NIHRDataInsights/HRCSData huggingface dataset:
Title: Understanding the molecular mechanism underlying mycolactone-dependent immunosuppression what mediates the gene-specific translational control? .
Funder: Wellcome Trust

Abstract: Buruli ulcer is a flesh-eating skin infection that affects some of the poorest communities in the world. It causes massive debilitating skin ulcers, often leading to disfigurement or amputation. This is due to a substance released by the bacteria called mycolactone. I have discovered that mycolactone shuts down inflammation by inhibiting a particular step in the cells production line that is responsible for making inflammatory proteins. Mycolactone only inhibits production of proteins with a common role in inflammation, meaning that these proteins must have a molecular switch that can be turned on or off by mycolactone. The objective of my study is to understand the functional interaction between this switch and mycolactone using laboratory molecular techniques. The findings of this project will be a step towards the development of sorely needed treatments for Buruli ulcer, which would prevent it from shutting down the immune system and therefore let the body heal more quickly . Eventually it could also benefit patients with many other diseases because drugs that target inflammation would be excellent treatments for those where this is a major contributor (such as rheumatoid arthritis, psoriasis etc).


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Induction of tolerogenic dendritic cells by the laminated layer of Echinococcus granulosus.
Funder: Wellcome Trust

Abstract: Parasitic worms establish long-lived infections in people and animals. It is now well known that these parasites have the ability to alter the host immune response in order to avoid being killed. Recent evidence from many different laboratories has shown that this inhibition of immune responses by parasites can protect people and animals from many autoimmune diseases as well as allergy. Animal models have shown that worm secretions can be used to mimic the protective effects of infection on t he immune system. There is therefore a strong interest in studying these worm products because they may provide potential therapies as well as help us understand the immune pathways that need to be activated to control these diseases. We are studying a worm that forms a cyst inside the body of people and animals and have found that the outer layer of the cyst, which interacts with the immune system, is potently able to inhibit cells that are responsible for initiating immune responses. In this project, we want to understand how the parasite material alters the function of the cells as well as define the specific molecules from the parasite that are responsible for these effects.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Turnover, differentiation and senescence of CD8 memory T cells in vivo
Funder: Wellcome Trust

Abstract: This proposal employs high-resolution modifications of several elegant techniques to examine whether CD57+ memory T-cells are truly senescent. The techniques employed include in vivo stable isotope labelling of human subjects with deuterated water, state-of-the-art multiparameter flow cytometric sorting, and T-cell clonotyping. Recent refinements to these techniques now allow reliable measurements from very low numbers of cells. Therefore, it is now possible to take full advantage of the power o f multiparameter, multidirectional fluorescence-activated cell sorting to simultaneously measure the kinetics of multiple, even rare, subpopulations of cells, including memory CD57+ CD8+ T-cells that are infrequent in healthy subjects. The key goal of this proposal is to reveal whether CD57+ CD8+ T-cells as well as antigen-specific CD57+ CD8+ T-cells accumulate in chronic infections because of increased proliferation or because of phenotypic conversion from a precursor memory T-cell subset. This information will help to illuminate the ontogeny and significance of memory CD57+ CD8+ T-cells and determine the impact of specific antigen-driven processes in the generation and maintenance of this enigmatic memory T-cell subset.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Functional and population genomics of the Anopheles innate immune system and its interactions with malaria parasites.
Funder: Wellcome Trust

Abstract: Malaria parasites are transmitted between humans through mosquito bites. When inside mosquitoes, parasites develop, multiply and invade tissues until they reach the salivary glands, from where they can infect new human hosts upon mosquito bite. Although mosquitoes strongly react to parasite invasion through their immune system, drastically reducing the infection burden, a handful of parasites are able to survive continuing the cycle of disease transmission. This research programme aims to deciph er how specific components of the mosquito immune system are activated during infection and why some parasites escape these reactions. Mosquito and parasite factors involved in this interplay, and how they interact, will be characterized in detail using experimental approaches developed in the current programme period and based on a wealth of preliminary results that serve as a starting point. The programme will provide molecular insights into why only specific combinations of mosquito and paras ite strains contribute to malaria transmission in the field. We will use a methodology that monitors the vast genetic diversity in field mosquito populations in Africa and detects how it is associated with outcomes of infection by different parasite populations.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: The influence of intracellular bacteria on MHC class II in relation to autoimmunity .
Funder: Wellcome Trust

Abstract: In Africa, non-typhoidal strains of Salmonella bacteria pose a serious health risk, with fatality rates in children of up to one in four. In affluent counties they may cause intestinal illness (salmonellosis) through contaminated food and other strains are responsible for typhoid. It is important to understand how the bacteria survive in human cells. As a clue to this, we showed that they have specific effects of immune system molecules, called MHC class II. In this grant we propose to dissect t he molecular mechanisms by which they achieve this. It may lead to understanding of how to treat infections with bacteria, like Salmonella, as well as bacteria that cause TB, that live inside human cells. This research could also have profound consequences for understanding autoimmune diseases such as diabetes, MS and arthritis, which afflict many people. This is because it may provide insight into how MHC class II functions in these conditions.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: T Cell Inducing Vaccines.
Funder: Wellcome Trust

Abstract: For the last ten years I have been developing a variety of innovative vaccine technologies that aim to induce a particular type of immunity that should allow new vaccines to be developed and commercialised against several important diseases, particularly malaria. Our immune system has two arms: the humoral arm which generate antibodies, and the cellular arm which involves white blood cells, particularly those known as T lymphocytes. Nearly all existing vaccines work primarily through antibody in duction and it has been very difficult to generate protective immunity by stimulating the cellular arm of the immune system. However, I have been able to increase the potency of such vaccines by almost 100-fold over the last ten years to the point where my team has recently developed the first T cell-based vaccine to show some efficacy in most vaccinees against malaria. I propose here to evaluate, pre-clinically, several new approaches to enhancing further the potency of this type of vaccine to the point where the technology should allow design of new effective T cell-based vaccines against a variety of infectious pathogens. I shall also investigate, pre-clinically, whether these new immunisation approaches can be used to induce immunity against tumour antigens and cancer.


Research activity codes: 3.4 VACCINES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Helminths and Allergy in Uganda.
Funder: Wellcome Trust

Abstract: Studies in animals show that parasitic worm infections can protect against allergic disease. Our key goal is to find out whether worms have this effect in humans, also. On one hand, we aim to find out whether de-worming programmes will result in an epidemic of allergy in low-income countries. On the other, we shall explore how worms protect against allergy, as this may provide important insights into ways of preventing or treating allergic disease. Our programme will be based in Ente bbe and neighbouring islands in Uganda. In studies among 3000 households, we will investigate whether de-worming programmes are likely to precipitate an allergy epidemic by comparing standard versus intensive de-worming schedules in the island communities (where worms are still common), and by observing the effects of the standard de-worming schedule in Entebbe (where worms have recently declined). We will explore effects of worm-exposure and de-worming very early in life in the Entebbe Mot her & Baby Study, where participants have been followed from pregnancy (i.e. before birth) to school age. We will apply cutting-edge laboratory techniques to find out how worms influence allergic responses in humans, and to determine whether effects are established by exposure to worms in very early life.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: A comparison of Pattern Recognition Receptor activation by human and horse strains of Streptococcus pneumonia.
Funder: Wellcome Trust

Abstract: The bacterium Strepotococcus pneumoniae is an important cause of serious lung infections in humans and horses. It produces the toxins, autolysin and pneumolysin. Autolysin causes the bacteria to disintegrate releasing pneumolysin and other bacterial fragments. Pneumolysin damages lung cells, but both pneumolysin and the bacterial fragments are recognised by receptors on host immune cells to drive a protective immune response to restrict the bacteria to the lung and prevent bacterial invasion. Th e combined effects of the bacterial toxins and the immune response, however, can also cause severe damage to the lungs. Horse strains of S. pneumoniae cannot produce either autolysin or pneumolysin. The lack of toxins should mean protective immunity is not stimulated in horses and the bacteria should invade and spread around the body, but clinically this is not common. This project hypothesises that the lack of toxins alters the type of bacterial products available for recognition by the hosts immune system. The key goals are to characterise the differences between how human and horse strains of S. pneumoniae are recognised by the host immune system and compare the different immune responses that are generated to identify processes which contribute to immunity against this serious infection.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Probing and manipulating viral receptor-sugar interactions using novel DNA-based multivalent carbohydrate ligands.
Funder: Wellcome Trust

Abstract: Virus surfaces have specific patterns of sugars that can be recognized by cell surface sugar-binding proteins (receptors) to provide immune protection. This is particularly important in early responses to infections. Some viruses (such as HIV, Hepatitis C virus and Ebola virus) can actually exploit this sugar-receptor interaction as a means to enhance the cell infections. However, information on how these viruses can achieve this and what structural changes are involved in this process are poorl y understood. This project will use two important viral receptors, DC-SIGN and DC-SIGNR, as model examples to study how viral surface sugar binding to these receptors can facilitate viral infectivity. I will develop a series of novel sugar-ligands with well-controlled distances between sugars such that they can match the arrangement of sugar-binding sites of the receptors to achieve strong and specific binding. These novel ligands can effectively compete with receptor-virus (surface sugar) inter action to block the initial virus-cell interaction and therefore prevent viral infection.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Controlling the intracellular fate of cytosolic pathogens.
Funder: Wellcome Trust

Abstract: Background: Several intracellular pathogens escape from phagosomes and reach the host cytosol where they can polymerize actin, leading to motility and cell-to-cell spread. However, only a small fraction of intracytosolic bacteria form actin tails, and a complete understanding of the molecular events restricting bacterial dissemination has not been obtained. Objectives: Using Shigella flexneri I will pursue the following aims: (1) To identify and characterize host and pathogen determinants un derlying the intracellular fate of cytosolic bacteria; (2) To investigate the role of discovered molecules and mechanisms in vivo using new experimental models of infection. Expected results: Completion of these objectives will provide insights into the mechanisms required for the control of infection by cytosolic host responses.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: The ontogeny of innate immunity in Gambian infants.
Funder: Wellcome Trust

Abstract: Too many infants still die from infection worldwide. If we wish to design new treatments or better vaccines to change this situation, we require detailed knowledge about how their immune system deals with infection.This project focuses on changes in specific components of the immune system of infants in their first year of life in a developing world country where infections are commonplace. The white blood cells are responsible for discovering and fighting infections by producing certain messen ger substances, if stimulated by infectious agents. I will therefore compare how the responses of the white blood cells change in the first year of life, both in how they appear and in what they do. We believe that the way infants respond to infections can be affected by many factors in early life. I wish to explore whether levels of vitamin D in an infant's blood has an effect on their response to infection. I am also interested in organisms responsible for dangerous infections which can be pr esent in the nasal passages of healthy infants. I wish to see whether the presence of these organisms in the nasal passages might prime the immune system to ensure a stronger response in later life.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: The effects of infection and inflammation on Hematopoietic stem cell activation
Funder: Wellcome Trust

Abstract: Hematopoietic stem cells (HSCs) are self-renewing progenitor cells that give rise to all the blood and immune cells. Although previously thought to be a dormant population, recent evidence suggests this population responds directly and immediately to infection and inflammatory signals. Using zebrafish, a prominent immunological model with a variety of transgenic lines available and a relatively short set-up time, the aims of this proposal are: - To determine if there is a subpopulation of highly dormant HSCs in zebrafishand to assess their response to inflammation and infection. - To determine the effect of inflammation on the proliferation of hematopoietic progenitors. Preliminary experiments will use TLR stressor polyI:C; Further experiments will use physiological stressors such as bacteria and dietary inflammatory components. - To use a transplantation model to assess HSC function following infection. - To generate transgenic zebrafish more accurately identifying the HSCs. - To use state of the art imaging techniques to acquire live imaging data and information regarding the HSC niche. - To determine if the HSC pool can be exhausted in zebrafish. Exhaustion of HSCs can occur following repetitive stimulation in mouse. However, this may not be the case in zebrafish due to their high regenerative capacities.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: The impact of mesenchymal stem cells on host immunity in bacterial lung infection and sepsis.
Funder: Wellcome Trust

Abstract: In fighting bacterial lung infection the immune system can cause significant lung tissue damage. Because of the way in which the lung is designed to optimise gas exchange there is a high functional price to pay for this damage. Antibiotic treatment is not always sufficient to help the immune system clear the infection. One novel approach being explored across several diseases is that of giving mesenchymal stem cell (MSC) therapy. MSCs are cells isolated from the bone marrow which have several be neficial properties. They have the ability to stop potentially damaging inflammatory cells from dividing, they make molecules which dampen down inflammation and have recently been shown to act directly against bacteria. However, their precise mode of action is poorly understood. My aim is to explore the potential of MSC therapy in mouse models of severe lung infection. I will assess MSC effect on survival, spread of infection and extent of lung tissue damage, as well as defining those genes wh ose expression in the lung is changed as a consequence of therapy. My goal is to shed light on the mechanisms by which MSCs achieve their beneficial effects, which should facilitate the pathway to their use in the clinic.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Discovering the antibody maturation defects in original antigenic sin to improve Influenza and Dengue vaccine design, and improving techniques for antibody cloning.
Funder: Wellcome Trust

Abstract: In this project we will be investigating how sometimes a previously infected immune system is worse at adapting to new infections than immune systems from animals that have not been infected at all. This is called Original antigenic sin (OAS) and is a medically important phenomenon that is likely to cause greater sickness in infections like Flu and Dengue and makes the protective effects of vaccines difficult to predict. OAS causes antibodies, the effector molecules of the immune system, to bind weakly. First we will determine if the antibody maturing organs are altered in OAS. Then by studying the evolution of antibodies against different virus proteins we will show whether OAS is caused because an antibody system committed to recognize a certain virus has lost the flexibility to adapt and strongly recognize other related viruses. These results will allow us then to test a new vaccine strategy to avoid OAS. Further results will also allow the interpretation of data from humans infe cted with flu, to help design better vaccines by understanding the effects of OAS. To help with the antibody analysis we will also improve an antibody cloning technique, which should be of benefit to many immunologists.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;3.4 VACCINES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Infection and immunity from a life course perspective: Life Study enhancement pilot study
Funder: Wellcome Trust

Abstract: We aim to understand how interactions between microorganisms, both pathogenic and theto understand how interactions between microorganisms, both pathogenic colonising microbiota, the immune system and clinical, social and behavioural factors durings during pregnancy, birth, infancy and childhood influence healtpregnancy, birth, infancy and childhood influence health throughout life. We therefore propose ange national birth cohort study that aims to recruit 90,000Infection and Immunity Enhancement to Life Study, a large national birth cohort study that aims to recruit 90,000 participants. This will enable collection of additional biological samples, from mothers and their babies at birth and from babies in their first year, to investigate causal pathways underlying adverse health outcomes over four interacting domains; the microbiota, acquisition of pathogens, host and microbial genomics and epigenetics, and the immune system.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Covering the tracks; peptidoglycan turnover, recovery and recycling in Gram positive bacterial pathogens and its role in evading the host immune system
Funder: Wellcome Trust

Abstract: The peptidoglycan sacculus is a key component of bacterial cell envelopes. During growth of the sacculus, material is not only added but constantly remodelled, releasing peptidoglycan fragments. Fragments released by bacterial pathogens are detected by host receptors, stimulating an immune response. The released muropeptides may also be sensed by other bacteria, triggering important events during infection. Gram negative bacteria have long been known to recover and recycle peptidoglycan, in part to evade the immune response of their hosts. Surprisingly, this phenomenon is almost completely unstudied in Gram positive bacteria, despite several extremely important pathogens occupying this group. In this project, I aim to identify the a putative peptidoglycan recycling pathway and to characterise the potential roles of involved components. I will then go on to assess the role that this pathway may play in the recycling of peptidoglycan, and ultimately its potential function in immune evasion. This would constitute a novel immune evasion mechanism in Gram positive bacteria. I also hope to characterise the roles of other muropeptides in bacterial communication and signalling during infection, and its relationship to peptidoglycan recycling. This could advance understanding of Gram positive infection and pathogenesis, potentially paving the way to novel antimicrobial compounds.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION