NIHRDataInsights/HRCSData huggingface dataset:
Title: Next generation tests for the detection of latent tuberculosis infection
Funder: Department of Health (England)

Abstract: The WHO estimates that a third of the world’s population is infected with tuberculosis (TB), but have no detectable signs or symptoms of this infection (latent TB). Latent TB may progress to active disease. The future of effective TB control will rely upon techniques that can successfully prevent active disease, either identifying latent cases that will progress or by vaccination. The predictive capacity of new blood tests for latent TB, Interferon Gamma Release Assays (IGRAs), to correctly identify individuals who will progress, may provide an essential tool in public health efforts. However, the most optimistic estimate of the positive predictive value (PPV) for IGRAs is about 12%, indicating that the vast majority of those testing IGRA positive will not go on to develop active disease. If progression could be more accurately predicted, the future of TB control will be revolutionised. New markers of the transition from latent to active tuberculosis are a pre-requisite for the future of TB control. This project aims to evaluate novel TB markers to improve the accurate identification of individuals who will progress to active TB.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Enabling Research Award: An evaluation of a multifaceted intervention to reduce antimicrobial prescribing in care home residents: a cluster randomised controlled trial (REducing Antimicrobials in Care Homes (REACH) ]- an exploratory and scoping study (Response to Antimicrobial Resistance Themed call; Health Services and Delivery Research funding stream)
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: Although the poster included no details on the higher numbers of deaths in the monotherapy arm (n=6 vs 1), these were apparently largely related to cancers and not attributed to treatment strategy. Finally, although the results reported overall mean (SE) drug costs of £21,260 (700) vs £30, 230 (860), with the PI/r monotherapy treatment saving £8,970 (-6,790 to -11,160) per person over five years, this did not take account of additional monitoring and costs associated with changing treatment in those patients with viral rebound.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: INFECTION
Title: Characterisation of immune mechanisms underlying the natural history of tuberculosis infection.
Funder: Wellcome Trust

Abstract: Tuberculosis (TB) is an enormous and increasing public health burden. Basic and translational research have potential to help control this epidemic, particularly in two key areas: improved diagnosis and an improved vaccine. Recent genomic advances have identified the RD1 genomic segment which is present in M. tuberculosis but absent from BCG.RD1 gene products thus present the opportunity to develop more specific tests for diagnosing MTB infection. Using a highly sensitive, yet rapid, ex vivo interferon-? (IFN-?) enzyme-linked immunospot (ELISPOT) assay, I enumerated T cells specific for ESAT-6, the first RD1 gene product to be identified, in TB patients, contacts and controls. These proof-of-principle studies have shown that this rapid T cell-based assay detects active and latent MTB infection with high sensitivity and specificity, and has the potential to improve tuberculosis control. I now propose to rigorously validate the assay (and incorporate a second RD1 gene product, CFP10) in the relevant target populations where it could be of major benefit. I will validate its clinical utility for the rapid diagnosis of active TB in a low prevalence population and for the diagnosis of TB meningitis in a high prevalence population. I will also apply this assay to investigate the basic parameters and pathways of MTB transmission and the natural history of TB in distinct epidemiologic settings, including populations with a high prevalence of both TB and HIV. Rational development and clinical evaluation of new TB vaccines requires an understanding of correlates of protective immunity. The host response largely determines the outcome of MTB infection, with long-term immunological control of latent bacilli being the best clinical outcome. My cross-sectional studies of TB patients and contacts suggest that ESAT-6 specific T cells may correlate with clinically-defined protective immunity. I am to follow through this observation with longitudinal studies of T cells specific for ESAT-6 (and other RD1 gene products) in recently exposed healthy contacts, using multiple techniques of ex vivo analysis. I will also study the kinetics of these MTB-specific T cell populations in HIV-positive individuals with latent MTB infection during anti-retroviral therapy, to see if they correlate with immune reconstitution. Simultaneously, I will investigate the effects of these CD4 and CD8 T cells on intracellular MTB in vitro. These studies will shed light on the phenotype, function and antigen-specificity of T cells associated with immunological control of MTB in vivo, and should thus assist the development and evaluation of new TB vaccines.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Molecular cell biology of cell morphogenesis, pathogenicity and evolution in Trypanosomes
Funder: Wellcome Trust

Abstract: This programme will study fundamental aspects of the relationships between gene organization and expression, cell morphogenesis, cytoplasmic inheritance and the pathogenic life style of T. brucei. We will extend our current work on the microtubule cytoskeleton and flagellum of the parasite to include studies of high order nuclear organization in relation to gene expression. We aim to focus our cytoskeleton studies on particular gene families (the new tubulins) and novel structures (the flagellum connector, basal bodies and the Tripartite Attachment Complex) with a view to providing molecular descriptions of their roles in shape, organelle segregation and parasite infectivitiy/transmission. Finally, in the context of both experimental approaches and comparative genomics we will extend our differentiation studies to a more holistic view of the evolutionary patterns linking the differing cell forms of kinetoplastid parasites, cytoskeletal structures, mechanisms of cellular morphogenesis and parasite life styles.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Inhibitory natural killer cell receptors: role and mechanism of action in hepatitis C virus infection.
Funder: Wellcome Trust

Abstract: We have recently shown that specific combinations of inhibitory killer cell immunoglobulin-like receptors (KIR) and their HLA class I ligands determine the outcome of hepatitis C virus (HCV) infection. The goal of this project to is to understand how this protection works at a molecular level. There are three specific aims: To determine the role of KIR in the response of chronically infected individuals to interferon-a based therapies and whether the KIR:MHC class I interaction impacts on HCV diversity To determine how expression of the activating and inhibitory receptors on NK are "balanced"; and how specific KIR alleles affect this balance such that some KIR alleles protect against chronic infection with HCV. To investigate the peptide specificity of KIR as a mechanism that underlies their protective effect in HCV infection. This will test the hypothesis that different KIR have different peptide specificities and that diversity in peptide specificity is one reason why only specific KIR alleles are protective in HCV infection. These studies will give novel insights into NK cell receptor biology and can thus inform potential NK cell based therapies for chronic HCV infection.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Malaria burden and control at national, regional and global scales.
Funder: Wellcome Trust

Abstract: The work in this application will provide the most complete understanding of the spatial distributions of malaria risk at national, continental and global scales since the 1960's. The approach will allow for a transparent, evidence-driven estimation of the public health burden posed by the malaria parasite and its diversity in space and time. The epidemiological platform will provide the means to articulate needs and model the impact of changing demographics, climate, poverty and intervention between 2005 and 2030. Effective control, however, will be predicated on a number of operational constraints which must be defined and understood to ensure that patients and communities most in need have access to interventions that work. How well interventions are delivered at national scales is the subject of a complementary programme of research: providing the link between the theoretical impacts of disease control and the likely operational efficiency of interventions when delivered as part of national policies in Africa.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFECTION
Title: Cellular immune responses in children with Plasmodium falciparum infection.
Funder: Wellcome Trust

Abstract: The diversity of Plasmodium falciparum isolates is an important determinant of the heterogeneity in clinical malaria. Many targets of the humoral immune response are polymorphic or undergo antigenic variation. Clinical immunity may be the result of cumulative acquisition of a diverse antibody repertoire. Antibody responses to a variety of malarial antigens are short-lived and detectable only during asymptomatic infection. However, the cellular mechanisms determining the nature of antibody responses in P. falciparum infection are not understood. One family of variant proteins, the P. falciparum erythrocyte membrane protein-1 (PfEMP-1) mediates adhesion of bloodstage parasites to host cells. Cytoadhesion is associated with (i) pathology, (ii) immune selection, and (iii) immune deviation. I have shown that cytoadhesion of parasites to CD36 modulates dendritic cell function in vitro and systemic cytokine responses in vivo. I now propose to determine the relationship between the phenotype of parasite isolates and the immune responses to PfEMP-1 and how this relationship evolves with exposure. I will define: (i) Whether there are differences in cellular immune responses to PfEMP-1 dependent on the adhesion phenotype of the parasite isolate. (ii) The cellular mechanisms underlying the evolution of unique and cross-reactive antibody responses to PfEMP-1 during the natural history of infection.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Target assessment for drug discovery against the Kinetoplastida
Funder: Wellcome Trust

Abstract: The overall objective is to discover, characterise and validate additional enzymes of trypanothione metabolism and pterin metabolism for the development of better and safer drugs for the treatment of African trypanosomiasis, Leishmaniasis and Chagas' disease. This research will complement the Drug Discovery for Tropical Diseases Initiative by providing input in the form of molecular targets and assays suitable for high-throughput screening as well asevaluating the output of "hits and leads" from the drug discovery initiative to evaluate the specificity and mechanism of action of at the target and cellular level. The specific aims are to:· Define additional roles of trypanothione and pterin metabolism in the African trypanosome· Identify key enzymes that are essential for parasite survival using genetic and chemical approaches· Provide mechanistic, structural and chemical information for selection and prioritization of targets for drug discovery· Evaluate the mechanism and specificity of action of hits / leads arising from the drug discovery initiative at the target and cellular levels· Examine the potential for resistance and the mechanisms of resistance· Determine the binding mode ofinhibitors to targets to aid structure-based drug design.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Characterisation and validation of drug targets in the Kinetoplastida.
Funder: Wellcome Trust

Abstract: African sleeping sickness, leishmaniasis and Chagas disease are uneconomic, neglected diseases infecting millions of people and killing about 140,000 patients every year. All of the drugs used to treat these diseases have dangerous side effects (e.g. melarsoprol kills 1 in 20 patients) and many are ineffective due to the parasites developing resistance to them (e.g. 60% of leishmaniasis patients cannot be cured with Pentostam). For obvious economic reasons pharmaceutical companies are unwilling to fill this unmet medical need. In Dundee, we are addressing this problem by carrying out the early stages of drug discovery in order to complete the risky first step in finding a new drug. Most drugs ("magic bullets") work by binding to receptors or enzymes ("targets") on or in a cell thereby disrupting normal biological functions. Our goal is to discover new targets and prove that they have the necessary attributes for drug discovery. We also assess whether novel compounds coming out of the discovery "pipeline" work as they are supposed to and provide the necessary biochemical and structural information to guide the subsequent rounds of chemical design and synthesis.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Carbohydrate export in bacteria.
Funder: Wellcome Trust

Abstract: Pathogens such as E. coli wrap themselves in a sugar coat known as the capsule. This coat acts as a disguise allowing the bugs to hide from the human immune system. The coat also protects them from our immune system. Without the coat, the bacteria are killed immediately by us. The process by which this coat is made and put on the surface of bacteria is poorly understood. In the same way that oil and water do not mix, the carbohydrate (polar like water) has to pass through the membrane (apoloar l ike oil), this is very difficult process. A better understanding of this process may help in the development of new treatments. The system we wish to study is a complex molecular machine with many components. We would like to be able to describe this machine in functional terms and relate this to its structure. The project is ambitious as it involves working on membrane proteins which are difficult to make and work with. We have made some good progress so far which we wish to build on. We will u se a variety of techniques to study this system including protein crystallography, biochemistry, molecular biology and electron microscopy.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Development of a recombinant Opa protein vaccine to prevent meningococcal disease:progression from pre-clinical studies to phase 1 clinical trials in humans.
Funder: Wellcome Trust

Abstract: In the UK, Neisseria meningitidis expressing the serogroup B capsule (MenB), causes 1500-2500 cases of invasive infection each year and is the leading infectious cause of death in childhood. Conjugate vaccines derived from meningococcal ACY and W135 capsular polysaccharide are highly effective from early infancy. Unfortunately, the serogroup B capsule is poorly immunogenic in humans due to its similarity with human antigens. Vaccine development has therefore focussed on subcapsular surface antigens, but has been hampered by their variability. We have found that expression of a group of meningococcal surface adhesins, the Opa proteins, is highly structured however, such that a limited repertoire of these proteins are associated with each of the hyper-invasive genotypes of meningococci. This provides the potential for prevention of MenB disease with a multivalent Opa vaccine. We have produced a set of recombinant proteins from hyper-invasive lineages and found that they are highly immunogenic in vivo, providing proof in principle for this approach. We now need to finalise a formulation for human testing based on Opa from ST-11 complex meningococci, manufacture to GMP and undertake a phase I study to evaluate safety and immunogenicity of an Opa vaccine in man.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Antigenic variation in malaria: A genome-wide approach.
Funder: Wellcome Trust

Abstract: Most deaths caused by malaria are due to a single parasite species, Plasmodium falciparum. The particular virulence of this parasite is due to the way in which it modifies the surface of the infected red blood cells by the insertion of parasite proteins. These proteins cause the infected cells to adhere to a number of host cell types leading to some features of severe disease. They are also targets of the host immune response but since the parasite is able rapidly to change the surface proteins expressed, it is able continuously to evade this response. The parasite proteins at the infected red cell surface are thus central to disease severity and to the development of natural immunity. In this proposal we seek to explore two fundamental features of these proteins. First we will study the mechanisms underlying the way the expressed proteins are changed over time. Second we will attempt to identify common features among different members of this protein family that are reported to be pre sent in parasites causing severe disease. This work will rely on some of our important novel data collected under Trust funding and may lead to new approaches to the control of malaria.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Impact of HLA class I alleles on immune control of adult and paediatric HIV infection.
Funder: Wellcome Trust

Abstract: The overarching aim of the work undertaken in the applicant's research group is to better understand what are the CD8+ T cell responses mediating effective control of adult and paediatric HIV infection. In a population-based study in KwaZulu-Natal, South Africa, we showed that only Gag-specific CD8+ T cell responses are associated with low viraemia in chronic infection. Env- or Accessory/Regulatory-specific responses are associated with high viral loads. The first aim of the proposed work is therefore to determine whether Gag-specific responses are inherently more effective than non-Gag-specific responses, or whether these discordant associations with viral load are merely the consequence of chronic infection. The second aim is to determine whether HIV adaptation at an individual level is reflected by adaptation at a population level to these effective CD8+ T cell responses in Gag. The third aim is to extend studies initiated to examine whether CD8+ T cell response play an important role in control of paediatric HIV infection. Our preliminary data suggest that they do, both via the specificity of the responses generated in infancy by the child, and also via the impact maternal CD8+ T cell responses might have on the replicative capacity of transmitted virus.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Partnerships and sexual behaviour in rural South Africa in the era of HIV and ART.
Funder: Wellcome Trust

Abstract: Diagnosed HIV positive people form an increasingly large sub-population in South Africa, one that will continue to grow with the advent of antiretroviral therapy (ART). ART introduces new influences on relationships, sexuality and sexual behaviour. It is not yet clear to what extent ART will impact sexual behaviour and HIV transmission, thus the pressing need to monitor trends in sexual risk behaviours. Given the recency of public access ART, few studies have examined the impact of treatment on sexual behaviour patterns in African populations. The fellowship aims to investigate the relationships between partnership, cohabitation, sexual behaviours and HIV risk in South Africa; and to measure the impact of ART on these factors. Historical, political, social, cultural and economic processes in South Africa have resulted in high migration, union instability, extra-marital births, concurrent relationships and HIV prevalence. The aims will be achieved using 10 years of longitudinal population-based dataon sexual behaviour, partnership and HIV, complimented by new data collection in migrant partners and in two ART clinical cohorts. The findings will inform future behavioural intervention development for couples in the era of ART.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: INFECTION
Title: Structure and mechanism of wzy-dependent pathway enzymes involving in biosynthesis of crucial and diverse carbohydrate virulence determinants O-antigen and capsule.
Funder: Wellcome Trust

Abstract: Fighting against bacterial infection is the most important task of modern medicine. Many HIV and cancer patients die from multi-drug resistant bacteria infection rather than from HIV and cancer. The multi-drug resistance bacterial infection becomes a very serious problem and novel reagents are required to cure such infectious diseases. Bacteria use their outermost layers, O-antigen and capsule polysaccharides to protect them in dehydration condition and also use O-antigen and polysaccharides to invade host and avoid host immune system. O-antigen and polysaccharide are essential for bacteria survival. Therefore the structure and mechanism studies i propose are important knowledge required for exploring novel medicine to control the multi-drug resistance bacteria.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Pneumococcal evolution by genetic recombination.
Funder: Wellcome Trust

Abstract: The pneumococcus is a bacterium that causes mild diseases like ear infections and life-threatening infections like pneumonia and meningitis, especially in young children. A new vaccine is available and it is being used to protect children in many countries. However, one problem is that the pneumococcus can alter its DNA when it is exposed to the vaccine, and thus can resist the effects of the vaccine. This is called vaccine escape , and is a specific example of evolution taking place in the pneumococcus. It is known how the pneumococcus changes its DNA, but not exactly where the DNA changes or how often the DNA changes. However, new genetics technology has made it possible to look large quantities of DNA in fine detail and I would like to use this technology to find and understand these genetic changes. By characterizing a carefully-selected set of pneumococci, comparisons will be made between pneumococci that were collected several decades ago to pneumococci collected in rec ent years, and this will reveal how the pneumococcus has evolved over time and in response to the vaccine. This will provide more information about pneumococcal evolution, and in particular, how to design better vaccines.


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