NIHRDataInsights/HRCSData huggingface dataset:
Title: The molecular basis for CD200R and SIRP paired receptor family function
Funder: Medical Research Council

Abstract: Paired receptors are families of membrane proteins with similar extracellular regions but different intracellular sequences so that one member can give inhibitory signals whereas the others can give activating signals. In the two families that we have characterised, CD200R and SIRP, the ligands for the inhibitory receptors are widely distributed membrane proteins, CD200 and CD47 respectively and the activating receptor gives negligible binding to these. These protein families are evolving rapidly and the theory is that pathogens target the inhibitory receptor but activating receptors evolve to act as a counterbalance. They are implicated in regulation of immunity, neuropathology and cancer. The project will focus on the three aspects of the CD200R and SIRP families. 1. Screen these paired receptors for pathogen, and in particular, bacterial binding. The molecular nature of the binding partner on bacteria will be established for a characterised paired receptor (PIRA) and extended to CD200R and SIRPs. Do the polymorphisms in the receptor affect pathogen binding? If pathogens affect myeloid activity in this way, what happens when both activating and inhibitory receptors are targetted? How does this type of interaction modify the response? The uncharacterised genes in the SIRP cluster will be characterised for gene expression and ligand binding to ensure a comprehensive analysis of the family. 2. CD200R signals by a different mechanism from all other leukocyte inhibitory receptors in that it involves binding of DOK adaptors rather than recruiting phosphatases. In other respects CD200R and SIRPs are very similar being present on similar types of cells. We will apply new quantitative mass spectrometry phosphoproteomic analysis to determine the timecourse for phosphorylation of CD200R and down stream proteins. This should reveal proteins involved in the signalling pathway that can be tested by direct binding using recombinant proteins and RNAi in functional experiments. Comparable experiments will be carried out on SIRP alpha signalling to compare the DOK2 mediated signalling with conventional ITIM mediated phosphatase recruitment. 3. Ligands for the SIRP and CD200R receptors have also been acquired by viruses indicating their importance in pathogen host responses. We will further characterise these. Does viral CD47 bind SIRP alpha and if not what does it interact with? Whilst viral CD200 from herpes virus 8 acts as a mimic, the homologues in other viruses do not appear to be typical membrane proteins so are they high affinity soluble ligands or do they act in another way such as association with other host/viral proteins?


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Investigation of the effects of intravenous fluid therapy and Imatinib administration in a human intravenous lipopolysaccharide (LPS) model of sepsis.
Funder: Medical Research Council

Abstract: Aim To investigate the biological effects of intravenous fluid therapy and Imatinib on microcirculatory function and injury and systemic inflammation in a human intravenous lipopolysaccharide (IV LPS) model of sepsis. Objectives 1. To determine the effects of IV fluid administration on (a) microcirculatory function (b) microcirculatory injury and (c) systemic inflammation in healthy human volunteers receiving an IV LPS challenge. 2. To determine the effects of imatinib administration on (a) microcirculatory function (b) microcirculatory injury and (c) systemic inflammation in healthy human volunteers receiving an IV LPS challenge. 3.To elucidate the mechanistic pathways involved in any effect of IV fluids and/or imatinib on (a) microcirculatory function and injury and systemic inflammation. Methodology Healthy human volunteers will receive 2ng/kg IV LPS to induce transient features of systemic inflammation reflecting sepsis. Participants will be randomised to receive IV LPS only, IV LPS and IV fluids, IV LPS and imatinib, or IV LPS and IV fluids and imatinib. Participants assigned to imatinib pre-treatment will receive a dose of 800mg orally 1 hour prior to IV LPS. Participants in the IV fluid therapy groups will receive 30mL/kg of IV fluid 1 hour following IV LPS. Microcirculatory function will be assessed by sublingual imaging with video microscopy. Levels of circulating biomarkers of microcirculatory injury, coagulation and systematic inflammation will be measured. Transcriptomic analysis will provide further data on immune response pathways. Comparison between groups will allow determination of the effects of each intervention. Scientific and Medical Opportunities This model provides a platform to investigate a range of therapies on the human microcirculation in sepsis. As microcirculatory dysfunction is common to many diseases, including diabetes and chronic kidney disease, this study has important implications for other disciplines.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: impact of COVID-19 pandemic on donor journey
Funder: Anthony Nolan

Abstract: impact of cryopreservation on cell grafts during the COVID-19 During the 2020 pandemic and in order to guarantee grafts were delivered to patients, most grafts were collected, cryopreserved and then administered when required. Understanding the impact of the cryopreservation will guide future provision of UD grafts

Lay abstract: AN relationship with its donors is of paramount importance for the future provision of cells both for immediate use for cell transplant as well as for clinical trials and research. Because of this, we have to understand the donor experience, how events in the last year have changed that experience and how we continue to improve it and make provision for future events which may affect it.

Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: The role and control of mast cell responses in intestinal helminth infection
Funder: Wellcome Trust

Abstract: Parasitic worms can infect people for many years, despite the efforts of the immune system to eject them. They achieve this through the release of molecules which suppress parts of the immune response designed to kill them. In this project, we will investigate how a parasite can suppress mast cells - an important component of the anti-parasite immune response. We hypothesise that parasitic worms may produce proteins which prevent mast cell responses - in this project we will identify and characterise these immunosuppressive proteins. We will also investigate how the immune system combats parasite infections through mast cell responses. Many parasitic worms infect by burrowing through our skin, and travelling through the blood to the gut, where they live for the rest of their lives. Recent evidence suggests that damage to the skin can be interpreted by the immune system as a parasitic infection, and leads to the accumulation of mast cells in the gut. We will investigate how this skin-to-gut communication is mediated, and how it can prevent parasite infection. We will also investigate the signals that travel from the skin to the gut, and how these act on mast cells to prepare the gut to eject parasitic worms.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: The mechanisms and dynamics of malaria transmission blocking immunity
Funder: Wellcome Trust

Abstract: Some individuals who are naturally exposed to malaria infection acquire immune responses that stop Plasmodium development in the mosquito gut, whilst others are highly infectious despite relatively low gametocyte densities. I intend to investigate naturally acquired malaria transmission modulating immunity to improve our understanding of malaria transmission and provide insight for malaria vaccinologists. Key goals, methods, and outputs: 1. Identify effectors of Plasmodium transmission modulation Methods: Immune profiling by Protein micro-array and luminex (cross-sectional samples with transmission endpoints) Outputs: A comprehensive list of antibody correlates of transmission-blocking immunity (TBI); a serological platform for assessing sexual-stage antibody titres; a statistical model determining the impact of antibody, parasite and cytokine metrics on the association between gametocyte density and mosquito infection. 2. Characterise the dynamics of sexual-stage immune responses Methods: Luminex (longitudinal cohort samples) Outputs: Estimates of the association between gametocyte density and antibody titre; improved understanding of the dynamics of immune response to gametocytes after natural and controlled malaria exposure. 3. Examine the maintenance and effectiveness of transmission modulating immunity Methods: Lab-based mosquito feeding assays, B-cell assays Outputs: Novel assays for the quantification of sexual-stage immune memory; detailed analyses of the relationship between antibody titre and transmission modulation (transmission enhancement and reduction).

Lay abstract: Humans can develop immunity against malaria parasites that passes into mosquitoes when they feed, and can break the cycle of malaria transmission by stopping mosquitoes from infecting more humans. We understand relatively little about this form of immunity, but it could be shaping the way malaria is transmitted, and importantly, it could be exploited to make vaccines to eliminate the disease. To do this, we must know more about how this immunity is acquired and maintained. During this fellowship, I propose to 1. Identify what human antibodies are linked to natural 'transmission-blocking' immunity, and develop tools to determine how much of an effect these have on malaria transmission. 2. Study this immunity over time, before and after malaria infections. 3. Investigate how humans form immunity that affects transmission, and how effective it is. This research would improve our understanding of malaria transmission, and provide valuable insight for vaccinologists.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Determining fate: Dissecting the dynamics of atypical memory B cell recruitment to protective immune responses in respiratory infection
Funder: Wellcome Trust

Abstract: Memory B cells (MBCs) are central to co-ordinated immune responses required to resolve viral infections and mediate protection following pathogen clearance or vaccination. I propose that a newly described subset of atypical MBCs (defined by expression of CD11c and T-bet) preferentially reside within peripheral tissues, where they can differentiate in-situ to provide rapid and localised protection against pathogenic threats. This project will investigate the mechanistic basis for CD11c+T-bet+MBC differentiation following immunisation, testing the hypothesis that Th1 skewed T follicular helper cells (Tfh) regulate the divergence of CD11c+T-bet+MBCs from classical memory responses and their migration to non-lymphoid tissues. CD11c+T-bet+MBC induction will be characterised alongside subsets of Tfh subsets in vaccinated humans and mice, with fate-mapping systems and interventional mouse models used to dissect: (1) the tissue homing capacity of CD11c+T-bet+MBCs; (2) their contribution to establishing protective immunity; and (3) the involvement of CD4-derived signals to CD11c+T-bet+MBC differentiation. These will be complemented by state-of-the-art imaging technologies to visualise the spatial dynamics of CD11c+T-bet+MBCs and Tfh within germinal centre responses following immunisation. Together, these data will reveal whether Th1 polarised Tfh seed populations of CD11c+T-bet+MBCs in tissues to establish local protection against infection. Findings may facilitate tailored development of strategies to enhance immunity.

Lay abstract: Memory B cells (MBCs) can be found in barrier organs such as the lung, where emerging data suggest they respond rapidly to provide a first line of defence against infection challenge. A unique subset – atypical MBCs – arise following immunisation and infection; however, their fate and contribution to immune protection in vivo remains an open question. I propose that atypical MBCs are preferentially recruited to tissue-localised immune responses to provide enhanced protection against future infections. Using human vaccination studies, interventional mouse models and imaging technologies, I will answer two questions: 1. What is the fate and relevance of atypical MBCs in protective immune responses after vaccination? 2. How is this process regulated by specialised subsets of CD4 T cells? By determining the signals responsible for driving their formation, it may be possible to manipulate this subset of MBCs to improve current vaccination strategies or develop new immunotherapies to treat chronic infections.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Linking human genotype and immunological phenotype to understand pathogenesis and improve treatment in tuberculosis
Funder: Wellcome Trust

Abstract: TB kills more people worldwide than any other infectious disease, yet its pathogenesis is still poorly understood which hinders therapeutic advances. The heterogeneity of immunological responses and clinical presentations make the investigation of the major determinants of outcome challenging. Host genetic variants regulate the immune response during infection, drive immunological pathogenesis of the disease, and can lead to poor outcomes. My aim is to link human genotype and immunological phenotype to better understand TB pathogenesis and thus improve TB treatment. The fellowship has three key goals: 1. Investigate the impact of dexamethasone on transcriptional profiling of the immune response, bacterial clearance and survival/death in TB meningitis 2. Determine whether LTA4H genotype can be used to predict inflammatory transcriptome and to identify additional genes associated with inflammatory transcriptome variation in TB meningitis 3. Link human genotype and transcriptional immune responses associated with treatment failure or relapse in pulmonary TB To pursue these goals, I will use RNA-Seq to provide data on both human variants and whole-genome gene expression. These results will reveal the pathogenesis of different forms of TB, including pulmonary TB, meningeal and multi-drug resistant TB. Pathways associated with inflammasome and neutrophil-driven immunopathogenesis will be a particular focus.

Lay abstract: TB kills more people worldwide than any other infectious disease, but if we are to reduce this burden we need to better understand how the disease develops. TB is a complicated disease with many different clinical forms and variations in human genes affect how the body responds to infection, and how a person responds to treatment. My aim is to better understand the links between human genes and the type and severity of disease and thus how treatment can be improved. We will investigate TB affecting the lung and the brain of Vietnamese adults by analysing the genetic messaging (RNA) expressed by the body to make proteins. This will allow me to compare the body’s response in different forms of TB, particularly the inflammation, and assess how different treatments are working. This fellowship has three key goals: 1. Investigate the impact of the anti-inflammatory drug dexamethasone on TB-associated inflammation, the body’s ability to kill bacteria, and survival/death from brain TB 2. Investigate how a special gene (called ‘LTA4H’) affects inflammation, and identify other genes that alter inflammation and outcome from brain TB 3. Investigate how genes and inflammation are associated with treatment failure or relapse in lung TB

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Unravelling the whipworm niche at the host intestinal epithelia
Funder: Wellcome Trust

Abstract: Whipworms infect hundreds of millions of people causing trichuriasis, a major neglected disease. Whipworms are large metazoan parasites that inhabit a multi-intracellular niche within their host caecal epithelia, where they manipulate mucosal physiology and inflammation through interactions with the intestinal epithelial cells and stem cell niche. These interactions enable chronic infections where whipworms are tolerated for years; but at a mechanistic level, how they operate is not understood. My research aims to define these interactions and bring a mechanistic understanding to how they underpin whipworm invasion, colonisation and persistence in their mucosal niche. This work will build upon a novel model I developed using caecal organoids (termed caecaloids), the first to reproduce whipworm infections in vitro, to address two fundamental aims. First, to determine how whipworms invade and colonise intestinal epithelia using imaging and transcriptomic analyses of infected caecaloids. Second, to define how whipworms impact stem cell niche remodelling to promote their persistence using microscopy, FACS and transcriptomics of infected caecaloids and chronically-infected mice. This research will transform our understanding of the whipworm mucosal niche potentially yielding new targets for anti-parasitic therapies, and provide novel insights into how the intestinal epithelia repairs damage with relevant application toward intestinal inflammatory diseases.

Lay abstract: Whipworms are parasites that live inside the gut lining of 500 million people worldwide causing the disease Trichuriasis. Whipworms remain in their host for years by interacting with the gut lining and surrounding cells to manipulate gut structure and immune responses. How the parasite mediates these interactions is not understood. I aim to determine how whipworms invade, colonise and persist in the gut. Using a new model I developed based on “mini-guts”, the first to mimic whipworm infections in a lab dish, together with microscopy and sequencing, I will characterise: 1) the molecular and cellular changes that happen in the whipworm and the gut lining and surrounding cells when the parasite enters and colonises the gut and; 2) the interactions that allow the parasite to persist and the gut lining to repair during chronic infections. This knowledge will open new avenues to eradicate whipworm infections and control gut inflammatory diseases.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Regulation of antiviral inflammation through reactive oxygen species localisation
Funder: Wellcome Trust

Abstract: A key area of current immunological research are the mechanisms that control and adjust inflammation. In my previous work, I discovered an important role for neutrophil reactive oxygen species (ROS) localisation in tailoring inflammation to microbe size during bacterial and fungal lung infections: ROS suppressed cytokine production and immune cell recruitment in response to small pathogens. I plan to extend this work by studying ROS localisation in response to viral infection and its impact on antiviral inflammation. In preliminary experiments, I observed that ROS are detrimental during influenza infection. Mice lacking ROS-producing NADPH oxidase Nox2 have a reduced viral load early after inoculation, increased numbers of lung-infiltrating immune cells and higher levels of proinflammatory cytokines, while the amount of type I and III interferons is reduced. The localisation of ROS during influenza infection is unknown. Neutrophils, major ROS-producing phagocytes, are recruited in great numbers during influenza infection. By elucidating ROS localisation and studying influenza infection in neutrophil-specific Nox2-deficient mice I will uncover ROS-affected signalling pathways and thus reveal how ROS control antiviral inflammation and virus clearance. Prospectively, these studies will enable the design of immunomodulators that control excessive immune responses and provide new avenues for the treatment of inflammatory diseases.

Lay abstract: Influenza causes 5,000,000 cases of severe illness annually, but we still don’t know to which extent disease is caused by direct viral damage or an excessive immune response. A poorly regulated response will lead to inflammatory tissue damage and pathology. Therefore, regulation of inflammation is vital. Recently, I showed that local production of ‘reactive oxygen species’ (ROS) suppresses excessive inflammation in bacterial and fungal lung infections and that size-sensing is crucial to this response. I now wish to extend my expertise to investigate influenza virus infection and examine the cellular localisation of ROS production during influenza infection. This area is unexplored at present, but could have a profound impact on antiviral inflammation. By studying ROS during viral infection, I will be able to show how ROS control antiviral inflammation and virus clearance. This programme could ultimately lead to new therapeutic approaches targeting novel signalling pathways in patients with severe influenza.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Defining the Protective Immune Response to SARS CoV2 Using a Human Challenge Model
Funder: Wellcome Trust

Abstract: Understanding the nature, effectiveness and durability of the human immune response to SARS CoV2 is crucial for vaccine development and effective public health management. We are beginning to understand the pattern and kinetics of the humoral response to natural infection but are less certain about other aspects of the response. We are unable to establish with certainty whether an individual with a particular titre of antibody, or a particular T cell response, is likely to be protected from reinfection and, if so, for how long. These are central questions for the development of an effective vaccine. A controlled human infection model will provide a more detailed understanding of the protective immune response. It will provide the opportunity to interrogate the full extent of the immune response at the time of exposure and will also allow the evaluation of the durability of immune responses of all kinds and how they correlate with protection.Key goals: 1. To establish an MHRA-approved SARS CoV2 viral stock for use in a controlled human infection model 2. To determine a challenge dose which is safe and allows virus to be recoverable from infected subjects


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