NIHRDataInsights/HRCSData huggingface dataset:
Title: Interactions between complement and Neisseria meningitidis
Funder: Medical Research Council

Abstract: Neisseria meningitidis remains a leading cause of bacterial sepsis and meningitis throughout the world. It is estimated that there are approximately 500,000 cases of meningococcal disease p.a., with around 50,000 deaths. The progression of meningococcal disease can be extremely rapid, with death occurring within hours of the onset of the illness in some instances, and a significant number of survivors are left with permanent disabilities including neurological deficits and/or loss of limbs. There remains an urgent need to understand the molecular basis of virulence of this important human pathogen, and to develop vaccines that are effective against a broad range of meningococcal strains. The goal of this application is to define the interaction between N. meningitidis and the complement system. The complement system is the most ancient component of the mammalian immune system and is vital for immunity against the meningococcus. Our initial studies will focus on the interaction between factor H, the main negative regulator of complement activation, and its receptor on the surface of N. meningitidis, factor H binding protein (fHbp), and will provide fundamental insights into the pathogenesis of meningococcal colonisation and disease. As fHbp is a component of meningococcal vaccines in current clinical trials, the knowledge and models generated during the course of this work will be translated into the development and assessment of novel vaccines against meningococcal disease. Furthermore, we will define the interaction between this important human pathogen and other complement factors, as this will provide further insights into mechanisms of immune evasion and might identify further vaccine candidates.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: MRC/UCL Centre for Medical Molecular Virology
Funder: Medical Research Council

Abstract: The proposed new UCL MRC Centre for Medical Molecular Virology builds on past achievements to develop three new programmes of research. These are host immune responses and immunity/immunopathology , viral genome associations with disease, and cellular molecules critical for viral replication. The focus remains on clinically relevant, persistent viral infections. Key to each programme, will be the establishment within the Centre of new technologies, including massively parallel sequencing and high-throughput screening, and sophisticated bioinformatic tools. These will support a systems biology approach to virus-cell and virus-host interactions. Our second objective is to develop our unique ?Bench to Bedside? 4-year PhD Programme. Science graduates will each have a clinical and a basic science supervisor and will develop a translational research project. MRC Centre funding of PhD studentships would allow us to develop virology training within this Programme.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Programming memory T cell homing to target immunization strategies.
Funder: Medical Research Council

Abstract: The design of conventional immunization strategies has mainly focused on improving the magnitude and duration of memory T cell responses. Besides these important parameters, selective localization of primed T cells to sites of antigenic re-challenge is paramount for rapid and protective recall responses. Following priming, T cells acquire the ability to establish molecular interactions mediated by tissue-selective adhesion and chemokine receptors (homing receptors) that direct them to specific organs, thus allowing them to ?remember? the site where pathogen invasion has originally occurred. Thus, imprinting T cells with an ?area code? of the site where pathogen invasion is likely to re-occur will greatly enhance the development of rapid, protective immunity. We have recently designed a novel immunization protocol in which T cell activation in the presence of gut-derived chemotactic factors (CCL25) favors the development of memory T cells that express gut-homing receptors and selectively localize to gut-asssociated lymphoid tissue and gut tissue when adoptively transferred in vivo. We propose to fully investigate this novel protocol of immunization with the aim to achieve topographic immunological memory leading to targeted, faster and more effective recall responses. Besides the potential in the control of gut infections, we provide evidence that tissue-selective immunization can be achieved in a variety of other tissues (including humans), and propose that this protocol can be applied in human organ-specific infectious diseases other than those affecting the gut.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Weatherall Institute of Molecular Medicine - Application for an MRC-Oxford University Translational Medicine Institute
Funder: Medical Research Council

Abstract: Over the past 20 years, scientists at the Weatherall Institute of Molecular Medicine (WIMM) have been at the forefront of research that brings together molecular biology, cell biology and clinical medicine. The Institute has also played a pivotal role in the training of clinical and basic scientists in these fields. To ensure that the WIMM maintains its prominent international research and training reputation, there is a need to expand the infrastructure so that its scientists can effectively incorporate new technological advances into the investigation of human disease. At the same time, strengthening links with the new Oxford Biomedical Research Centre will accelerate translation of WIMM research to clinical trials of new therapies and vaccines. This award supports the scientific base of the Institute and will refurbish the two oldest floors of the WIMM to enable recruitment of six early career scientists as MRC Fellows, to bring new blood into the Institute. At the same time the two existing MRC Units will align themselves more closely with the University of Oxford and the Biomedical Research Centre, with the aim of developing joint research programmes. The WIMM. will become an MRC-University Institute with expertise in translational medicine, giving the MRC a strong presence in Oxford in this field and giving the UK new opportunities for moving basic research to the clinic in order to help patients.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);3.4 VACCINES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Molecular mechanisms of innate immune signal tranduction by the Toll-like receptor 4
Funder: Medical Research Council

Abstract: The discovery of pattern recogniion receptors (PRRs) is one of the most important advances in immunology of the last 20 years. One class of PRRs, the Toll-like receptors (TLRs) are now understood to play critical roles in the initiation of inflammatory responses to infection by viruses, bacteria and other microbial pathogens. TLR4, the receptor for Gram- lipopolysaccharides, is of of particular importance in this regard and recent studies have also implicated it as a key mediator of the sterile and allergic inflammatory responses charcteristic of chronic diseases such as rheumatoid arthritis and asthma. This Programme Grant has three objectives all of which aim to understand the molecular mechanisms of signal transduction by TLR4 and to use this information to develop novel therapies for sepsis, allergic asthma and sterile inflammation. Firstly we will use structural biology and the emerging technique of single molecule imaging to study the signal transduction process in living cells. This approach will allow us to visualise the formation of transient signalling complexes in real time and define the molecular basis of signalling specificity, the stoichiometry of the constituent subunits and the cooperativity of the signalling process. In the second part of the programme we will use biophysical, biochemical and cell based techniques to determine the mode of action of lipid bearing aeroallergens and the endogenous ligands fibronectin and tenascin C all of which activate or enhance signalling by TLR4. Finally, in collaboration with Pfizer Inc we will determine how at the structural level antagonistic antibodies directed against TLR4 are able to inhibit signalling and use structure based design to develop novel inhibitors of TLR4 for use in the treatment of endotoxic shock and other inflammatory diseases mediated by TLR4.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Duodenal ulcer promoting gene (dupA): skewing the immune response to Helicobacter pylori and hence disease pathogenesis
Funder: Medical Research Council

Abstract: Helicobacter pylori (Hp) colonises the stomachs of half the world‘s population and is the main cause of peptic ulcers and gastric carcinoma. Little is known of disease-specific bacterial factors that promote duodenal ulceration (DU). T-helper 1 (Th1) response in gastric mucosa is important in pathogenesis. Duodenal ulcer promoting gene (dupA) is a novel Hp gene recently linked to the specific clinical outcome of DU and negatively associated with gastric carcinoma. dupA+ strains are associated with more intense antral neutrophil infiltration and higher antral IL-8 levels in vivo, giving biological plausibility to a role in DU pathogenesis. We have shown polymorphism at the dupA locus and that dupA is associated with an undescribed type IV secretion system, tentatively designated tfs4. Our preliminary data using dupA disruption to explore phenotypes suggests that this virulence mechanism targets immune cells, in contrast to other Hp virulence factors which target epithelial cells. We found significantly higher Th1 cytokine levels, particularly IL-12, in mononuclear cell supernatants following culture with dupA+ strains than following culture with their dupA null mutants and dupA- strains. Disruption of other putative tfs4 components also significantly decreased IL-12 production. Flow cytometry suggested monocytes are an important source of this IL-12 in ex vivo specimens. This study will investigate the immune response to dupA+ Hp strains in the human stomach and its role in pathogenesis. Objectives 1. To characterise the cytokine response to dupA+ Hp strains in the human stomach, hypothesising that they are associated with a Th1 cytokine response with antral predominant inflammation in keeping with the pathophysiology of DU 2. To investigate the relationship between tfs4 genes, dupA type and cytokine response 3. To establish how the tfs4 / dup virulence system effects an immune response Design/Methodology Cytokine levels in antral and corpus gastric biopsies from Hp+ and Hp- donors attending for upper GI endoscopy will be characterised using real-time qPCR, along with dupA status, tfs4 profile, bacterial load and histological data. These samples and a human mononuclear cell model will be used to characterise the effect of dupA/tfs4 profile on cytokine induction, and our hypotheses tested using isogenic Hp mutants. To clarify possible mechanisms we will use flow cytometry, leukocyte cell lines and transcription factor/signalling assays. Scientific/Medical opportunities This will provide insights into the role of a novel Hp virulence system in orchestrating inflammatory signalling in the stomach and help determine why some patients develop DU rather than gastric carcinoma.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Peptide antagonism and NK cell activation: mechanism and relevance
Funder: Medical Research Council

Abstract: Natural killer cells are key components of the immune response to viruses and tumours. Their functions are controlled by activating and inhibitory receptors including the killer cell immunoglobulin-like receptors (KIR). Traditionally it has been considered that down-regulation of the MHC class I ligands of the KIR was a major mechanism for NK cell recognition of infected and cancerous cells. However we have recently demonstrated that natural killer cells are exquisitely sensitive to changes in the peptide content of MHC class I. This follows from our original observation that specific MHC class I bound peptides can antagonize KIR-mediated NK cell inhibition. The aims of this project are to understand the mechanism of this inhibition and to determine its relevance for viral infection. We will use the TAP deficient T2 and the NKL cell lines to dissect out the mechanism by which peptide antagonism of NK cell inhibition occurs. This will be performed by confocal microscopy to assess NK synapse formation; standard biochemical techniques to assess NK cell signalling; and single chain MHC class I-B2m-peptide trimers to assess how much change in peptide is required to antagonize NK cell inhibition. We will then use influenza and hepatitis C to assess how the peptide repertoire changes following viral infection. This will be performed in two stages. The first is to define the time-frame in which peptide repertoires change and hence define the earliest time point at which this mechanism could be relevant. The underlying hypothesis for this is that the peptide repertoire is made up of defective ribosomal products (DRiPs) which can change within two hours of viral infection and this could be highly relevant to NK cell activation. Peptides will be eluted from MHC class I and the peptide repertoires analysed by HPLC. The second stage will be to sequence peptide repertoires from infected and uninfected cells. This will be performed by stable isotope labelling of the infected cells and sequencing the peptides by mass spectroscopy. We will then synthesize key peptides for use in assays of NK cell function to determine the relevance of any changes in peptide sequence that we observe. These experiments will define the mechanism underlying the loss of NK cell inhibition in the presence of a normal levels of cell-surface MHC class I expression. The project is therefore important in defining the immune response to viral infections and tumours that do not down-regulate MHC class I.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: The role of Th17 immunity in pneumococcal disease
Funder: Medical Research Council

Abstract: Background: Pneumococcal disease is a major human health problem. Current vaccines induce humoral immunity to capsular polysaccharide. However, protection is limited by the diversity of cap-sular serotypes. Recent evidence implicates the Th17 group of T lymphocytes in cell mediated, serotype-independent pneumococcal immunity. Aim: To investigate the role of Th17 in pneumococcal immunity. Objectives: 1. To characterise human Th17 and other T helper cell responses following infection with S. pneumoniae 2. To determine the role of pneumolysin (PLY) and IL-1? production in a) induc-tion of a Th17 response to pneumococci and b) recall responses in recolonised individuals 3. To determine the role of IL-22 in defence against pneumococci 4. To determine the optimal route and adjuvant to generate Th17 responses in the nasal mucosa following immunization with candidate pneumococcal vaccine targets. Methods: 1. Blood samples will be collected from healthy volunteers of various ages, adult patients with positive blood cultures for S. pneumoniae and adult patients with positive blood cultures for Es-cherichia coli. Antigen presenting cells (APCs) will be infected with S. pneumoniae or exposed to various vaccine candidate proteins and the stimulated APCs will be co-cultured with memory CD4+ lymphocytes. Th17 development will be assayed by measuring the production of IL-17 and IL-22 by ELISA in supernatants and by intracellular staining for IL-17, IL-22 and Interferon- along with sur-face CD4 and analysis by flow cytometry. Results in healthy volunteers will be correlated with colonisation status. 2. The role of pneumolysin in inducing IL-1 secretion and inflammasome activa-tion will be investigated using cultured dendritic cells and macrophages and a murine colonisation model. NLRP3 knockout mice will be used to clarify the role of inflammasome activation in inducing a Th17 response. 3. Mice with inactivation of the IL-22 gene will be used in standard models of colonisation and infection with S. pneumoniae to determine the role of IL-22 in host defence against pneumococci. 4. Animals will be immunised with via intranasal, intradermal and intramuscular routes and the Th17 responses in nasal and splenic lymphoid tissue compared with that induced by nasopharyngeal colonisation with live S. pneumoniae. Anticipated outcomes: This study will determine the role of Th17 cells and their associated cyto-kines in mucosal and systemic immune responses to S. pneumoniae. This will be important not only in improving understanding of how Th17 responses develop through infection but also for the future use of pneumococcal proteins in human vaccination.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: A genome-wide approach to understand the interplay between bacterial virulence genes and host immune responses
Funder: Medical Research Council

Abstract: The main aim of the research is to understand which genes in Salmonella enterica are required for fitness and virulence in models of immunodeficiencies known to pre-dispose to salmonellosis in humans. We will use a cost effective, global approach to screen libraries of Tn5 and Mu transposon mutants of S. enterica for their ability to infect gene-targeted immunodeficient mice and grow in their tissues (gp91-/-, IFN-gamma-/- and T-cell deficient mice). These bacterial mutants will be analysed using Transposon Directed Insertion-site Sequencing (TraDIS), which uses Illumina deep-sequencing to assess the genotypes and relative fitnesses of individuals within complex pools of bacterial transposon mutants. The work will give a quantitative measure of the extent to which individual mutants in the pools are negatively or positively selected during infection, with those mutants that are lost during infection being indicators of the genes required to colonise the particular mouse knock-out strain being used as host. The work will allow us to identify candidates for development into live attenuated vaccines that would be safer to use in situations and or/geographical areas where these immunodeficiences might be prevalent and in many cases latent or undiagnosed.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Study of the role of polymorphisms within KIR and HLA-C in the immune control of Cytomegalovirus infection
Funder: Medical Research Council

Abstract: KIR and HLA interactions mediate important inhibitory and activatory signals to cytotoxic cells within the immune system. Interestingly, the KIR and HLA-C genes are amongst the most polymorphic within the human genome and this has been correlated with the clinical outcome of a wide range of human diseases. However, the mechanisms that have driven this diversity, and its functional significance, remain unclear. Cytomegalovirus (CMV) is a common chronic infection and considerable evidence suggests that KIR & HLA-C polymorphism may influence immune control. In particular infection is less common in HLA-C2 patients in some ethnic groups; CMV reactivation in transplant patients is related to KIR and HLA-C genotype, and mouse CMV proteins have been shown to interact directly with NK immune receptors. The aims of the study are to:- - determine if HLA-C or KIR genotype plays a role in protection against primary CMV infection. - understand how HLA-C and KIR genotype modulates the quality of the immune response to CMV in chronically infected individuals. - study the functional implications of such polymorphism on NK and T cell recognition of CMV using both in vitro and in vivo analysis. The objective is to use the analysis to increase understanding of the biology of the human KIR-HLA-C interaction for future translational application. The design of the study will comprise an epidemiological analysis of KIR and HLA-C genotype in relation to CMV infection status and assessment of how genotype can influence the magnitude and phenotype of the CMV-specific immune response in chronic infection. Finally, we will determine how the function of CMV-specific effector cells is modulated by KIR-HLA interactions both using established in vitro analyses on infected cells as well as in vivo analysis of the immune response in stem cell transplant patients undergoing episodes of CMV reactivation. Methodology will comprise detailed assessment of the magnitude, function and phenotype of the cellular and humoral CMV-specific immune response, genotypic assessment of the KIR and HLA genes and statistical analysis of data sets. The scientific opportunities include assessment of the mechanisms by which KIR and HLA-C interactions contribute to the control of one of the most common and immunodominant human infections. Medical opportunities will arise from an understanding of how KIR interactions can serve to regulate human immune responses and how this may be manipulated in infectious, auto-immune and malignant disease.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION