NIHRDataInsights/HRCSData huggingface dataset:
Title: A study of the pathogenicity of ocular strains of Chlamydia trachomatis using molecular and spatial determinants of trachoma on the Bijagos Archipelago of Guinea Bissau, West Africa.
Funder: Wellcome Trust

Abstract: Chlamydia trachomatis is the leading infectious cause of preventable blindness and the most common sexually transmitted bacterium. There is a paucity of basic research into chlamydial pathogenicity due to technical challenges presented by their obligate intracellular development. Trachoma presents a unique environment to investigate chlamydial pathogenicity, the conjunctivae serving as an accessible model with an objectively observable phenotype. There is a significant burden of both active and scarring trachoma on the Bijagos Archipelago of Guinea Bissau, with some of the highest disease rates in the world. The reasons why disease is so prevalent and severe on these islands are unclear and may be related to pathogen diversity and virulence. This study will investigate the pathogenicity of C trachomatis using whole genome sequencing techniques to characterise strains circulating on the archipelago. Prospective cross sectional and longitudinal population based survey methodology will be employed to map this information in the context of geospatial, risk factor and clinical data (including disease phenotype and bacterial load). This information will enhance knowledge of the pathogenicity and virulence of C trachomatis and of pan-chlamydial genomic diversity, pathogenesis and transmission of this infection. Disease risk maps will be constructed for use in programmatic activities.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFECTION
Title: Tipping the balance: pathogen manipulation of microRNA regulatory pathways.
Funder: Wellcome Trust

Abstract: Proper cellular function requires that gene expression is tightly controlled. One of these control mechanisms is a class of noncoding RNA, miRNAs, which regulate the precise amount of proteins made in a cell at a given time. During viral infection, miRNAs mediate changes in protein production that are required to control the virus. I have found that a virus can counter this effect by targeting a cellular miRNA. Here I will characterize how this occurs and examine whether other viruses use si milar mechanisms to control miRNA expression. This will shed light on how viruses manipulate host cells which could lead to better strategies for treating disease. Recent work also suggests that miRNAs are secreted by cells and may serve as a form of cell-to-cell communication. I will examine how miRNAs are stabilized in this form and whether extracellular pathogens use miRNA secretion to manipulate their hosts.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Development of a novel vaccine against Plasmodium vivax malaria using adenovirus of chimpanzee origin and Modified Vaccinia Ankara (MVA) as recombinant vaccines.
Funder: Wellcome Trust

Abstract: Plasmodium vivax is the most widespread malaria parasite globally and it is considered to threaten nearly 40% of the human population and current estimates indicate a burden between 132 and 391 million cases per year of malaria caused by P. vivax which results in an overall cost of around US$ 1.2-4.0 billion per year. Despite the substantial disease burden there has been remarkably little vaccine development specifically for vivax malaria. The lack of substantial research and development of a va ccine approach for P. vivax malaria will make this disease very difficult to eradicate. Vaccines using genetically engineered viruses expressing antigens P. falciparum malaria have shown an extraordinary capacity to stimulate protective immune responses. Unfortunately, those responses do not protect against P. vivax malaria, as the two parasites are different. My goal is to develop a vaccine that specifically targets the P. vivax parasite to stop its development in the liver. This parasite, howe ver, presents a special challenge consisting on the establishment of dormant forms that can reactivate months after the first infection to cause a relapse. I will assess if this vaccine approach is able to target this dormant forms called hypnozoites.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Improving the management of severe dengue in adults: predicting patients at risk of disease progression and assessing the efficacy of prophylactic platelets for the prevention of haemorrhage.
Funder: Wellcome Trust

Abstract: Dengue is a viral infection transmitted by mosquitoes and is a growing global health problem. Clinical dengue ranges from mild illness through to life-threatening severe disease. Severe dengue affects ~500,000 people annually. It is so common in endemic areas that it can overwhelm health facilities - being able to recognise patients at risk of severe disease would aid clinicians and have a positive impact on health systems. Dengue is a model for the challenges faced by health systems trying to respond to rapidly evolving surges in patient demand. There are lessons that can be learned from dengue that may be applicable to other emerging diseases. I will conduct a prospective cohort study to assess whether changes in basic laboratory assays are associated with progression to severe disease. Despite limited evidence, platelets are commonly administered in the course of illness to prevent the development of bleeding. I will conduct a randomised controlled trial assessing whether platelet therapy is effective in preventing bleeding in dengue. In addition I will assess whether genetic variation in the MICB gene is associated with severe disease in adults and aim to further characterise the role of MICB and natural killer cells in dengue pathogenesis.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Epidemiology and natural history of human papillomavirus in a cohort of Tanzanian girls after sexual debut
Funder: Wellcome Trust

Abstract: An analytical cohort study is proposed to characterise genital human papillomavirus (HPV) acquisition in adolescent girls after sexual debut. Information of this kind is lacking in sub-Saharan Africa where the majority of the burden of HPV related diseases lies. Specifically this study will describe type specific incidence of HPV and sexual behavioural and demographic factors associated with this. Evaluation of risk factors associated with HPV persistence, clearance and re-infection will be undertaken. 325 participants will be recruited from the control arm of a school-based vaccination trial and will be followed up 3 monthly for a total of 18 months and asked to provide self-administered swabs. These will be tested for 13 high-risk and 24 low-risk genotypes. The study will be based in Tanzania, a country with an extremely high burden of cervical cancer and mortality and will provide data for modelling HPV infection and informing vaccination and screening programmes.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFECTION
Title: Understanding TB Control: technologies, ethics and programmes.
Funder: Wellcome Trust

Abstract: This research will explore issues around the implementation of the WHO STOP TB Strategy. Countries have been broadening the arenas of TB control activities to include: TB / HIV, drug-resistant forms and issues of marginalised populations; health system strengthening; empowering people and communities; and developing operational research. Four aspects of this will be researched: 1. In what ways have the Global Fund stimulated civil society and the private sector involvement? How has this cha nged the approach to TB control? Nepal's situation will be compared with that of Papua New Guinea. 2. What public health and ethical issues are revealed in the production and implementation of guidelines for drug resistant tuberculosis? How are these issues resolved in country? The legal and ethical implications of incarceration of patients with XDRTB in South Africa, Nepal and India will be compared. 3. Drug resistant forms of tuberculosis raise complex issues for diagnosis. New techno logies have been developed (for example Gene Xpert) and are being adopted by countries around the world. What are the implications of introducing and scaling up these new technologies both in terms of tuberculosis outcomes, but also for broader laboratory and health systems performance? This will be conducted in India and Nepal. 4. Patient and community empowerment strategies will also be explored. Working with co-infected HIV / TB groups in Nepal, research will be developed together to lo ok at issues of stigma and marginalisation, and how this can be addressed. A key goal will be feedback for WHO and country policies.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: INFECTION
Title: Using the Controlled Human Malaria Infection Model to Assess Functional Laboratory Assays of Immunity to Malaria.
Funder: Wellcome Trust

Abstract: Malaria is one of the most important causes of death and disease in the developing world. Over time and repeated exposure to malaria, individuals can develop natural immunity to malaria which protects adults, but not children against severe disease. The mechanism of this protection is not currently understood. Controlled human malaria infection (CHMI) studies where healthy volunteers are infected with malaria are a key tool in assessing how effective new drugs and vaccines are at treating an d preventing malaria. To date, these studies have only been performed in volunteers who have never had malaria and have never been used to understand the mechanisms of natural immunity. In this project I propose to conduct a CHMI study in healthy African volunteers who have varying immunity to malaria. I will closely analyse their immune responses following infection in order to better understand the mechanisms of natural immunity and validate laboratory tests of natural immunity. This info rmation will be extremely important for the field of malaria vaccine research, helping to inform vaccine design and improve vaccine effectiveness.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: The cost-effectiveness of home-based HIV testing and counselling.
Funder: Wellcome Trust

Abstract: Countries in Africa are struggling financially to provide much needed care to the millions infected with HIV and the problem is expected to get worse with millions more becoming infected. However, there are hopes that through improving peoples awareness to their HIV status, those infected could get access to life-saving treatment earlier so that they will live longer and have better health-related quality of life, and the costs of providing services may be reduced. A study has begun in Blan tyre, Malawi where individuals are offered HIV testing in the privacy of their own homes. I will complement this study by comparing the health-related quality of life and costs to individuals who use the new service with those who go for testing at their local clinic. I will follow-up those who test HIV positive in both groups to see how their health-related quality of life changes and how much is spent in providing their care. I will combine this information with data from the parent study, the community and from past research to build an economic model that can help policy makers decide whether this service is cost-effective and whether it will make providing HIV care more affordable in the long-term.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: INFECTION
Title: Investigating the epidemiology of tuberculosis and the cost effectiveness of novel diagnostic screening pathways in migrants to the UK.
Funder: Wellcome Trust

Abstract: Tuberculosis is an infectious disease that has a wide range of complications and symptoms The number of cases detected each year in the UK is increasing despite our best efforts to control it. Tuberculosis is therefore a significant public health problem requiring further research to establish the best ways to tackle it. In 2009 73% of cases were in individuals born outside the UK, a figure that continues to rise despite a screening programme in new migrants. This study aims to establish ra tes of disease in migrants on entry to the country; the subsequent levels of newly occurring disease; and the proportion of tuberculosis acquired in the UK or abroad. Using all of these data, the project will create a mathematical model to compare the effectiveness of different screening options, including newly available diagnostic tests, to establish the most cost effective combination of screening investigations. Effective screening in migrants has the potential to reverse the increasing number of tuberculosis cases in individuals not born in the UK and subsequently in the general population. This will benefit wider society and migrants, who represent a particularly vulnerable group with a high burden of disease.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;4.4 POPULATION SCREENING
Health categories: INFECTION
Title: Unravelling the networks that determine and control norovirus infection and pathogenesis.
Funder: Wellcome Trust

Abstract: Noroviruses are the major cause of outbreaks of gastroenteritis worldwide and are one of the most prevalent and economically important pathogens current circulating. Despite this, noroviruses represent some of the most poorly studied of all pathogens and no vaccines or antivirals are currently licensed. There are two aims to this project: 1) Noroviruses isolates known as GII.4 have caused at least 5 pandemics over the past 15 years. We aim to try to understand why these isolates appear to be better at infecting people and spreading in the population. This information will be important for the development of possible norovirus vaccines. 2) We also aim to determine how norovirus infection affects a cell. This will enable us to identify cellular proteins important for virus replication and drugs that prevent or control virus infection. At the end of this project will have identified drug candidates for further development as anti-norovirus therapies, identified methods of making mutated noroviruses as possible approaches to vaccination and gained insights into why viruses use error prone enzymes to replicate their genome.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Modulating cytokine expression by T cells to protect the mucosa from chronic viral infections.
Funder: Wellcome Trust

Abstract: Mucosal surfaces including the mouth and lung have constant contact with micro-organisms from the outside world. Our bodys defence, or immune system, employs specialised mechanisms to protect these sites. However, it also stops itself from over-reacting to harmless materials such as food and dust. Viruses exploit these suppressive mechanisms to enable their persistence and spread. Using the mouse cytomegalovirus (MCMV) model of chronic infection, I discovered that a suppressive soluble factor, i nterleukin-10 (IL-10), is produced in mucosal sites by immune cells called T cells during chronic infection. IL-10 inhibited antiviral responses that otherwise stopped MCMV persistence. I will characterise these cells, identifying the mechanisms inducing IL-10 production and discovering factors that promote their development. IL-22, (an IL-10-related soluble factor), attacks bacterial infections of mucosal surfaces and I have discovered that it also protects from MCMV. I will identify how this o ccurs, subsequently uncovering novel mechanisms that protect mucosal surfaces from viruses. Finally, I will identify how to trigger IL-22 production by antiviral T cells. By discovering how to switch off and on IL-10 and IL-22, respectively, these experiments will identify therapeutic strategies to enable optimisation of antiviral T cells by vaccines to protect our mucosal surfaces from chronic viral infections.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Measuring the control and elmination of neglected tropical diseases in Africa.
Funder: Wellcome Trust

Abstract: I have two main goals for the next five years. Firstly, I want to better understand how the spatial risks of two globally important parasitic diseases, intestinal worms and lymphatic filariasis, have changed across Africa in recent years; how much of this change is due to specific interventions; and how risks might change as strategies in control evolve in the future. I will address these questions using a combination of disease mapping, spatial analysis and statistical modelling. Secondly, as p rogress in control is made, I want to identify the best approach to the monitoring and surveillance of infection risks that both takes into account the inherent epidemiology of infection and the resource constraints faced by national control programmes. Answering these questions will give policy makers and donors a better sense of recent achievements in controlling these diseases and the challenges that lie ahead.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFECTION
Title: The molecular and cellular basis for the function of the HIV-1 Vpu protein in the targeting of host antiviral and immuno-modulatory factors.
Funder: Wellcome Trust

Abstract: HIV-1, the causative agents of AIDS, avoids the human immune system in part because they encode small proteins that counteract these responses. A common strategy used by viruses is the removal of proteins required for these immune responses from the surface of the infected cell. The HIV-1 Vpu protein induces the cell-surface removal of a general-purpose antiviral molecule, Tetherin, which blocks the release of new virus particles from infected cells. This attribute seems to be associated with ef ficient spread of HIV-1 between individuals, and potentially important for the ability of the virus to cause disease. We will study the mechanism by which Vpu and other viral proteins counteract Tetherin, particularly how Vpu redirects Tetherins localization in the cell away from newly assembling viral particles, and which cellular proteins Vpu uses to achieve this. We will characterize a novel target of Vpu that we call TOV3, a protein that transports the amino-acid glutamine into the cell. The growth of human T-cells is dependent on TOV3 expression, and we hypothesize that Vpu targeting of TOV3 affects the survival or growth of infected T-cells to facilitate viral replication in vivo. We will also attempt to identify new Vpu targets relevant for HIV/AIDS pathogenesis.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Insecticide Quantification Kits (IQK) for Vector Control Programmes in India.
Funder: Wellcome Trust

Abstract: Visceral leishmaniasis (VL) transmitted by the sandfly Phlebotomus argentipes, and malaria, transmitted by mosquitoes, are widespread in the Indian subcontinent. Bednets and indoor residual spraying with insecticides are the most effective ways to kill the insect vector, but only if done properly - i.e. if enough nets or houses are sprayed with the correct amount of insecticide. It is therefore critical to ensure effective spraying by tight quality control and regular monitoring. However, there are no easy ways to do this other than using sophisticated equipment or complex biological assays. Indeed , high cost and impracticality has prevented the normal quality assurance and response modes expected for public health initiatives to be implemented for large-scale insecticide use. Our aim is to develop, validate and roll-out insecticide quantification kits that are cheap and easy to use for monitoring indoor residual insecticide spraying for control of leishmaniasis, malaria and other insect borne diseases . This will involve assay refinement and verification, kit development and field trials to demonstrate effectiveness, practicality and reliability. The tests will provide easy visual quantification of insecticides to allow disease control operatives to maximise the benefits of vector control and minimise risk to public health and environment.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: INFECTION
Title: Assessment of the HIV-1 viral reservior following chemotherapy in HIV-1 infected patients
Funder: Wellcome Trust

Abstract: An HIV vaccine remains elusive, and there are serious doubts as to whether large scale antiretroviral therapy can be maintained. Curative strategies are therefore now being explored. These approaches require an understanding of theHIV reservoir. I wish to explore the impact of stem cell transplantation and/or cancer chemotherapy, on markers of HIV replication, to understand the site of the reservoir, and the nature of viral re activation in vivo.


Research activity codes: 5.1 PHARMACEUTICALS;5.2 CELLULAR AND GENE THERAPIES
Health categories: INFECTION
Title: Identification and characterisation of novel inhibitors and Hepatitis C virus infection
Funder: Wellcome Trust

Abstract: We are intrigued by the way that relatively small structural changes in the cyclic peptide cyclosporin A (CSA) can effectively suppress its immunostimulation property, while maintaining or enhancing its antiviral potential. The currently high interest in Alisporivir shows the high potentialfor antiviral activity, in this case specifically against hepatitis C virus, in analogues of CSA. Our research question is therefore: how can we further modify the structure of CSA to improve further its potency and/or selectivity of antiviral action, while maintaining suppression of immunostimulation? The second research question is more broad involving the development of novel therapeutics against HCV. The research question here is how we can apply infectious cell-based assay for high-throughput screen to identify novel classes of anti-HCV compounds?


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Molecular mechanisms of membrane trafficking in pathology and infectious disease.
Funder: Wellcome Trust

Abstract: Human cells are subdivided into multiple compartments with distinct chemical environments, thereby allowing distinct (and potentially non-compatible) chemical processes to take place simultaneously. However, this compartmentalisation presents the cell with a logistical dilemma: How can it transport cellular components between compartments? The cell has tackled this problem by evolving a complex system of intracellular trafficking that is tightly regulated to ensure only the right compartments fuse and thereby allow mixing of their contents. I am interested in how this fusion step of intracellular trafficking is regulated, as aberrant regulation of fusion leads to numerous human pathologies. I will purify the proteins that regulate intracellular compartment fusion, map interaction networks between these protein and solve their structures at atomic resolution in order to build up a molecular model of how intracellular compartment fusion is regulated. I am also interested in how huma n pathogens such as viruses subvert the cell's trafficking system to their own ends. I will study how viruses recruit the cellular proteins necessary to re-model intracellular compartments to their own ends, concentrating on how viruses ensure their progeny (daughter viruses) are able to fuse with the surface of, and thereby escape, infected cells.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION