NIHRDataInsights/HRCSData huggingface dataset:
Title: A new approach to the treatment of pneumoccoal induced toxaemia using drugs that selectively inhibit the activity of the pneumococal toxin, pneumolysin.
Funder: Wellcome Trust

Abstract: We aim to produce a patented pre-clinical lead compound, and a patented chemically distinct backup, which will be attractive for further development for use in treatment of pneumococcal diseases. Streptococcus pneumoniae causes a very high number of cases of pneumonia, meningitis and bacteraemia, worldwide. Current treatments are inadequate, not least because they fail to address the toxaemia due to the toxin, pneumolysin. In a new treatment approach, we identified five small molecules that inhibit pneumolysin and are effective in vivo. The project aims, through a programme of medicinal chemistry, combined with in vitro and in vivo testing, to optimise these lead structures to maximise their efficacy, pharmacokinetics and toxicology. The project has ten workpackages designed to achieve the aim in three years, via three milestones. For M1 (month 18), cycles of chemical synthesis, tests of effectiveness in vitro and in vivo and pharmacology (PK/ADME), will identify lead series compounds. These will receive in-depth pharmacological and toxicological profiling, and further efficacy assays, to reach M2 (month 27); namely provision of one or two compounds for stage 3. These will have further toxicity testing and assay of efficacy before preparation of a portfolio for investors, describing the final compound (M3, month 36).


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Blood-feeding insects semiochemical analytical facility.
Funder: Wellcome Trust

Abstract: Our research group at Keele University currently uses a range of analytical equipment to identify the chemicals that insect disease vectors use to communicate with each other (e.g. sex pheromones) and their environment (e.g. potential food sources or places to lay eggs). We are using this information to develop new methods to control these disease vectors. The equipment was originally bought with Wellcome Trust funding 15 years ago and is now effectively obsolete; it is no longer supported by the manufacturers and is consequently liable to catastrophic failure leaving current projects vulnerable. We need to replace this equipment with modern versions that will allow us to continue existing projects and bring additional benefits such as improved sensitivity, data-processing and enhanced access. These improvements will facilitate and enhance ongoing and planned projects over the next 5 -10 years. To maximise the scientific return on the equipment capital investment we are also seekin g funding for a technician who will carry out routine analyses for the applicants and help with data analysis. This will enable access for a greater number of staff and a greater range of projects than is currently possible and will greatly enhance our opportunities for collaborations with other laboratories.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Protein-protein and protein-ligand interactions in the glycolytic pathway.
Funder: Wellcome Trust

Abstract: T. brucei is a small parasite that causes African trypanisomiasis, commonly known as sleeping sickness, in humans and nagana in cattle in Africa. It has life cycle stages in both the mammalian host and the tsetse fly vector and makes several morphological and biochemical changes when migrating between the two. The mechanisms and control of cell proliferation and differentiation is essential to the life cycle of the parasite and thus understanding the details of these processes is important for the discovery of new drug targets to combat this disease. The genome of T. brucei and other related parasites have been sequenced and many biochemical and genetic tools are available to enable molecular dissection of the genes involved in cell division and differentiation. Previous studies of the structural mechanics of cell division have provided us with some understanding of the temporal and spatial organisation of the cell organelle and cytoskeletal structures [1]. However, much more needs to be understood about the three-dimensional spatial organisation of the cytoskeletal structures and how co-ordination of assembly and cytokinesis is performed in order to better understand the phenotypes presented by the molecular dissection experiments. During my 10 week project I used scanning electron microscopy (SEM), transmission electron microscopy (TEM), immunofluorescence microscopy, and video microscopy to gain more insight into cytoskeletal organisation during cell division, and to compare the processes in the procyclic and the bloodstream forms of the parasite. SEM and video microscopy revealed important differences between the procyclic and bloodstream forms during cell division regarding attachment and growth of the new flagellum, the degree of staggering of the daughter cells during cleavage furrow ingression and the nature of the cytoplasmic connection between the two daughter cells, present just before cell abscission. Fluorescent labelling of ?-tubulin and TEM images provided some evidence for the presence of microtubules in the cytoplasmic connection in the procyclic form, although more evidence is needed.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Bacterial epidemiology, evolution and bioinformatics for public health.
Funder: Wellcome Trust

Abstract: Control of sexually-transmitted infections is a health priority and depends on a knowledge of how they spread within communities. One issue, we will address, is the extent of sexual contact between men who have sex with men and heterosexual groups. This is important as HIV is much more common in male homosexuals than heterosexuals and a low rate of sexual contact between men who have sex with men and heterosexual groups slows the transfer of HIV into heterosexuals. The issue will be addressed. Chlamydia trachomatis causes the most prevalent sexually-transmitted infection worldwide. Many important questions about the epidemiology of Chlamydia infections remain unanswered and we will develop new tools that allow these questions to be addressed. Further work will aim to understand the geographic origin and the patterns of global spread of the pathogen Burkholderia pseudomallei, the causative agent of melioidosis. We maintain important international databases that allow clinical and basic scientists to precisely identify strains of major pathogens via the internet (e.g. MRSA strains). These databases and analysis tools are widely used and we will continue to maintain and improve them. We are also integrating spatial mapping, tools that allow field workers to interact with databases using mobile phones.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Wellcome Trust Clinical PhD Programme at the University of Liverpool: 'Early goal directed therapy for adult bacterial meningitis in Malawi.'
Funder: Wellcome Trust

Abstract: The mortality rate associated with adult bacterial meningitis (ABM) in Malawi is 54% and has not been impacted by two adjunctive interventions (Dexamethasone and Glycerol). Death from paediatric meningitis in Malawi has been reduced significantly using early antibiotics and specialist in hospital care. Resuscitation delivered through early goal directed therapy (EGDT) has shown a relative mortality reduction from adult sepsis in developed countries by 25% (Absolute Reduction 9%). We hypothesise that early resuscitation of adults with suspected ABM, using an EGDT bundle of interventions which are appropriate for resource limited settings, will significantly improve immediate and long term survival. Key goals: 1. We will test the bundle in a before/after study with sequentially phased prospective control and intervention groups in the new Wellcome Trust supported adult emergency and trauma centre (AETC) at Queen Elizabeth Hospital. The bundle will include nurse led rapid assessment and triage and targeted delivery of resuscitation to all subjects with suspected ABM using clear, achievable goal directed targets. Subjects will be excluded retrospectively if an alternative diagnosis is made subsequently. 2. We will assess the following study end points between the two groups: mortality (acute and at 6 weeks), neurological disability, epilepsy and hearing loss.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Diarrhoea diagnostic device: from bench to bedside.
Funder: Wellcome Trust

Abstract: Clostridium difficile infection is a global problem that afflicts over 50,000 people annually in England and Wales, 8000 of whom die. Managing C. difficile costs Europe 3B/year. It is the most common bacterial cause of hospital acquired diarrhoea. Rapid diagnosis would assist therapy, facilitate recovery and saving lives and money. With support from the Wellcome Trust, we have shown that C. difficile infection can be diagnosed by analysis of gases from stool. The work culminated in our building laboratory based prototype medical devices that respond to such gases but which require a skilled operative. The main goal is to develop our technology so that an unskilled operative in a hospital setting can simply place a stool sample in the diarrhoea diagnostic device and within less than 15 minutes obtain a readout of the presence or absence of C. difficile in the stool. Then, to assess the prototype, a large study is proposed in two major hospitals in the South-West, to analyse stool from patients with C. difficile and with other causes of diarrhoea. Our ultimate goal is to deliver an investment-ready point-of-care device which can then be rapidly brought to the market place to improve patient care.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Investigating the functions of remnant mitochondria of human parasitic protozoa.
Funder: Wellcome Trust

Abstract: We will test the hypothesis that the essential role of microsporidian mitosomes is in cellular Fe/S protein biosynthesis, using subcellular fractionation to provide material for in vitro assays of organelle function, complemented by genetic and biochemical studies, and by quantitative immunolocalisation of key proteins at the electron microscope (EM) level. The ultrastructure of microsporidian mitosomes will be elucidated using sophisticated EM methods, to provide a detailed understanding of mi tosome biogenesis and inheritance during parasite division. The transport proteins used to support the metabolism and energy needs of microsporidian and Giardia mitosomes will be identified and functionally characterized to provide further insights into the functions of these organelles. The characterisation of microsporidian transport proteins that are expressed on the parasite surface will, in conjunction with genomic-based inferences of parasite metabolism, provide clues to parasite-host me tabolic inter-dependencies that may be essential for the growth and survival of these obligate intracellular parasites.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Defining the role of the chemokine CXCL10 in determining traversal of trypanosomes across the blood-brain barrier in experimental and human trypanosomiasis.
Funder: Wellcome Trust

Abstract: Human African trypanosomiasis (HAT), or sleeping sickness, is a devastating disease caused by parasites called trypanosomes. Untreated the disease is always fatal. HAT occurs in 36 countries in sub-Saharan Africa, 60 million people are at risk from the disease, and it kills tens of thousands of people every year. The disease has two stages-the early stage, in which the parasites multiply in the bloodstream, and the late-stage, in which the parasites cross the blood-brain barrier (BBB) and invad e the central nervous system (CNS), often causing a fatal inflammatory reaction. The most commonly used drug (melarsoprol) for CNS disease kills 5% of all patients who receive it. It is essential to understand how trypanosomes cross the BBB both for more accurate staging of the disease and developing more effective drugs. This Wellcome Trust-funded project will use established rodent models of sleeping sickness to investigate whether a key chemical messenger called a chemokine (CXCL10) facilita tes the passage of trypanosomes across the BBB. We will also carry out parallel studies in human patients with HAT in Africa to determine whether levels of CXCL10 increase when the CNS stage has occurred. These combined studies should significantly increase our potential to diagnose and treat HAT.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: How Inactive is Inactive Tuberculosis?.
Funder: Wellcome Trust

Abstract: Latent tuberculosis infection (LTBI) is said to affect 2 billion people and refers to the development of a detectable immune response following exposure to tuberculosis. Although people with LTBI are completely well some may harbour bacteria in an inactive state and are subsequently at risk of developing active tuberculosis following reactivation. Conversely many may have eliminated infection but still demonstrate an immune response. Global eradication of tuberculosis therefore requires identif ication of those at risk and new ways to treat them. The presence of nodules and scars on chest X-ray ( inactive tuberculosis) and HIV infection both increase risk of developing active tuberculosis. We propose to define the frequency and significance of these chest x-ray abnormalities in people with early HIV infection in Cape Town. Of the 1600 screened we plan to follow the immune response of 125 though treatment. For 36 of them we will assess the metabolic activity of these lesions by examining glucose uptake using positron emission tomography scanning. We will then assess the relationship between the metabolic activity and the type of immune response the individual mounts before and during treatment. Through this we hope to learn more about latent tuberculosis and how best to manage it.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Molecular mechanisms of encystation.
Funder: Wellcome Trust

Abstract: A large variety of unicellular protists is present in all ecosystems Many feed on smaller organisms such as bacteria, but some have developed a parasitic life style. They can be ingested from contaminated water, injected into the bloodstream through insect bites, or enter the body through skin lesions. They feed on host cells and cause sickness and often death by destroying host tissues. Although protist pathogens can be killed by antibiotics, many form dormant cysts with a thick protective wal l. As cysts they are impossible to kill and cause chronic or recurrent infection. We recently identified some of the proteins that control cyst formation in a non-pathogenic protist Polyspondylium pallidum. In contrast to most protists, this organism can easily be genetically manipulated and cultured. We want to use P.pallidum to identify the proteins that regulate cyst formation and germination. From genome sequencing projects and further experimentation we can subsequently determine whether pa thogenic protists use the same proteins. By manipulating the activity of these proteins by drugs we can either prevent encystation, or cause cysts to germinate and then be killed by antibiotics.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Developing and applying theoretical frameworks in the epidemiology of sexually transmitted infections.
Funder: Wellcome Trust

Abstract: Sexually transmitted infections (STIs) including HIV cause a great deal of disease and deaths globally but are very difficult to prevent, partly because cases are difficult to find and treat and partly because sexual behaviours are difficult to change. To improve programmes to control STIs a good understanding of the factors determining how they spread and who is at risk of infection is very useful. In this proposed research we will explore the biology of STIs and the behavior of those at risk i n a range of different populations. A major part of the programme will be to identify how best to model the chains of contacts set up by the formation of sexual partnerships within populations. By fitting models to data we will estimate model inputs and then we will explore the potential impact of new interventions. These interventions will including anti HIV drugs to prevent the spread of HIV. Models are currently used to estimate the extent of the HIV epidemic and who is at risk of HIV infecti on, these models will be further developed to take account of the changing patterns of the HIV epidemic and the increase in data available.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: INFECTION
Title: The role of newly identified proteins with gelatinase activity expressed in human fallopian tubes after infection with Neisseria gonorrhoeae
Funder: Wellcome Trust

Abstract: Neisseria gonorrhoeae (gonococcus) causes the sexually transmitted disease gonorrhoea. Infection in women can lead to a clinical condition called pelvic inflammatory disease, which can often involve the Fallopian tubes (FT) and eventually cause chronic pelvic pain and damage that results in ectopic pregnancy and infertility. These outcomes are recognised as important issues for women s health world-wide and they are worsened by the increasing numbers of infected individuals seeking treatment and also by the emergence of antibiotic resistance bacteria, thus making it more difficult to treat infection. Gonococcal infection therefore is a considerable problem for public health and social services in both developed and developing countries. The focus of our research is to understand how the bacterium causes infection in the FT. Uniquely; we are fortunate for our studies to have access to a large amount of FT tissue from women. Our plan is to examine in the laboratory the mechanisms by w hich the bacteria change the environment of the infected FT and damage the tissue, which has serious consequences for women s reproductive health. Understanding how these changes occur will provide us with information that will be useful for the development of new preventative and curative treatments.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Modulation of host immunity by human cytomegalovirus.
Funder: Wellcome Trust

Abstract: Cytomegalovirus (CMV) is related to the herpes virus that causes cold sores. Like herpes, CMV is carried for life and can reactivate at any time to cause disease. Most people worldwide are infected with CMV, yet do not know. However, in hospitals CMV is well-known and a major problem. CMV can cause severe multi-organ disease in individuals whose immune system has been compromised by infection (e.g. HIV AIDS), drugs (for bone marrow, heart or kidney transplant) and most distressingly following in fection of the foetus in the womb. CMV is by far the most complex of any human virus with >181 genes. We need to understand better what all these genes are up to in us. Natural Killer (NK) cells are crucial in fighting infection (CMV in particular) and cancers. They detect signals on the surface of other cells that indicate whether things are normal or not. If not, NK cells are fierce, rapidly killing problem cells and triggering the immune system too. Only recently have we really begun to u nderstand exactly what signals activate NK cells. CMV research is clearly important in its own right, yet it is also helping us understand how NK cells work.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: NleH effectors of EPEC and EHEC block apoptosis by subverting Bax inhibitor-1.
Funder: Wellcome Trust

Abstract: Ecscherichia coli constitute part of the normal gut flora, however several strains acquired additional genes that enable them to cause disease. Enteropathogenic (EPEC) and enterohaemorrhagic Escherichai coli (EHEC, known E. coli O157) cause disease when they inject specific virulence proteins, known as effectors, into the mammalian cell. EPEC is the leading cause of infantile diarrhoea in developing countries. EHEC (particularly E. coli O157:H7), which is predominant in developed countries, caus e diarrhoea, haemorrhagic colitis and haemolytic uraemic syndrome (HUS); the young and the elderly are most at risk. EHEC-induced HUS is the leading cause of acute paediatric renal failure in the UK and USA. Better understanding of the role of virulence factors is essential for the development of new specific and effective treatments. We recently found that the effector protein NleH blocks signal transduction pathways leading to programmed cell death, which under physiological conditions contrib utes to homeostatic functions as well as elimination of infected cells. The aim of this study is to investigate the mechanism by which NleH inhibits cell death. The outcome of this investigation will enhance our knowledge of EPEC and EHEC infection and the physiological programmed cell death pathways, which remain poorly understood.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Mechanisms of severe acute influenza consortium (MOSAIC).
Funder: Wellcome Trust

Abstract: We have assembled a team of 42 investigators from England and Scotland, bringing their combined expertise to the intensive study of a group of hospitalised patients with influenza. The integration and coordination of all the studies is a logistic challenge, and case ascertainment, definition and sample collection underpins the collaborative network. On this base, some of the UK s best clinical and basic research groups will conduct an integrated study of influenza virology, host RNA transcri ptome and of cellular and humoral immune responses to influenza viral infection. The same patients will also be tested for levels of soluble mediators (cytokines and chemokines) in various body fluids, so allowing the cross-correlation of the clinical features, virology and RNA transcription profiles on a population basis. All of this will be linked to the study of the host genome and the bacterial and viral microbiota present in the respiratory tract as disease evolves, using 16s RNA methods to characterise bacterial populations without the need for culture. The collaborative study of a single set of hospitalised individuals will lead to a wealth of information and the cross correlations between different research outputs will provide unprecedented opportunities for understanding the pathogenesis of influenza.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION