NIHRDataInsights/HRCSData huggingface dataset:
Title: Retroviral immunology
Funder: The Francis Crick Institute

Abstract: Adaptive immunity is the most advanced defence against infection and cancer, but misdirected causes autoimmunity. Our main interest is the first principles of induction and maintenance of adaptive immunity. We focus on CD4 T helper (Th) cells, the central orchestrators of the immune response, which we study in a mouse model for infection with murine leukaemia virus (MLV), a mouse retrovirus. Our understanding of retroviral infection cannot be complete without considering the numerous endogenous retroviruses (ERVs) that have invaded the germline. We are also interested in the impact of ERVs on host physiology and pathology, both in mice and humans. Diversity of the T cell receptors (TCR) repertoire is essential in protection against an unpredictable antigenic universe. We want to know how repertoire diversity is maintained and its relation with self- and foreign-antigen reactivity. We are exploring how the TCR repertoire can be ‘engineered’ or ‘shaped’ to contain the most protective clonotypes against infection or cancer, whilst avoiding autoimmunity. An important property of adaptive immunity is that is has memory, which forms the basis for vaccination. Much of our work focuses on the fundamental mechanisms of immunological memory (e.g. TCR clonotypic evolution) and the practical aspects of vaccine design (e.g. efficacy of different viral vectors). Recent single-cell RNA-seq data indicate a unique ability of human adenovirus-based vaccines to induce Th cells with cytotoxic activity, typically restricted to CD8 T cells. The mammalian host carries a multiplicity of chronic infections and interacts with a considerable number of symbiotic species, including the microbiota, ERVs and other retroelements. ERVs expression is frequently elevated in infection, autoimmunity and cancer. We described the complex interplay between immune stimulation by symbiotic or pathogenic microbes, the genome-wide activity of well-annotated ERVs in the murine host, and immune competence. We are currently probing immune pathways necessary to control or induce ERVs, both in mice and humans. We are extending our studies to the biological activity of ERV proteins, including the primate-specific ERVK Env and Rec. Not only is adaptive immunity to ERVs possible to induce, it also critical to prevent ERV ‘resurrection’. We are exploring how immunological tolerance to ERVs can be broken, to elicit effective anti-ERV immunity. Although autoimmune in nature, we are seeking to utilise anti-ERV responses in the protection against tumours, taking advantage of ERV induction in transformed cells.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;3.4 VACCINES
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: Phase 1 COVID-19 Immunity - National Core Study
Funder: Medical Research Council

Abstract: The magnitude and quality of the immune response remains a central determinant of clinical outcome following SARS-CoV-2 infection and vaccines now provide an approach for pandemic control. The National Core Study - Immunity (NCSi) programme in Phase 0 was designed to co-ordinate and build on UK investment in COVID-19 immunity and initiated a number of investments in 2020/21. These were based on four themes which seek to predict and manage individual risk, protect acute infection and late effects, prevent primary or re-infection and prepare for future pandemic challenges. In Phase 1, these will continue and comprise: PREDICT: 1. Centre for Cytokine Autoantibodies will interrogate serum sample collections, including those from the NCSi/UKB collaboration, to determine the clinical importance of antibodies against a range of cytokines in order to define clinical risk and develop new therapeutic opportunities. 2. DIRECT: Determining the Immune Response in Ethnic minority healthcare workers to COVID-19 infecTion will determine the importance of ethnicity in relation to immune response to natural infection and post-vaccination. 3. EVITE study of shielding efficacy through evaluation of NHS records, questionnaire responses and blood test results at 12 months after shielding and subgroups such as those with cancer, BAME or living in deprived communities. 4. Asymptomatic COVID19 in Education (ACE) Immunity Study will examine SARS-CoV2 across the (young) population to influence student/school movement policies PROTECT: 1. NCSi collaboration with UK Biobank will undertake detailed analysis of Covid-specific immune responses and cellular phenotype in a world-leading unique 3000 participant repeat-imaging study. 2. Understand Immune senescence and its impact on natural immunity and vaccine responses in the CAIRO vaccine cohort and associated studies of vaccine response in secondary immune suppression with chronic lymphocytic leukaemia that is seen in older people. PREVENT: 1. Next Generation Immune Assays will be commissioned to transform the sensitivity, specificity and logistics of serological and cellular assays. 2. Vaccine Responses: The OCTAVE study of immune monitoring after vaccination will be maintained and supported with further investment. Phase 1 investment circa £1.1m, 75% funded by UKRI and 25% funded by the Vaccine Task Force. For more details please see https://www.ukri.org/news/new-study-tests-third-jab-for-people-with-weakened-immune-systems/ 2b. OCTAVE ADOLESCENT. Phase 1 investment funded by UKRI in partnership with the Vaccines Task Force circa £330,000 3. Re-infection, vaccine failure and viral Variants of Concern will comprise a portfolio of studies including an open commissioned call to determine mechanisms of inadequate immune protection in (re-) infection after natural or vaccine-induced immunity.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigation of fever as a protective mechanism in sepsis
Funder: Medical Research Council

Abstract: I aim to explore the nature and role of mechanisms underlying fever in sepsis and its association with improved survival. I will focus on mitochondrial uncoupling and futile calcium cycling via SERCA as these heat-generating processes may increase markedly in sepsis. Diverting oxygen use away from ATP production towards heat, or increasing utilization of ATP for heat production, may induce a cellular metabolic shutdown akin to hibernation/estivation. While affecting cell functionality in the short-term, this may offer protection through reduction of damaging reactive oxygen species generated in excess in sepsis by mitochondria. Alternatively, beiging of white adipose tissue, which occurs after 1-2 weeks in burn patients, may arguably be detrimental to recovery by maintaining a catabolic, cachectic phenotype. I will use well-established long-term rat models of sepsis, isolated cells and tissues, and cell lines, and biopsies of fat and muscle taken from septic patients at different time points to explore this hypothesis. On identification of mechanisms responsible for fever, I aim to modulate them using specific inhibitors or siRNA knockdown, to determine whether such a strategy is protective and/or detrimental in the short or long term. I will also investigate a novel carbon monoxide releasing agent that enhances mitochondrial function but also induces mild uncoupling. I will use 3-day and 14-day rat peritonitis models, employing in vivo echocardiography, metabolic monitoring and thermal imaging and taking blood and tissue samples for identification of uncoupling proteins and sarcolipin-induced SERCA-1 cycling. Ex vivo techniques will include respirometry, dual photon beam confocal microscopy, and immunohistochemistry, and standard methodologies such as Western blot and ELISA. This original study has the potential to identify important mechanisms underlying sepsis (and other critical illnesses) that may be used for novel therapeutic targeting.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: Developing Host-directed therapy in Cryptococcal Meningitis
Funder: Medical Research Council

Abstract: BACKGROUND Cryptococcal meningitis (CM) remains a significant cause of death in AIDS patients in sub-Saharan Africa. Modulating the host immune response is a potential method to improve outcome and trials of adjunctive interferon gamma (IFNg) are promising. However, further study is required to understand which patients are likely to benefit and any unintended consequences. We have previously reported an immune phenotype associated with mortality characterised by monocyte and T cell deactivation, raised neutrophils and IL-10. This study aims to explore this phenotype further to determine whether it can be used to better predict poor outcome and guide anti-fungal and immune modulatory therapy. SPECIFIC AIMS 1. Better understand the immune response in CM, particularly whether monocyte and T cell deactivation is associated with mortality 2. Determine whether immune deactivation can be reversed with immune modulatory agents 2. Establish whether simplified immune assays can be used to predict poor outcome and guide anti-fungal and immune modulatory therapy APPROACH We propose a prospective observational study nested at 2 sites of the AMBITION-CM trial (https://blogs.lshtm.ac.uk/ambition/). We will assess the host immune response in cryopreserved samples from patients with CM using a variety of techniques including RNA-sequencing of blood, flow cytometry of PBMCs and cerebrospinal cells, whole blood LPS stimulation assays and phagocytosis assays. We will examine associations between this immune signature and poor outcome. Additional experiments will examine ex vivo reversibility of immune deactivation by incubation with IFNg and other cytokines. We will then examine the performance of simplified immune assays in predicting poor outcome over the whole trial cohort. IMPACT This will provide important data to inform future trials of immune modulation in CM and allow the development of prognostic assays/scoring systems to guide intensification of treatment.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigation of the hyporesponsive endotype to inform a precision medicine approach to sepsis
Funder: Medical Research Council

Abstract: The dysregulated host response that characterises the clinical syndrome of sepsis is recognised to be highly heterogeneous. Transcriptomics can be used to define specific sepsis disease endotypes based on gene expression signatures in peripheral blood, and in particular to identify patients with evidence of hyporesponsiveness (including immune cell tolerance and exhaustion) who have the worst outcomes. The ability to distinguish such patients provides a timely opportunity to progress towards a precision medicine approach to managing sepsis. This is important as disease heterogeneity currently limits therapeutic options and is a major contributory factor in the failure of clinical trials that have sought to modulate the host response in sepsis to improve survival. We aim to define this endotype with greater precision by consensus endotyping, determine the most informative RNA biomarkers, and investigate how the endotype evolves during the septic episode. We will investigate genetic drivers contributing to the endotype based on association with gene expression or endotype membership. We will then use single cell -omic approaches to determine the specific cellular drivers of the leukocyte transcriptomic signature, and investigate the nature and extent of cellular dysfunction during the acute septic illness and in survivors. Our final objective will be to assess the impact of knowledge of the hyporesponsive endotype on the design and interpretation of a clinical trial investigating immune stimulation therapy. Our longer-term goal is to enable the development of therapies to modulate the host response in sepsis that can be appropriately timed and targeted to the individual patients most likely to benefit.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: An International Collaboration to Implement and Evaluate at Scale the Active Prevention and Treatment of Maternal Sepsis (APT-Sepsis Programme)
Funder: Medical Research Council

Abstract: Objective: Evaluate through a cluster randomised trial if implementation of the APT-sepsis programme reduces infection related maternal mortality and severe morbidity, evaluate implementation of the programme, and determine cost effectiveness. Study Design: Multi-country, parallel cluster randomised trial with baseline phase Project duration: 42 months Research location: Malawi and Uganda Population: Clusters will be health care facilities managing > 1,500 births per year, offering comprehensive emergency obstetric care. The primary outcome will be collected from all women who are admitted whilst pregnant or within 42 days of delivery. Intervention: APT-Sepsis is a complex intervention, developed to target care providers behaviours to improve adherence to best practice in 1) hand hygiene, 2) prevention and management of maternal infections 3) maternal sepsis management, including the FAST-M maternal sepsis bundle. It includes a carefully optimised set of implementation co-interventions to promote behaviour change. Control: Passive guidelines dissemination Randomisation: 30 of the 60 health facilities will be randomly allocated to the intervention; minimisation for facility size, country and primary outcome baseline rate Primary outcome: The primary outcome is maternal infection related mortality and severe morbidity. This is a composite of infection related maternal mortality, infection related maternal near-miss or severe infection related morbidity (adapted CDC definition of deep surgical site infection or body cavity infection). Implementation evaluation: Mixed-methods evaluation will be undertaken to provide detailed understanding of the process of implementation, facilitate interpretation of trial outcomes and enable development of a longer-term implementation strategy. Health economic evaluation: Evaluate the cost effectiveness of the APT-sepsis intervention, from a provider perspective Sample size: 172,500 births


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: AGILE: Seamless Phase I/IIa Platform for the Rapid Evaluation of Candidates for COVID-19 treatment
Funder: Medical Research Council

Abstract: AGILE is a 'proof-of-confidence' engine designed to rapidly identify those compounds in phase I which could be game changers in the battle against COVID-19, validated to the point of readiness for onward inclusion into Phase IIb/III trials. Our vision is to build a single UK-wide phase I/IIa trial platform working to evaluate a strong portfolio of credible treatments, advancing only those most plausible compounds onwards. Unique features are the inclusion of COVID-19 patients from the outset (including first-into-human), statistically efficient trial design enabling rapid decisions, and ability to evaluate patients in the community as well as hospitals. Establishing this national early-phase trial platform will also advance preparedness for future epidemics of new viral diseases. AGILE utilises a multi-candidate, multi-stage, Bayesian adaptive approach, and comprises a Master Protocol with each investigational compound included as a separate trial arms. AGILE is pragmatic (assessing outcomes in small numbers of patients), flexible (adopting primary endpoints appropriate to the action of each compound, with recruitment tuned to its anticipated therapeutic deployment) and seamless (progressing from first-into-human through dose optimisation to early efficacy evaluation). Staggered cohorts (each with 4 treatment, 2 controls) will be sequentially and flexibly added until the optimal dose is established, and thereafter for safety and efficacy evaluation. The adaptive design allows for i) discontinuation of a dose or candidate due to the probability of any promising effect being too low; ii) adding more participants at the same dose, or iii) recommending further evaluation in a late phase trial, through pre-defined stopping criteria for harm or futility. We have built strong links with UK Phase II/III platforms, the Global Therapeutics Accelerator, WHO and the PHE preclinical COVID19 drug screening platform which is in development.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: A UK underpinning platform to study immunology and immunopathology of COVID-19:The UK Coronavirus Immunology Consortium
Funder: Medical Research Council

Abstract: Incomplete understanding of mechanisms of protective immunity and immunopathology following SARS-CoV-2 infection limits development of diagnostics, treatments and vaccination. The UK coronavirus immunology consortium (UK-CIC) will link the UK immunology community to deliver, at pace, a coordinated and agile national research programme. This will focus around 17 centres of excellence and address five key research themes: -The primary immune response and clinical outcome Here we will integrate immune datasets from patients at the time of primary infection to assess how this relates to clinical risk factors such as gender, ethnicity and age. We will compare and contrast patients with mild and severe disease -long term protective immunity This theme will focus on mechanisms of cellular immunity, how these responses are maintained over time, and how they relate to the severity of initial infection. The consortium incorporates intensive deep phenotyping of an ISARIC 4C follow up cohort. -mechanisms and prevention of immunopathology Using primary tissue samples and post-mortem material we will utilise start of the art technology to assess how viral replication and immune mechanisms mediate pathology, and how these can be prevented. -cross reactivity with seasonal coronaviruses Here we will focus on T cell cross-reactivity between SARS-CoV-2 and seasonal coronaviruses, using fresh and historical samples -viral immune evasion The virus mediates disease by evading host immunity. Here we will use molecular, proteomic and cellular approaches to define new, and potentially reversible, mechanisms of viral evasion. Research outcomes will be translated rapidly to policy makers, academic & industrial collaborators, and the public. The UK has one of the strongest immunology communities in the world and UK-CIC will bring this together to hasten pandemic control and serve as an exemplar for potential future challenges.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: Dissecting innate immune determinants of severity and resolution in a longitudinal study of COVID-19
Funder: Medical Research Council

Abstract: The knowledge gap in COVID-19. The clinical, social and economic disruption caused by SARS-CoV-2 infection and its unpredictable progression to Acute Respiratory Distress Syndrome (ARDS) and chronic poor-health represents a global public health emergency. Emerging COVID-19 studies attribute pathogenesis to immune dysregulation, particularly implicating innate immunity to host tissue disruption. Severe lung pathology is associated with an aberrant inflammatory hyper-cytokine response, predominantly from myeloid cells (monocytes/macrophages). Age, gender, BMI and underlying medical conditions are risk factors, but there is a knowledge gap of host mechanisms that fail to restrain this aberrant response in acute-severe and long-term disease as compared with milder resolving disease. Our hypothesis is that myeloid cells from patients with severe and chronic COVID-19 have impaired endogenous homeostatic mechanisms that limit the pathogenic monocyte and lung macrophage activation in milder forms of disease. Study protocol: (i) Longitudinal study of matched blood and lung lavage myeloid cells during the disease trajectories of moderate compared with severe COVID-19 with long-lasting ill-health. Single-cell phenotyping (transcriptome/proteome) will identify innate immune mechanisms determining acute and long-term pathogenesis and resolution. (ii) Ontogeny trajectory modelling of paired blood and lung lavage myeloid cells, in conjunction with epigenetic mapping (scATACseq) of identified pathways, will pinpoint monocyte drivers and biomarkers of acute and long-term pathogenic or resolving lung responses. (iii) An in vitro 2D and 3D model of human lung cell infection with SARS-CoV-2 will test the therapeutic potential of pathogenic and resolving pathways identified above. Deliverables: Predicative myeloid biomarkers of acute and long-term COVID-19 severity, and therapeutic targets that could restrain aberrant pathogenic responses.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: TBK1 kinase acts like a parking brake to prevent premature activation of NLRP3 inflammasome
Funder: Medical Research Council

Abstract: The aim of this work is to understand what sites in the NLRP3 inflammasome are regulated by TBK1, the mechanism by which TBK1 controls NLRP3 inflammasome, and how this mechanism may be dysregulated in COVID-19 disease. Objective 1: Identify TBK1-controlled sites in NLRP3 complex and map at which stage of priming or activation TBK1 blocks the pathway activation. We found that TBK1 controls NLRP3 pathway, independently of the known inhibitory phosphorylation of NLRP3-serine 3. TBK1 had no such control over other inflammasomes, suggesting that its client protein is either NLRP3 or its upstream interacting partner, e.g NEK7. We will test whether TBK1 phosphorylates mouse and human NLRP3 directly (using in vitro kinase assay), identify the TBK1 regulated phospho-sites in NLRP3 complex (by proteomics), and test at which stage of pathway activation TBK1 blocks the NLRP3 activity (by imaging and functional assays). Objective 2 Describe whether viruses such as Coronavirus SARS-CoV-2 that are known to inhibit TBK1 activation, cause NLRP3 pathway overactivation by releasing the TBK1-regulated NLRP3 brake. NLRP3 inflammasome is activated in response to SARS-CoV-2 infection and higher levels of NLRP3 activity are associated with poor clinical outcome. Papain-like protease (PLpro) from SARS-CoV-2 was recently described to inhibit TBK1 activation. We will test whether PLpro from SARS-CoV-2, when ectopicaly expressed in macrophages (as a part of the inert vector), inhibits TBK1, and boosts NLRP3 pathway activity. As controls we will use cataliticaly inactive PLpro and PLpro from SARS-CoV-1. We showed that TLRs introduce TBK1-dependent brake on NLRP3, to prevent spontaneous NLRP3 activation during NLRP3 priming. We will also test the role of TBK1 in NLRP3 activation upon viral sensing by monitoring NLRP3 phosphorylation and activation in BMDMs upon pharmacological activation of cytosolic viral sensors in the presence or absence of TBK1 inhibition.


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