NIHRDataInsights/HRCSData huggingface dataset:
Title: The relationship between innate immune cell function and bacterial infections in severe acute malnutrition
Funder: Wellcome Trust

Abstract: Severe acute malnutrition (SAM) underlies one million deaths in children under 5 years old annually. Immunodeficiency is implicated in SAM mortality because deaths are predominantly due to infections and infectious mortality persists after nutritional rehabilitation; however, we know very little about how malnutrition affects immune cell function. This fellowship will characterise the relationship between bacterial infections and the anti-bacterial functions of monocytes and dendritic cells (DC) using blood samples collected from children admitted to hospital with SAM (n=200) and track this relationship during hospitalisation and over 48 weeks of community-based nutritional rehabilitation (n=100). I will evaluate both the capacity of monocytes and DC to bind and respond to bacteria in vitro, and how pro-inflammatory mediators in plasma, which are elevated in SAM, affect healthy monocyte and DC. These assays will generate a detailed profile of monocyte and DC function in each child which I will use to determine whether innate immune function is: 1) compromised relative to adequately-nourished controls (n=200); 2) associated with bacterial morbidity and mortality; and, 3) restored by treatment. Understanding the relationship between innate immune cell dysfunction and bacterial mortality in children with SAM could identify new immunotherapeutic targets to improve clinical outcomes in this high-risk population.

Lay abstract: Severe acute malnutrition (SAM) underlies one million deaths in children under 5 years old annually. SAM is identified by extreme weight loss, but deaths are predominantly due to infection, particularly with bacteria. The immune system is critical for controlling infections, but we know very little about how immune cells function in malnourished people. This fellowship will characterise the relationship between bacterial infections and the anti-bacterial functions of two innate immune cell types, monocytes and dendritic cells (DC), using blood samples collected from children hospitalised with SAM (n=200), and track this relationship during hospitalisation and over 48 weeks post-discharge (n=100). I will culture blood with bacterial components to determine how well monocytes and DCs bind to and become activated by bacteria, indicators of their capacity to control infection. I will also characterise how healthy monocytes and DC change when exposed to blood from children with SAM. I aim to determine whether monocyte and DC function are: 1) compromised relative to adequately-nourished controls (n=200); 2) associated with death and illness due to bacterial infections; and, 3) restored by treatment. Understanding which defects in innate immune cell function contribute to bacterial infections in SAM could identify more effective ways of treating malnutrition.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Communication between immune and stromal cells is key to immunological memory within pathogen infected tissues
Funder: Wellcome Trust

Abstract: Pathogens trigger an accumulation of immune cells in the infected tissue. Incoming immune cells adapt to their new environment, communicating with infected stromal cells to ensure pathogen control. Tissues do not immediately return to homeostasis following pathogen clearance. Some pathogen-specific T cells remain, differentiating into Tissue Resident Memory cells (Trm). The tissues’ stromal cells also retain an imprint of the infection with prolonged expression of immune-related genes. Currently, we have only limited understanding of the cells and molecules involved in establishing and maintaining these infection-induced changes and how immune and stromal cell communication impacts on protective immunity. These are key question for vaccines that aim to induce immune protection within tissues to provide rapid protective immunity. This proposal is based on our findings that antigen-presentation and inflammatory cytokine production drives prolonged changes in lung CD4 Trm cells and epithelial cells and fibroblasts. Our key goals are to define the mechanistic basis for these changes by identifying the cells and molecules that influence the generation, maintenance and protective responses of infection-altered immune and lung stromal cells. This research will provide a conceptual breakthrough in our understanding of how cell commination influences protective memory and novel insights relevant to improved vaccine design.

Lay abstract: Cell talk: communication is the key to remembering how to fight off bugs Infection causing bugs turn on immune cells. Some immune cells specifically recognise the bug and can remember what it looks like and where in the body it caused disease. If the same bug causes another infection, these ‘memory’ cells quickly attack it. We call this immunological memory: it is the basis for the success of vaccines. We study immune cells called CD4 T cells as they co-ordinate protective responses. We will investigate how influenza virus infection generates memory CD4 T cells in the lung, where they can quickly control the virus. We think that incoming immune cells, including CD4 T cells, talk with infected epithelial cells and cells called fibroblasts that support other lung cells. We will test how communication between these cells supports prolonged changes in the tissue that improves immune protection to further ‘flu infections.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Type III interferons in immunity against bacteria
Funder: Wellcome Trust

Abstract: Interferons (IFNs) are induced in response to recognition of non-self by the innate immune system. Type III IFNs (IFN&lambda;s) are emerging as important mediators of immunity in the intestine. However, their specific roles in bacterial infections have not been studied. I found that IFN&lambda;s are induced in response to bacteria and are important for the control of Salmonella infection in vivo. In addition, IFN&lambda; blocked Salmonella replication and protected the epithelial barrier from Salmonella or Shigella-mediated damage in vitro. I also found that Salmonella, Shigella and enteropathogenic E. coli block type III IFN expression, implying a role for IFN&lambda;s in the defense against these bacterial pathogens. My goals are: 1. To study the activities of type III IFNs against enteric bacterial pathogens in in vitro and in vivo models of Salmonella, Shigella and E. coli infection. 2. To characterize the cell signalling pathways activated by host cell receptors to drive type III IFN expression in response to bacterial challenges. 3. To identify them echanisms through which bacterial pathogens block IFN&lambda;s. I expect that this work on type III IFN signalling and functions will greatly contribute to our understanding of host bacterial interactions at mucosal surfaces.

Lay abstract: In order to communicate, cells of the immune system secrete proteins that are termed interferons (IFNs). I study IFNs of the type III family (IFN&lambda;s), that are important regulators of intestinal immunity. I have found that IFN&lambda;s are produced in response to infection with intestinal bacteria such as Salmonella, Shigella and E. coli. I also found that mice that do not have an IFN&lambda; system can’t fight Salmonella infection as efficiently, and that IFN&lambda;s protects the intestinal barrier from damage inflicted by bacteria. Pathogenic bacteria have also devised virulence mechanisms to block IFN&lambda; production. My findings suggest that type III IFNs are indeed important for our immune system to fight bacterial infections. My project aims to study this in greater detail. For example I will study if and how IFN&lambda;s block bacterial growth in infected animals and infected cells. My project also aims to identify how host cells produce IFN&lambda;s in response to bacterial components. Lastly, I aim to identify the bacterial factors that pathogenic bacteria use to block IFN&lambda; expression and signalling. This project will advance our understanding of intestinal immunity and how some bacterial pathogens cause disease by interfering with this aspect of the immune system.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Molecular determinants of intraepithelial lymphocyte function in intestinal infection
Funder: Wellcome Trust

Abstract: Intraepithelial lymphocytes (IEL) are the first immune cells that pathogens encounter in the gut. These lymphocytes lie within the epithelial layer, and are central to controlling infection, stress or transformation of the gut epithelium. Despite their importance, we have a poor understanding of how IEL sense and respond to stress in epithelia, partly due to the lack of genetic tools that specifically target IEL. To get unbiased insights into the complex biological processes underlying IEL function, I determined the quantitative proteomes of three main intestinal IEL subsets. This unique dataset reveals that IEL are phenotypically and functionally distinct from conventional T cells. The IEL proteomes provide unprecedented insights into the effector functions of intestinal IEL and suggest new hypotheses of how their function might be regulated. Based on these data, I will (1) explore the apoptotic and non-apoptotic functions of abundantly expressed granzymes in IEL, (2) develop novel genetic tools to dissect the role of IEL in the early immune response to pathogens, and (3) address the contributions of inhibitory receptors and their signalling pathways to IEL homeostasis and sensing of epithelial dysbiosis. In summary, the proposed research will reveal how IEL communicate and respond to bacterial and parasitic infections.

Lay abstract: Our bodies are home to trillions of bacteria and most of them reside in our guts. Recent research has suggested a strong link between intestinal bacteria and inflammatory diseases including cardiovascular complaints, obesity, and more directly, inflammatory bowel diseases. A single layer of epithelial cells forms the first line of defence in the gut and is the largest interface between microbes and our bodies. This layer of cells is interspersed with specialized immune cells that aid in its protection. In this study I will explore the function of these special cells, named intraepithelial lymphocytes (IEL), and investigate how they identify an epithelial cell that has been infected with a disease-causing microbe. I will explore the nature of the IEL response, and how IEL kill infected cells. A clearer understanding of the early immune reaction that result from such pathogenic infections, and the mechanisms used, will help us understand how the immune system mounts an appropriate response to clear the disease. This work will identify key factors that must be induced for efficient vaccine design against gut pathogens, and in turn would help us fight infectious diarrhoea, one of the leading causes of global morbidity.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Tuft Cell Activation and Intestinal Immunity
Funder: Wellcome Trust

Abstract: Immunity to nematode parasites requires sequential activation of innate and adaptive immunity in a concerted "Type 2" response dependent on the cytokines IL-4, IL-13 and IL-25. Our work, and that of others, has identified a novel epithelial cell type that is critical to initiation of this response, known as tuft (or brush) cells. Most significantly, tuft cells are a major source of IL-25 during gastro-intestinal nematode infection, which induces IL-13 production from innate lymphoid cell type 2 (ILC2s), to activate further innate and adaptive cell populations. They also express high levels of the enzymes that produce acetylcholine and lipid mediators implicated in immunity. Tuft cells are found in other mucosal locations, including the lungs, and are highly conserved across the Mammalia, including in ruminants where intestinal nematodes are a major problem. A fascinating aspect is their expression of taste receptors suggesting that they may chemically ‘sense’ the presence of nematodes. In this proposal we seek to (i) determine the immune effector functions of tuft cell mediators; (ii) identify molecules from parasites that may activate tuft cells; and (iii) establish whether tuft cell functions are conserved in ruminants and may lead to new strategies for control of nematode infection in sheep.

Lay abstract: Nematodes or roundworms are common parasites of animals and humans. These parasites have an extraordinary ability to dampen down the immune response of their hosts and establish long-term, chronic infections. In animals they are becoming increasingly difficult to treat because of drug resistance. In this application we will study the interaction of nematodes with a hitherto neglected cell type in the intestine, the tuft cell. This cell is key to the development of a protective immune response and we aim to identify the parasite molecules that interact with tuft cells with a view to developing new ways of controlling infection. Tuft cells express taste receptors and we will determine whether they may be able to 'taste' the presence of worms in the intestine. We will attempt to develop 'organoids' from sheep, a new way of studying disease in culture rather than in whole animals.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Reversible ADP-ribosylation signaling in the control of coronavirus infection
Funder: Wellcome Trust

Abstract: The interferon (IFN) immune response induces an antiviral state by triggering the expression of IFN-stimulated genes and is the primary line of defence against infection. The proteins encoded by these genes fulfil a variety of functions, including degradation of viral RNA and reduction in protein translation. Unsurprisingly, viruses have evolved compensatory mechanisms to suppress the IFN response. One such family of viruses is Coronaviridae, responsible for the current COVID-19 pandemic. Suppression of IFNs by Coronaviridae has been attributed to the macrodomain module present within the multidomain Nsp3 protein. The macrodomain functions as an ADP-ribosylhydrolase to neutralise the actions of the antiviral members of the poly(ADP-ribosyl)polymerase (PARP) family. However, the mechanisms through which antiviral PARPs and macrodomains impact the IFN response remain unclear. This proposal will provide a molecular understanding of how antiviral PARPs suppress coronavirus infection and how SARS-CoV-2 macrodomains oppose their activity to evade IFN signalling and promote viral replication. Furthermore, comparative analyses of the macrodomains from different coronaviruses and their impact on interferon response may explain the variations in their pathogenicity. Collectively, our studies will inform interferon-based disease management strategies to prevent spread within and between infected hosts and provide novel biomarkers of susceptibility and antiviral drug targets.

Lay abstract: Coronaviruses have been responsible for worldwide outbreaks of SARS, MERS and, most recently the cause of the COVID-19 pandemic, SARS-CoV-2. The body is defended from infections, viral and otherwise, by the immune system. During an antiviral immune response, enzymes called PARPs transfer small chemical groups onto proteins, altering their function. These changes help to stop viral growth and prevent an infection. Typically, this includes the activation of the interferon response, which signals the location of an infection and prevents it from spreading to surrounding areas of the body. However, viruses have evolved tools to escape our immune responses; coronaviruses use an enzyme called macrodomain to oppose the antiviral PARPs. This project aims to identify exactly how PARPs helps to prevent infection, as well as how coronavirus subverts these defences. Understanding these processes will help develop new tools and strategies to prevent spread of infection and future outbreaks.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Molecular regulators of the alarmin IL-33 in health and disease
Funder: Wellcome Trust

Abstract: IL-33 is a critical cytokine in allergy, obesity, helminth infection, sepsis, and respiratory viral infection. Blockade of IL-33 (or its receptor, ST2) is currently being trialled in a range of allergic and inflammatory conditions, including Covid-19. The cytokine has a short half-life on release, but conversely has effects at distal sites and over long periods. Furthermore, innate immune cells in the intestine are poorly responsive to IL-33, but susceptibility to intestinal helminths is strongly controlled by IL-33. This project will investigate: 1) How, at a protein structural level, parasite proteins effectively block IL-33 responses. Determination of the effects on the parasite and host of blocking parasite modulation of the IL-33 pathway. 2) What are the roles and targets of IL-33 released from the intestinal epithelium, both locally (in parasite infection) and systemically (in diet-induced obesity). 3) The role of soluble IL-33 receptor in stabilisation of IL-33, and its effects at distal sites. To achieve these aims will we will use structural biology, in vivo models of IL-33-dependent responses, creation of cell-specific ST2-deficient mouse strains, and generation of a soluble ST2-deficient mouse. Finally we will use human blood samples and three-dimensional culture methods to ensure translation of these findings to humans.

Lay abstract: The protein IL-33 acts as a messenger for the immune system. It is released when damage occurs, and activates immune cells to fight off infection and heal damage. IL-33 is important in a large range of diseases - IL-33 release suppresses weight gain and is required to eject parasitic worms, but conversely induces allergic diseases such as asthma, and is thought to have a role in the inflammatory response to Covid-19. In this project, we will investigate how IL-33 responses are controlled. We have found that parasitic worms, in an effort to survive immune system assault, suppress IL-33 responses - we will investigate how they do this at the molecular level. Conversely, we will investigate how the immune system stabilises IL-33 in the blood, sustaining its effects. Lastly, we will investigate which cells of the immune system respond to IL-33 in different organs, and how the parasite affects these.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: The role of innate immune regulation in viral pathogenesis and the development of anti-viral T cell memory
Funder: Wellcome Trust

Abstract: Immune mechanisms that regulate antiviral immune responses determine whether the host can control pathogen replication and virus-induced immunopathology. The pathogenic human cytomegalovirus (HCMV) establishes chronicity and induces inflammation-associated pathologies. Cytomegalovirus (CMV) also induces the largest known expansion of T cells, and thus represents an important tool for identifying mechanisms inducing robust T cell immunity. CMV may also be exploited as an attenuated vaccine vector. Using a CMV model of viral pathogenesis, I identified that immune regulation during initial infection determines the extent of virus-induced inflammation and development of long-lived virus-specific immunity. The key goals of this proposal are: 1. Identify innate immune components that mediate viral pathogenesis and understand how they are controlled 2. Test whether innate immune pathways can be a) safely targeted therapeutically to treat viral disease and/or b) used to predict genetic risk of CMV pathogenesis 3. Identify the early immunological events that promote CMV-specific T cell memory development, and elucidate whether regulatory pathways controlling these factors can be harnessed to enhance virus-driven memory T cell formation induced by attenuated viral vectors This research will determine whether innate immune activation can be exploited to: 1) safely treat viral pathogenesis and/or 2) enhance virus-induced T cell memory responses.

Lay abstract: Our body’s immune system protects us from infection, but sometimes it over-reacts and causes organ damage. A protein called Ifitm3 limits severe viral diseases. Ifitm3 is known to stop some viruses dividing but I discovered that Ifitm3 also suppresses overactive immune responses, known generally as inflammation, triggered by viruses. I will study cytomegalovirus, a virus that causes disease in immune-suppressed individuals and young children. My study will find out how Ifitm3 limits inflammation. I will then examine whether targeting these pathways can help treat clinical problems caused by virus-induced inflammation. Vaccinations work by triggering immunological memory that can remember, respond to and control infections. Cytomegalovirus promotes long-lasting strong immunological memory. Studying how this virus triggers memory could help design vaccinations. Furthermore, if made safe, cytomegalovirus itself may be used as a vaccine. I will identify early events required for cytomegalovirus-triggered immunological memory formation and identify whether factors that dampen these responses can themselves be targeted to enhance immune protection afforded by safe cytomegalovirus-based vaccines. Thus, I will uncover how early inflammatory events can: 1) be inhibited to treat clinical problems caused by virus-induced inflammation and 2) be enhanced to improve vaccine-induced immune protection.

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