NIHRDataInsights/HRCSData huggingface dataset:
Title: Orchestrating resident memory B cell responses in the lung during secondary infection with influenza virus
Funder: Medical Research Council

Abstract: An important advance from the past decade has been the recognition that adaptive immune cells are not only capable of remembering the antigens they encountered but also the specific sites in which these encounters occurred, such that tissues that are susceptible for infection are reinforced with protective clones. This type of localized immunity proved highly effective in the case of resident memory T cells, leading to accelerated pathogen clearance and reduced widespread of infection in multiple tissues and infection types. Recently, B cells were also reported to establish a similar form of non-recirculatory bona-fide tissue-resident population that develops and persists in the lungs of influenza infected mice and humans. However, little is known about the mechanisms and functions of these cells. Using 2-photon microscopy and new mouse models that we developed, we studied how resident memory B (BRM) cells respond to secondary infection with influenza virus in situ, within live sections of infected lungs. We found that upon rechallenge, BRM cells quickly migrate to newly infected sites, and we showed that a few days later plasma cells accumulate in these regions, directly near sites of viral replication. Alveolar macrophages orchestrated these events, in part by inducing expression of Cxcl9 and Cxcl10 by infiltrating cells. Here, we will build on this work in order to 1) explore the cellular mechanisms that act downstream to alveolar macrophages to mediate BRM cell mobilization to infected sites, 2) identify factors that promote local differentiation of plasma cells directly within these regions, 3) define the roles of BRM cells as antigen presenting cells and explore their contribution to short- and long-term immunity. We anticipate that these studies will enhance our basic understanding of pulmonary humoral immunity, findings that may eventually lead to the design of new vaccines and therapeutic treatments against influenza virus and, possibly, other diseas


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: Does SARS-CoV2 infection imprint changes in regulatory T cells in rheumatoid arthritis patients treated with anti-TNF?
Funder: Versus Arthritis

Abstract: Anti-TNF antibody therapy boosts regulatory T cell (Treg) number and function in rheumatoid arthritis (RA). Our current research is aimed at unravelling how anti-TNF alters Treg function to understand how RA inflammation can be suppressed by modulation of Treg and therefore identify novel therapeutic targets. The COVID-19 pandemic is an unprecedented health care crisis. It remains unclear whether patients with RA treated with immunomodulatory agents such as anti-TNF are more (or less) at risk of COVID-19 and its complications. COVID-19 leads to changes in effector T cells skewed towards Th17 and alterations in Treg. We have shown that anti-TNF-induced Treg can suppress Th17 responses in RA. Therefore, we postulate that anti-TNF-induced Treg may reduce the severe inflammation observed in some patients with COVID-19 infection. We have pilot data showing unique alterations in Treg subtypes and expression programs after anti-TNF therapy in RA patients using single-cell RNA sequencing (scRNA-seq). We propose to adapt our research using scRNA-seq to address whether anti-TNF induced Treg are primed to limit COVID-19 associated inflammation and how SARS-CoV2 might modulate Treg and impact the efficacy of anti-TNF for RA either during or after infection. This work will generate pilot data to inform future grant applications with the aim of identifying novel Treg related targets for therapy in the context of COVID-19 and RA.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: A large-scale and comprehensive investigation into the B-cell receptor (BCR) and T-cell receptor (TCR) repertoires during the dynamic immune response to sepsis and recovery
Funder: Wellcome Trust

Abstract: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to often-unknown pathogens. Following recovery, individuals exhibit long-term immunosuppression. B and T-cells are vital components of the adaptive immune response, each B/T-cell expresses copies of a single, unique surface B cell/T cell receptor (BCR/TCR) respectively, for antigen binding. Diversity in receptors is generated by V(D)J recombination and for BCRs, through somatic hypermutation and class-switching. The pool of BCRs/TCRs within an individual is termed the BCR/TCR repertoire. In healthy individuals this is highly diverse, yielding a complex immune architecture. However, studies suggest abnormalities in the repertoires of septic shock patients. I will generate the first comprehensive analysis of the BCR/TCR repertoire in sepsis using high-throughput BCR/TCR sequencing at multiple timepoints over the course of disease/recovery; one of the largest studies of this kind. Reactivation of Epstein Barr Virus (EBV) is common during sepsis and EBV induces B-cell somatic hypermutation. Therefore, I will use single-cell RNA sequencing to investigate the B-cell transcriptional profile associated with EBV reactivation in sepsis and relate to prognosis. Finally, I will investigate the effect of immunomodulatory therapies (steroids, anti-TNF) on the BCR/TCR repertoire, thus improving our understanding of how therapies can be combined in sepsis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: Investigating the mechanisms of thromboinflammation induced by infection
Funder: Wellcome Trust

Abstract: Thrombosis is estimated to contribute to 25% of deaths worldwide, yet our understanding of the mechanisms behind thrombus formation and related inflammation remain poor. This so-called thromboinflammation can occur as a result of severe infection, for example in sepsis and severe COVID-19. We aim to probe the lifecycle of the thrombus, and understand why it differs between different organs. To do this, we will use the well-established mouse models of Salmonella infection to study the composition of thrombi in different organs. We also aim to investigate the response of human platelets (the main component of many thrombi) to different strains of Salmonella, allowing identification of host and bacterial-specific factors that are affecting the thrombotic response after infection. This research will help further our understanding of the mechanisms behind the dysregulated inflammatory processes that occur upon infection, including during COVID-19, that can lead to fatal consequences.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: The role of ADAM10 in modulating cell-cell interactions
Funder: Wellcome Trust

Abstract: Efficient clearance of dying and dead cells, a process called efferocytosis, is crucial for tissue homeostasis and a healthy, well-regulated organism. Dying/dead cells are cleared by cells called phagocytes, principally macrophages. We recently identified the leukocyte-expressed glycoprotein CD43 as a molecule that acts as a ‘don’t-eat-me’ signal for macrophages, and showed it was rapidly and completely cleaved from the surface of dying T cells. We also demonstrated that ADAM10 (A Desintegrin And Metalloproteinase Domain-containing protein 10) is the enzyme responsible for CD43 cleavage from dying cells, therefore removing the don’t-eat-me signal, triggering phagocytic uptake. CD43 cleavage by ADAM10 is a novel observation that may be more generally applicable to other ‘mucin-like’ glycoproteins with similar don’t-eat-me properties. To explore this, we will take two approaches: i) probe leukocyte surface molecules with similar biophysical properties to CD43 for ADAM10 cleavage; ii) take an unbiased broader approach using mass spectrometry (MS) to reveal other proteins cleaved by ADAM10 during cell death. Once identified, we will analyse their function in regulating efferocytosis of dying leukocytes. This will shed light on how these molecules modulate clearance of dying and dead cells to ensure healthy tissue homeostasis, and will yield insights into immune cell-cell interactions.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: Human Immune Response Variation in Tuberulosis
Funder: Wellcome Trust

Abstract: I aim to discover novel mechanisms by which differences in human immune responses influence the outcome of Mycobacterium tuberculosis (Mtb) infection. I hypothesise that host-genetic polymorphisms lead to variation in immune responses that determine the clinical outcome of Mtb infection by affecting host-cell restriction of mycobacterial growth. We will use transcriptional profiling at the site of tuberculin skin tests (TST) to make comprehensive molecular and systems level assessments of in vivo human immune responses to a standardised mycobacterial challenge. In order to identify human immune responses that increase risk of disease in people exposed to Mtb, we will test the hypothesis that the TST transcriptome will reveal immune phenotypes associated with progression of LTBI to active TB. We will test the role of host genetics by identifying genome-wide expression quantitative trait loci (eQTL) associated with variation in the TST transcriptome. We will then recall participants by genotypes associated with selected traits to undertake in vitro mechanistic studies in primay immune cells. We will validate the causal association between genetic and phenotypic variations, and test their impact on Mtb restriction by macrophages. The findings will inform clinical risk stratification, vaccine design and development of host directed therapies for TB.

Lay abstract: Tuberculosis remains a major threat to global health. Infection with the bacteria that causes this illness is widespread, but not everyone who is infected develops the disease and we do not understand why. I aim to test the question that our individual risk of tuberculosis disease may be due to differences in the way our immune systems respond to infection and that these differences are genetically inherited. We will use an innovative approach to measure the activity of immune genes at the site of a skin test for tuberculosis, as a model for how the immune system functions at the site of real disease. We will then link differences in immune responses between infected individuals with differences in their genetic code and the likelihood of their infection progressing to disease. These studies will reveal how and why some people develop tuberculosis disease whilst others control the infection. The findings will help us target preventative therapies to those who need them most and to develop better vaccines or new treatment for tuberculosis aimed at improving our immunity.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: Harnessing tissue-resident CD8 T cells to manipulate hepatic immunity
Funder: Wellcome Trust

Abstract: Hepatitis B virus (HBV) kills two thousand people a day from immune-mediated liver disease. New treatments aim to recapitulate the “functional cure” seen following natural resolution of infection, with residual virus kept under long-term immune control. Recent work has revealed that tissue-resident T-cells, which cannot be sampled in the blood, play an essential role in frontline immunosurveillance. We therefore hypothesise that profiling T-cells compartmentalised in the liver of subjects with resolved HBV will decipher mechanisms of immune control of this important human pathogen. Capitalising on unique access to intrahepatic T-cells from contrasting infection outcomes, we will define successful local immune responses to HBV. Specific aims include investigating the functional and metabolic adaptations that allow liver-resident T-cells to survive and thrive in this hostile niche, and testing strategies to induce such responses using in vitro and in vivo HBV models. To provide fundamental insights into organ-specific immunity, we will characterise the interplay between gut-translocated bacterial products and a novel population of CD14-expressing CD8+T-cells with both pro- and anti-inflammatory potential in human liver. Results will define “gold-standard” antiviral T-cells for HBV monitoring and immunotherapy and inform therapeutic manipulation of the balance between hepatic immunopathology and immunoregulation.

Lay abstract: More than 250 million people have chronic infection with hepatitis B virus worldwide, resulting in over 700,000 deaths a year. Existing treatments can rarely cure this infection. Our research aims to develop approaches that harness the natural capacity of the immune response to control this virus. We have discovered that some immune cells with specialised properties for controlling hepatitis B can be found in the liver but not in the blood. We can harvest these cells from surgical liver samples, allowing us to study them in detail so that we can apply this information to develop effective immunotherapies for chronic hepatitis B infection. A further aspect these samples will allow us to study is the influence of bacterial products draining into the liver from the gut, that could shape immune responses and regulate the balance between liver inflammation and immunity.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: Defining mechanisms of mycobacterial protective immunity using human experimental medicine and murine models
Funder: Wellcome Trust

Abstract: Progress in the development of an effective TB vaccine is hindered by an incomplete understanding of protective immunity, and by a lack of knowledge as to which proteins from Mycobacterium tuberculosis (M.tb) are protective. Most of our understanding has come from studies in mice, and studies using blood from patients with TB. The lung is the primary site of infection in TB. Lung and blood responses may differ, and murine and human responses can also differ. I have developed a safe human infection model in which BCG, a replicating mycobacterial strain, is delivered by aerosol directly to the lungs of healthy volunteers. I will use this model to define the innate and adaptive, systemic and mucosal immune responses, in humans. I will then use an in-vitro mycobacterial growth inhibition assay to assess whether these responses are protective. I will use this information to identify which components of host immunity are important in protection in humans. We will also use state-of-the-art mass spectrometry to identify which M.tb proteins are naturally presented to the human immune system, and determine if these proteins confer protection in a murine M.tb challenge study. This information will facilitate the development of effective vaccines.

Lay abstract: Most of what we know about how to develop a better TB vaccine comes from studies in mice, and human studies in the blood. Responses in humans are not always the same as in mice and responses in the lung and blood can differ. We need to understand more about what happens in the lungs in humans when people are infected with TB, as TB enters the body via the lungs. We cannot deliberately give humans TB. However, I have developed a safe way of giving BCG, which is very like TB, directly into the lungs of healthy volunteers, to help understand, for the first time, which bits of the immune system respond to mycobacteria. I will also identify which of these responses can kill the real TB in the test-tube. Working out how BCG works is vital, but we actually need to do better than BCG. I will also identify new proteins that are in TB which are naturally presented to the human immune system. I will then see, in mice, whether these proteins can work as a vaccine.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: C-type lectins in antifungal immunity
Funder: Wellcome Trust

Abstract: I have established that C-type lectin receptors (CLRs) play a central role in antifungal immunity. In this proposal, I will capitalize on our exciting recent discoveries to address two questions that represent novel aspects of CLR biology: 1. How do CLRs regulate antifungal adaptive immunity? We discovered dendritic cell expressed CLRs, the KLRs, which regulate the development of adaptive immunity during fungal infection. Our objective is to determine the physiological role of the KLRs, elucidating their cellular expression and function, the nature of their T-cell ligand(s), their influence on T-cell immunity and their importance in anti-fungal immunity. 2. What is the impact of fungal secondary metabolite recognition by CLRs? We identified two novel CLRs that recognise fungal secondary metabolites, including secreted toxins such as aflatoxin (a major clinically significant fungal-derived carcinogen). Our objective is to gain a definitive understanding of the functions of these receptors and the immunological and physiological impact of their ability to recognise these secreted fungal products. Using a variety of in vivo and in vitro approaches, this research programme will significantly advance our knowledge of the underlying mechanisms of antifungal immunity, and will open new fields of investigation in the areas of adaptive immunity and medical mycology.

Lay abstract: Fungi have a huge impact on human morbidity and mortality. I discovered that C-type lectin receptors (CLRs) are important for controlling these infections, although we do not yet fully understand how these receptors mediate their protective effects. I aim to determine how new CLRs that we have recently identified are able to regulate adaptive immune responses, which are critical for protecting against fungal infections, and mediate responses to secreted fungal products, including carcinogenic compounds such as aflatoxin. Using a variety of cell-based and biochemical approaches, along with comparative in vivo analyses of wild type versus genetically altered mice, I will determine the cellular and immunological roles of these novel receptors. This research programme will significantly advance our understanding of the physiological functions of CLR in antifungal immunity, and open new fields of investigation in immunology and medical mycology.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: Understanding cerebral inflammation in viral encephalitis - how does neuron-glial signalling drive blood-brain barrier permeability?
Funder: Medical Research Council

Abstract: CONTEXT In the devastating brain infection herpes simplex virus (HSV) encephalitis, the inflammatory response, characterised by leucocyte migration, blood-brain barrier (BBB) breakdown and cerebral oedema, is associated with poor outcome, despite antivirals Broad immunosuppression with corticosteroids may help or worsen outcome due to uncontrolled viral replication. I identified that BBB permeability and outcome correlate with several mediators in cerebrospinal-fluid (CSF), but corticosteroid impact is unknown Targeted immunotherapy ameliorating BBB breakdown and detrimental leucocyte migration, without impairing viral control, is urgently needed. We must understand how HSV infection of neurons triggers inflammatory mediator cascades by glia and BBB breakdown AIMS 1. Establish the mediators most closely associated with BBB permeabilisation in HSV encephalitis and which are/are not corticosteroid responsive 2. Interrogate effects of abrogating these mediators on BBB permeabilisation, leucocyte migration and viral control 3. Delineate mediator signalling networks between neurons, glia and BBB cells METHODOLOGY 1. Analyse CSF mediators in a unique cohort of HSV encephalitis patients receiving corticosteroids/placebo (from RCT) by bead array/proteomic approaches relative to BBB permeability (CSF:serum albumin ratio and neuroimaging oedema quantification) 2. In my murine model, determine impacts of cognate receptor knock-outs and neutralising antibody-treatment, on phenotype, intravenous tracker leakage and real-time leucocyte migration by intravital microscopy 3. In this model, use a single-cell RNA-sequencing time course and confirm findings in our BBB in vitro model, relative to leucocyte dynamics OPPORTUNITIES Understanding critical mediator pathways driving BBB breakdown and cerebral oedema in HSV encephalitis will direct targeted immunotherapy, has implications for other forms of encephalitis, and will help me become a field leader


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM;NEUROLOGICAL
Title: Restoring innate immunity in cirrhosis with faecal microbial transplantation
Funder: Medical Research Council

Abstract: Background: Chronic liver disease (CLD) is characterised by perturbations in the healthy gut microbiome with reduced microbial diversity and relative over-expression of pathogenic species termed 'cirrhotic dysbiosis'. This correlates with the severity of underlying liver disease and predicts survival. Cirrhotic dysbiosis is associated with gut barrier dysfunction and bacterial translocation, culminating in systemic inflammation and driving profound innate immune dysfunction. Faecal microbial transplantation (FMT) is a novel therapeutic strategy undergoing randomised controlled trial (RCT) evaluation in patients with advanced cirrhosis however the cellular and molecular mechanisms underlying its beneficial impact are poorly understood. Hypothesis: We have developed a research tissue biobank of cirrhotic patients at baseline and on days 7, 30 and 90 following FMT (n=24) or placebo (n=8). Our preliminary work demonstrates stark contrasts in the diversity and type of bacterial species in patients with CLD that is sustainably impacted upon by FMT. I hypothesize that FMT will ameliorate MAIT cell dysfunction and restore systemic innate immunity in patients with CLD and cirrhosis-associated immune dysfunction (CAID). Key Goals: - To explore whether FMT restores peripheral MAIT cell frequency and function in cirrhotic patients. - To investigate the oligoclonal MAIT cell repertoire in cirrhotic dysbiosis and the impact of FMT. This project proposal will be the first demonstration of links between chronic perturbations of the gut microbiome in cirrhosis and the reshaping of innate immunity in a human model of dysbiosis. These experiments will advance our understanding of microbiota-host interactions and will offer mechanistic rationale for the use of FMT to manipulate immune cell function, not only in cirrhotic patients but also in other diseases with underlying dysbiosis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION;INFLAMMATORY AND IMMUNE SYSTEM;ORAL AND GASTROINTESTINAL