NIHRDataInsights/HRCSData huggingface dataset:
Title: Vasopressin vs Noradrenaline as Initial Therapy in Septic shock (VANISH) Trial
Funder: Department of Health (England)

Abstract: Objective: To determine if vasopressin is superior to noradrenaline when used as the initial vasopressor in the management of adult patients who have septic shock. The second objective is to assess if there is an interaction between vasopressin and corticosteroids when used in the treatment of septic shock.Design: A two stage investigation. 1). A small controlled trial to test for a biological interaction between vasopressin and corticosteroids and to act as a pilot study for investigation 2). A multi-centre double-blind factorial 2x2 randomised controlled trial.Investigation 1: 60 adult patients who have sepsis requiring vasopressor treatment. All patients will receive vasopressin as the initial vasopressor and then be randomised to receive hydrocortisone or placebo. Outcomes: Plasma levels of vasopressin, haemodynamic data, and vasopressin requirements and renal biomarkers levels between groups.Investigation 2: 292 patients who have sepsis requiring vasopressor treatment. Patients will be randomised to receive an intravenous infusion of either vasopressin (0-0.06 U/min) or noradrenaline (0-24 µg/min) If the maximum rate of this first study drug is reached patients will receive either intravenous hydrocortisone or placebo.Primary outcome: Days alive and free from renal failure within 28 days of randomisation.Secondary outcomes: 28-day, ICU and hospital mortality rates, other organ functions over 28 days (SOFA score) and renal biomarkers.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Improving the diagnosis and management of tuberculosis in children in the UK
Funder: Department of Health (England)

Abstract: Tuberculosis (TB) is a significant health problem also in the UK. It is unclear if the NICE recommendations for the management of latent TB in children are safe, and many paediatricians choose not to follow them. In collaboration with UK paediatricians caring for families affected by TB, Medicines for Children Research Network (MCRN) and the Health Protection Agency (HPA), we propose 1. to develop an extended data collection tool for TB in children, which can link a history of TB exposure to management and outcome, and 2. to conduct a multi-centre prospective cohort study of children exposed to TB to determine if it is safe not to give chemoprophylactic treatment to children who have a positive tuberculin skin test (TST) but a negative TB- specific blood test, as now recommended by NICE.This work will allow us to comprehensively characterise TB in children in the UK, validate the NICE recommendations and streamline diagnostic and treatment approaches. The established clinical network and database will serve as a platform for future studies of novel interventions.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: The effect of age at infection with common herpesviruses on immune function in children in a multi-ethnic population.
Funder: Wellcome Trust

Abstract: There is considerable evidence that early life infections influence subsequentrisk of immune disorders, but no large studies using laboratory evidence of infections in the first two years of life. This project will investigate the influence of age at infection with common herpesviruses on immune function. The study will be conducted within the multi-ethnic 'Born in Bradford' cohort.Blood samples will be taken at 12 and 24 months to estimate the age-specific prevalence of CMV, EBV and VZV infection. Congenital CMV infections will be identified using cord blood samples. Maternal CMV, EBV and VZV seroprevalence by ethnic group and country of birth will also be estimated using blood samples collected in pregnancy. Antibody response to measles, tetanus and pneumococcal vaccines will be measured at age 2 to provide measures of immune response, and the association with age at CMV and EBV infection will be quantified. This study will help elucidate the role of herpesvirus infections in immune development and demonstrate how age at infection may influence the risk of immune disorders in later life. It will provide unique population-based data on age-specific prevalence of these viruses and will help evaluate the potential benefits and risks of future vaccine programmes.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Infection and Immunity Research and Training for Uganda.
Funder: Wellcome Trust

Abstract: This is a capacity building proposal for research and training in infection and immunity for Uganda. Key goals are: 1. To create an academic partnership between two internationally-respected Ugandan Institutions: the Uganda Virus Research Institute (UVRI) and Makerere University. 2. Through this partnership, and regional and international collaborations, to provide an exceptional research platform for outstanding mentorship and research training. 3. Using this platform, to establ ish a UVRI/Makerere Research Training Programme to produce East African scientists capable of competing internationally for sustainable research funding. Opportunities for research experience will range from primary school to post-doctoral level: young people will be introduced to excellent science through Open Days and undergraduate internships; a competitive scheme of fellowships from Masters to post-doctoral level will offer an attractive academic career path to high-calibre Ugandan and East African scientists. Projects will address problems in infection and immunity relevant to the developing world. By offering an outstanding programme in Uganda, we aim to reduce the loss of talented Africans to northern institutions during the formative stages of their research career. By a programmatic approach, we aim to achieve a critical mass of expertise in infection and immunity in Uganda, beyond the reach of piecemeal funding strategies.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Molecular characterisation of NOD1 and NOD2 mediated ligand recognition and signal transduction.
Funder: Wellcome Trust

Abstract: Some bacteria and viruses, known as pathogens, can cause illness and disease. Humans recognise and respond to pathogens through an amazingly complex system known as the immune response. Part of the immune response uses special proteins to identify pathogens. Two examples are NOD1 and NOD2. These proteins are found inside cells and recognise parts of the cell wall of bacteria. My research will be performed at the University of Cambridge investigating how the NOD1 and NOD2 proteins become aware o f bacteria; how they help start an immune response; and how they can go wrong. I will work out the 3-dimensional shapes of important regions in NOD1 and NOD2 using a technique called X-ray crystallography. This gives clues to a protein s 3-dimensional shape by looking at patterns formed from X-ray pictures of protein crystals. I will also look at what other proteins NOD1 and NOD2 interact with in a cell when they find parts of the bacterial cell wall, as well as finding out how changes to NOD1 a nd NOD2 alter their function. Together this information will help the development of new drugs to fight bacterial infection and treatments for diseases such as the bowel disorder Crohn s disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Chronic innate immune activation in HIV-1 immunopathogenesis.
Funder: Wellcome Trust

Abstract: HIV-1 is the virus responsible for the fatal disease acquired immunodeficiency syndrome (AIDS), characterized by the inability of the immune system to respond to infections. It is still not known how HIV-1 causes such disease, limitating our possibilities to develop new treatments or a definitive cure. I utilize two comparative studies to investigate how HIV-1 interacts with the immune system. On one side, I compare the effect of HIV-1 and HIV-2 on the immune system. HIV-2 is a virus closely re lated to HIV-1, and causes AIDS only in rare cases. The immune system is capable of controlling HIV-2 replication, suggesting that HIV-2 is significantly less pathogenic than HIV-1. This renders HIV-2 an important comparative tool to understand the mechanisms of HIV-1 pathogenesis. On the other side, I study the effect of HIV-1 on immune cells from humans and chimpanzees. Chimpanzees are the natural host of HIV-1, which replicates at high levels in these animals without causing AIDS. Thus, chim panzees cells respond to the virus differently than humans , even though they can be similarly infected. Identifying the key events of the pathogenic interaction of HIV-1 with the human immune system may help us understand how to manipulate them for therapeutic purposes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Human T lymphocyte responses in Japanese encephalitis.
Funder: Wellcome Trust

Abstract: The mosquito-transmitted virus Japanese encephalitis virus (JEV) is a leading cause of viral encephalitis, a disabling and often lethal condition characterised by severe inflammation of the brain. Japanese encephalitis (JE) looks likely to remain a public health problem. Less than 1% of infections are symptomatic, leading to the important question of what the difference is between individuals who develop JE and those who are asymptomatically infected. Previous work by my Indian supervisor Profes sor Satchidanandam has shown that there is reduced production of the important immune effector molecule interferon-gamma in response to JEV that correlates with residual disability in patients who have recovered from JE. This fellowship will extend Professor Satchidanandam s earlier work by examining in more detail exactly which parts of the virus the human immune system responds to. This will be done in subjects with previous disease, asymptomatically infected subjects and patients with acut e JE. I will also look at responses to the live JEV vaccine, a model system in which there is active viral replication but no disease. Responses will be compared between disease and health, and between subjects who have had previous dengue fever which cross-reacts with JEV. This last point has implications for vaccine effectiveness.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Multiparameter flow cytometry : application to the study of infection and immunity.
Funder: Wellcome Trust

Abstract: A number of substances exhibit the property of fluorescence, namely they adsorb light at one wavelength and then emit it at a higher wavelength. This property has been widely used for tagging, and hence tracking or imaging biological structures, such as antibodies, cancer cells, viruses etc. A key piece of equipment in this field is the flow cytometer, which takes cells one at a time, passes them through one or several laser beams of light, at particular wavelengths, and then measures the fluo rescent light they emit. The information is collected by a computer, and can be used to give information on what type of cells are present, or to follow the progress of a chemical or biological process within the cell, such as viral infection, or protein breakdown. This equipment is now part of the standard repertoire of all major laboratories involved in the study of infection and immunity. This application requests a new flow cytometer for the Division of Infection and Immunity at UCL, to repl ace an older and now obsolete instrument.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Exploring the impact of vertically acquired HIV infection on the quality of humoral immunity in early adulthood .
Funder: Wellcome Trust

Abstract: Millions of children are infected with HIV through mother-to child transmission. Anti-viral therapy, where available, enables children to survive into adulthood; however, the impact of childhood HIV infection on the development of the immune system is unknown. This must be understood to ensure that these children receive optimal care to reduce the impact of this global disease. In this study we will look at how HIV infection in childhood affects: the development of immunological memory the development of natural immunity to the common bacteria pneumococcus, to which this population are particularly susceptible the quality of immune protection provided by pneumococcal vaccines. To determine which effects are the generic consequences of HIV infection and which effects occur specifically in individuals infected from birth, a comparison between young adults infected at birth, those infected in adulthood and uninfected individuals will be made. This information will be u sed to anticipate the medical needs of increasing numbers of children with HIV infection now entering adulthood. In addition, it will lay the foundations for future studies to explore the role of timely treatment of HIV infection in childhood to minimise the effect of HIV infection on a developing immune system.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Impact of early infectious and microbial exposures on the development of immunity and allergic inflammatory disease in children living in a tropical region of Ecuador.
Funder: Wellcome Trust

Abstract: Exposures to geohelminth and other infectious and microbial substances in early life provide important signals for the development and regulation of human immunity and are likely to affect the later development of allergic and other inflammatory diseases. Geohelminth infections and enteric microbes are likely to affect also immune responses to vaccines, particularly those administered via the oral route. A birth cohort of 2,300 infants will be used to examine the role of early life infectiou s and microbial exposures on: 1. The development of immunity in early life in the Tropics, 2. The development of protective immunity to vaccines in infancy and childhood. 3. The developmen of inflammation (i.e. allergic sensitization) in childhood, 4. The development of allergic inflammatory diseases, specifically, asthma and eczema, in childhood. 5. Explore gene-geohelminth interactions in the development of allergic sensitization and allergic inflammatory diseases


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Mediators of regulation and immunity in helminth infections.
Funder: Wellcome Trust

Abstract: Over 2 billion people in the world today are infected with helminth parasites, such as hookworms, filarial and schistosome parasites. In addition, nematode infections of livestock are highly prevalent in developed countries. Drug treatments are available, but provide only short-term respite before reinfection. This proposal seeks to identify general scientific principles underpinning the ability of parasites to neutralize host immunity, and the individual molecular parasite mediators responsi ble. We have found that both a mouse gut parasite, and an important human parasite, are able to expand a cell type within the immune system which is normally responsible for suppressing untoward reactions to self-antigens and innocuous substances such as food materials. We have also identified the molecular pathway by which one of these parasites is able to manipulate the host immune system. The proposal is to explore in both detail and breadth, the components of this immune suppression, lookin g both at the events following parasite infection in the mouse, and also the products released from parasites which modulate host immunity. Such products are likely to be effective vaccine antigens. The project also aims to demonstrate individual parasite molecules with potential to treat allergy and autoimmunity.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Systematic analysis of genes and gene networks that mediate differential macrophage response to Toxoplasma gondii and inflammatory stimuli
Funder: Wellcome Trust

Abstract: AJ and C57BL/6J mice exhibit variable susceptibility to many infectious and inflammatory diseases, including toxoplasmosis. The AXB/BXA recombinant inbred mice, derived from AJ and C57BL/6J, have stable and virtually homozygous genomes, and are ideal for identifying genomic regions modulating AJ and C57BL/6J phenotypic differences. Using thesemice, we identified quantitative trait loci (QTL) mediating variable macrophage response to inflammatory and infectious agents. Besides the QTL on chromosome 5 and 6 thatregulate mRNA splicing or editing, we observed individual QTL that mediate the expression of several genes (eQTL hotspots) on chromosome 12 and 15, on chromosome X, and onchromosome 2, 10 and 13, in response to IFNã/TNFá, CpG, and Toxoplasma, respectively. Additionally, we identified QTL on chromosome 2 and 3 that modulate Toxoplasma gene expression or proliferation. Furthermore, functional and shRNA analyses, revealed Ddx1 as a regulator for IFNã/TNFá-induced macrophage nitric oxide levels. We propose to build on these observations to: 1. Identify the genes that mediate macrophage transcriptional response to Toxoplasma, IFNã/TNFá, and CpG. 2. Identify the mouse genes that regulate Toxoplasma gene expression and growth. 3. Functionally characterize mRNA splicing and editing in macrophages. 4. Use this dataset to collaborate with groups working on other intracellular pathogens.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Defining liver-homing CD8+ T cells which sense bacteria
Funder: Wellcome Trust

Abstract: The overall aim of this research is to discover how the immune response contains persistent pathogens and how such pathogens evade immune responses. In particular I focus on hepatitis C virus (HCV), an infection which affects nearly 200 million people globally and is a major cause of liver disease. During the last fellowship we defined a number of key features which affect the way that CD8+ killer T cells interact with the virus to protect certain individuals against disease. In doing so we discovered an unexpected feature of the T cells which are responding to viruses in the liver. This group of T cells have distinct functions, which comprise release of molecules which have a role in tissue healing together with conventional antiviral factors. In the renewal of this fellowship I will define the full functional repertoire of these cells and their role in protection against viruses and liver disease. I aim to establish how such cells are turned on and off, and how they interact wi th infected liver cells. Finally, I will use mouse models of persistent infection to track antiviral T cells over time in tissues, and establish their overall importance in protection against disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: The Trypanosome flagellar pocket -functions and adaptations in differentiation, pathogenicity and immune evasion.
Funder: Wellcome Trust

Abstract: African trypanosomes are a type of single celled parasite. They are transmitted by the bite of the tsetse fly and cause African Sleeping Sickness in humans, and nagana in cattle. African Sleeping Sickness causes over 50000 deaths each year and the economic consequences of nagana are devastating to rural communities. Cellular architecture is particularly important for single celled organisms The goal of my research is to gain a better understanding of how trypanosomes use a specialised inv agination of their cell body called the flagellar pocket (FP) as the host/parasite and vector/parasite interface to sense, interact and respond to their environment. In the first part of the project, I will investigate structural features and possible unidentified roles of the FP in the transmissible form of trypanosome by building a detailed 3-dimensional model of the FP. I will then relate the FP architecture to specific roles of the FP. In the second part of the project, I will use adv anced genetic, molecular biological and live cell microscopy to ask: i) how are specific types of proteins are retained within the FP? ii) how are they released in response to the environmental changes experienced in the tsetse fly?


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: The regulation of B cell responses during malaria infections.
Funder: Wellcome Trust

Abstract: Malaria, caused by Plasmodium parasites, remains one of the most important infectious diseases for humans, affecting ~250 million people annually and causing >750,000 deaths. Although people living in endemic areas develop immunity to the most severe forms of the disease, immunity takes multiple infections to develop and is short-lived in the absence of repetitive exposure to parasite. The literature provides strong evidence that the generation of optimal antibody responses (humoral immunity) is impaired during malarial infections. We propose to examine the mechanisms by which antibody responses are regulated during malaria infections in mice. We will genetically modify Plasmodium parasites to permit us (for the first time) to track, analyze, and visualize (within the live mouse, by microscopy) individual B lymphocytes as they respond to the infection. We will test our hypothesis that the release of large amounts of Plasmodium protein antigens can impair the generation of long-lived an tibody secreting cells. We hope these experiments will advance our understanding of how B cell responses are regulated during malaria infection, and guide our thoughts as to how more effective immune responses might be promoted.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: Integrated studies of the targets, regulation and consequences of human immunity to malaria.
Funder: Wellcome Trust

Abstract: Finding what protects children from malaria requires us to know who are protected and who are susceptible. There is no test for this, so we need to follow individuals over long periods of time to see who gets ill and how severe the illness is. Our group has set up the mechanisms for following children in this way and for analysing the information. This proposal seeks funding to continue and develop this approach. With this framework we will identify: (1) the molecules on the surface of the two stages of the parasite that are open to attack: the free stage that has to enter red blood cells and then the surfaces of those cells, which are modified by the parasite; (2) the ways in which these responses are controlled and regulated by the host; (3) the way the parasite changes in terms of the amount and type of its constituent molecules in different times and places and under different levels of transmission. We will then (4) apply mathematical models to this information to underst and these changes and to predict the effects of different levels of transmission and immunity on the parasite and on the disease which it causes.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFLAMMATORY AND IMMUNE SYSTEM;INFECTION