food introduction and other househ old factors such as latrines and water supply. Better understanding of the cause of EE could guide use of targeted treatment/prevention approaches such as vaccines to treat/prevent this condition of great population-level health significance. By following a group of rural Kenyan infants from birth, I aim to describe the pattern of acquisition of EE during the first 9 months of life. I will also test for relationships between EE and its possible causes. These include the presence (with or with out diarrhoea) of specific bacteria/virus/parasite species in faeces, the genetic material of these species, short illnesses, an overgrowth of bacteria in the normally-sterile small bowel, and household factors as described above.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFECTION
Title: Assessment of the cause and effect of gene expression changes in primary CD4 positive T-cells at early time points following infection by Human Immunodeficiency Virus Type 1
Funder: Wellcome Trust

Abstract: A large part of the disease caused by HIV-1 virus occurs because it infects specific white blood cells known as CD4+ T-cells (which are essential to the immune system). Research has shown that when these T-cells are infected by HIV-1, they change the pattern of genes that they are expressing (using to function). This may be because the cells recognise the invading virus and are responding to infection. Alternatively it may be that the virus manipulates the cells to express genes that help it survive. We predict that both processes occur and the interplay between them determines whether the virus successfully infects the cell. The first project aim is to find out which components of the virus are manipulating the genes the


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Characterising control of mycobacterial growth in patients with TB disease and M. tuberculosis infection.
Funder: Wellcome Trust

Abstract: TB, caused by Mycobacterium tuberculosis (M.tb), remains a significant cause of disease worldwide, responsible for 9 million new cases and over 1 million deaths annually. To combat this, approaches combining a variety of strategies are required, including effective vaccines, rapid diagnostic tests, and new drug treatments. However, a significant hurdle to developing new interventions remains our lack of understanding of how the human immune system copes with M.tb infection. Individuals may hav e either latent or silent infection (M.tb infection is present, but does not cause obvious disease) or active, obvious, disease that requires at least 6 months of antibiotics for treatment. We have found that the latter group have a better ability to control the growth of M.tb in laboratory experiments which may be related to how much the pathogen stimulates an individuals immune system. Different types of particular classes of immune cells, B and T cells, may contribute to these differences in control. By studying the immune and genetic profiles of these cells in individuals, and correlating these with the growth studies, I propose that we will be able to identify key immune pathways that will help in the development of new interventions so crucially needed to control TB.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Fundamental and therapeutic insights into tuberculosis from the zebrafish and its application to humans.
Funder: Wellcome Trust

Abstract: My laboratory pioneered the zebrafish-Mycobacterium marinum model of tuberculosis to make surprising discoveries about tuberculosis with profound clinical implications. We will pursue these discoveries and approaches: 1. Mycobacterial entry: We will pursue our new findings that mycobacteria manipulate host macrophages at the site of entry to their advantage. 2. The tuberculous granuloma: We have found the granuloma, the hallmark structure of TB long thought to be a critical host protective structure, actually promotes bacterial expansion and dissemination. A bacterial virulence factor ESAT6 promotes macrophage migration to the growing granuloma through MMP9 induction neighboring epithelial cells, combined with death of infected macrophages. The arriving macrophages phagocytose dying infected macrophages, thus becoming infected and providing mycobacteria with new replication niches. We will pursue a detailed understanding of each of these steps. - How does ESAT6 induce MMP9 in epithelial cells? - How does MMP9 induce macrophage chemotaxis? - How do arriving macrophages find, and phagocytose dying macrophages? We will take biochemical, pharmacological and in vivo approaches to fully dissect these pathways. 3. Zebrafish mutant screen: Our pilot zebrafish mutant screen identified the leukotriene B4 synthesis pathway to play a complex role in human TB through modulation of inflammation. This understanding has led to new therapeutic possibilities. We will join an ong oing comprehensive zebrafish mutant phenotype screen at the Sanger Centre to gather a comprehensive zebrafish mutant library with altered susceptibility to M. marinum. We will understand the mechanisms of their altered susceptibility.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Epidemiology and ecology of Neisseria species in the African meningitis belt before and after vaccine implementation.
Funder: Wellcome Trust

Abstract: The bacteria Neisseria meningitidis is the major cause of meningitis in a Sub-Saharan region of Africa called the Meningitis Belt. This bacterium can be isolated from the throat of healthy individuals, a phenomenon called carriage. It is believed that in order to understand the disease it is important to study the carriage of N. meningitidis. In 2010 a new conjugate vaccine (PsA-TT, MenAfriVac ) was introduced in the belt. This vaccine aimed to reduce carriage of the major cause of the disease, serogroup A N. meningitidis. The African Meningococcal Consortium (MenAfriCar) was initiated to evaluate the impact of this vaccine. They undertook three carriage surveys between 2010 and 2012 in seven countries of the Belt before and after the vaccination and collected all suspected Neisseria bacteria characterized by microbiological techniques and sequencing. The goal of this study is to further characterize the carried bacteria, using advanced molecular techniques (MLST, whole genome sequenc ing) in order to determine the changes in the bacterial population before and after the vaccination. Secondly to compare the genome sequences of carried isolates to the ones isolated from hospitalized meningitis patients to identify differences in genes or alleles of genes that could explain the difference in phenotype.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;3.4 VACCINES
Health categories: INFECTION
Title: Towards a better understanding of pulmonary tuberculosis outcomes in Sao PauloState, Brazil: a feasible and practical clinical prediction model.
Funder: Wellcome Trust

Abstract: Tuberculosis is one of the most common infections spreading around the world and mostly observed in the lungs. One of the main problems with this disease is that the treatment is long and it demands daily care from the patients. Because of these aspects, many patients give up on the treatment and this causes the relapse of the disease, and could develop a resistance to the drugs and its spreading. One of the ways to approach this problem is called the DOTS strategy, which means that a patient wo uld have a personal sponsor to follow through with this treatment. In order to do this, the patients who are under high-risk of giving up on the treatment should be identified and assigned to their sponsor. The data from the official tuberculosis program in Sao Paulo, Brazil will be used together with social and economic-related indexes. Through the use of this data and statistics it will be possible to classify patients at the beginning of their treatment, and offer the most appropriate strate gy in each case. This study does not bring any risk to the patients, being that previous collected data will be analyzed, and confidentiality will be guaranteed.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING
Health categories: INFECTION
Title: Role of arginase activity in the increased rate of relapse and treatment failure of patients with visceral leishmaniasis and HIV con-infection
Funder: Wellcome Trust

Abstract: Visceral leishmaniasis (VL) in Ethiopia is caused by the parasite Leishmania (L.) donovani. This disease has one of the highest mortality rates: if left untreated, it is almost always fatal. VL belongs to the most neglected tropical diseases, affecting the poorest populations. VL is worsened when the patients are co-infected with HIV. We have recently shown that patients with VL and HIV co-infection (VL/HIV patients) have increased levels of an enzyme, arginase, in their blood. This enzyme has b een shown to prevent cells of the immune system to mount an efficient response. In this study, I propose to determine whether high arginase might contribute to the poor prognosis associated to VL/HIV patients. To test this, we will recruit VL/HIV patients from Gondar hospital. I will measure the activity of arginase and measure how immune cells can become activated before and after treatment against leishmaniasis. In addition, I will evaluate whether the levels of arginase activity can help to predict whether a patient will relapse after treatment. The results from this study will improve our understanding of the role of arginase in VL/HIV patients and might help to design new treatments to control these co-infections.


Research activity codes: 5.1 PHARMACEUTICALS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION