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St George's, University of London
Country: United Kingdom
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144 Projects, page 1 of 29
  • Funder: UKRI Project Code: G0500628
    Funder Contribution: 264,336 GBP
    Partners: SGUL

    HIV infection causes disease by progressively depleting the number of a particular type of immune cells, ?CD4 cells?. We do not fully understand how infection results in loss of CD4 cells over time. Although HIV infects and destroys CD4 cells directly, the body normally just makes more cells to replace the lost ones. We believe that what determines how HIV affects the body?s CD4 cells is the exact type of cell it infects. There are several sub-types of CD4 cells. Different strains of virus prefer to infect different sub-types of CD4 cell according to the receptors (like locking devices) on the cell surface. Two receptors, ?CCR5? and ?CXCR4?, appear particularly important. We hypothesise that the interaction between the viral CCR5/CXCR4 preference (?tropism?), the type of cell infected and the speed at which those cells are dividing determines the long-term effect of HIV on CD4 cell numbers. To investigate this concept, we will measure how fast different sub-types of CD4 cells are dividing and disappearing within the body. Although much has been learnt from investigating cells and viruses in test tubes, answering such questions about CD4 loss can only be done by studying virus and CD4 cells within the body of people infected with HIV. We have recently developed a way of doing this using glucose containing an excess of deuterium. Deuterium is a naturally-occurring non-radioactive form (or isotope) of hydrogen which behaves exactly like hydrogen but can be measured using a mass spectrometer. We will give deuterium-labelled glucose (which is harmless) as a drink (half-hourly for 10 hours) to people with HIV infection, then take blood samples over the following 3 weeks. The glucose is used by dividing, but not non-dividing, cells to make new DNA. By separating the cells into their subtypes and measuring the deuterium in their DNA using a mass spectrometer, we can measure how fast CD4 subtypes divide and how long they survive in the body. We will also test the virus in the bloodstream for its CCR5/CXCR4 tropism. We will compare the results to those from a group of people without HIV infection. We will use these measurements to create a mathematical picture or ?model? of how HIV interacts with different immune cells to explain why CD4 cells are destroyed slowly over time and why changes in viral tropism trigger accelerated loss of CD4 cells.

  • Funder: UKRI Project Code: BB/D01882X/1
    Funder Contribution: 250,920 GBP
    Partners: SGUL

    FtsK is a multifunctional enzyme with the key role of coupling bacterial chromosome segregation and cell division. It is fixed to the DNA septum, a ring structure separating daughter cells, and functions as an ATP-driven DNA motor to pump chromosomal DNA through the closing septal ring. Moreover, it interacts with topo IV, an enzyme that separates topologically interlocked chromosomes and whose activity is blocked by quinolone drugs. These agents are widely used to treat infections caused by Streptococcus pneumoniae and other Gram-positive pathogens. Quinolones trap a topo IV-DNA complex that is converted into a lethal double stranded DNA break by motor proteins that track on DNA. Despite its fundamental scientific and pharmaceutical importance, little is known about topo IV, its interactions with FtsK and quinolones. By using a soluble truncated FtsK protein that retains the DNA motor activity, we aim to study how pneumococcal FtsK directs and modulates topo IV and its targeting by quinolones. The work will lead to significant advances in our understanding of chromosome segregation and cell division, and how antimicrobial quinolones disrupt these processes. In the longer term, the work should aid the development of more effective antibacterials.

  • Funder: UKRI Project Code: MR/J01477X/1
    Funder Contribution: 454,041 GBP
    Partners: SGUL

    Buruli ulcer is a neglected tropical disease caused by infection with Mycobacterium ulcerans (Mu) which is common in rural parts of West African countries including Ghana. It causes large, disfiguring skin ulcers mainly in children aged 5 to 15 years although any age can be affected. Access to treatment in rural areas is limited and many cases present late because of fear, suspicion about conventional medicine and the economic consequences for poor families. The disease is highly focal and in Ghana, where these investigations will be carried out, it is not seen at all in the North, most cases occurring in particular parts of the Ashanti Region. The mode of transmission remains unknown but there have been major advances in understanding the mechanism of disease since the establishment of the WHO Buruli ulcer initiative in 1998 together with improved diagnosis and management. The aim of the proposed studies is to identify markers predictive of a rapid response to antibiotic treatment and to investigate the pathogenesis of paradoxical reactions and oedematous lesions in Mu disease. When someone is infected with Mu, the first sign is a nodule under the skin which gradually enlarges and breaks down in the centre to form an ulcer. This is because Mu produces a toxin that spreads outwards and damages subcutaneous tissue. In about 15% of cases the skin around the ulcer is swollen with oedema, that is fluid in the tissue, and in this situation the ulcer enlarges more rapidly so that it may involve a whole limb for example. In recent years it has been found that instead of removing ulcers by extensive surgery it is possible to heal them by antibiotic treatment for 8 weeks with daily tablets and intramuscular injections. This is unpleasant, particularly for children, and it would be better if the treatment could be limited to a shorter time. Our previous studies suggest that it may be possible to do investigations at the beginning of treatment that distinguish people who need only 4 weeks antibiotic treatment. A wide range of tests will be investigated in detail to identify markers for people in whom the infection is at an early stage with low numbers of the Mu bacteria and low levels of the toxin in the skin. During antibiotic treatment the rate of healing will be measured carefully to find out which markers are most reliable and practical for use in countries where Buruli ulcer is endemic. After antibiotic treatment some patients develop new areas of inflammation or a sudden increase in the size of a healing ulcer, giving the impression that the infection is still active. It is not known what causes these paradoxical reactions but it is thought that there is an increasing immune response to residual dead Mu organisms in the tissue. In the proposed studies the immune response to Mu will be investigated serially during antibiotic treatment and when patients develop a paradoxical reaction. Oedematous disease is the most severe form of Buruli ulcer. The cause of it is not known but a likely explanation is that larger than normal amounts of the Mu toxin mycolactone are produced and diffuse away from the initial site of infection. This will be investigated by measuring mycolactone in the skin of patients and studying mycolactone production by the strain of Mu cultured from patients with this form of the disease.

  • Funder: UKRI Project Code: MR/T030925/1
    Funder Contribution: 970,232 GBP
    Partners: SGUL

    Group B Streptococcus (GBS) is a bacterium (a bug) that causes serious infections (iGBS) in young infants in all regions of the world. Worldwide in 2015 it was estimated that there were at least 319 000 infants under 3 months of age with invasive GBS disease (iGBS), resulting in 90 000 deaths and at least 10 000 children with long term disabilities. Around 20% of all pregnant women carry GBS in their bowel and vagina and babies mostly acquire the GBS bacteria from their mothers around the time of birth. The global burden of iGBS is therefore high and the options for prevention are currently limited. An effective vaccine that could be given to pregnant women has the greatest potential to benefit mothers and babies worldwide and such vaccines are now being tested in clinical trials, including in pregnant women. To license a new vaccine so that it can be recommended for routine use normally requires evidence that the vaccine is safe and effective in preventing the disease. This usually means undertaking a large trial in which the new vaccine is given to half of the subjects, who are then compared to the other half who did not receive the new vaccine. Such trials are expensive and time-consuming to perform. Another way of licensing a new vaccine is to show that when it is given to relevant groups of people it is able to produce levels of immunity (usually measured as antibody) in their blood that are known to result in protection. Such levels are called serocorrelates (because they "correlate" with protection). Although there is considerable evidence that high levels of antibody against GBS in pregnant women do correlate with protection against iGBS disease in their babies, the precise level (the serocorrelate) is not currently known - we aim to establish this in a case-control study. In order to do this we will collect a small sample of cord blood from new-born babies at delivery and store these samples in the freezer. With the cooperation of paediatricians and microbiologists we will be alerted if any of the babies develop iGBS disease over the next 3 months (they are the cases). For those who do develop iGBS, we can then compare the antibody levels in their cord blood samples with the antibody levels in the cord blood samples of other babies who were also exposed to GBS at delivery, but did not develop iGBS disease (the controls) - we are in the process of recruiting the controls in a separate study. Although GBS is the most common cause of serious early infections in UK babies it is still relatively rare overall, so we will need to follow around 180 000 babies in order to find at least 170 babies with iGBS disease (of which 100 will have disease with the most common type, STIII) which is around the number we need to establish the serocorrelates of protection. However, it may also be possible to obtain blood at the time of disease in iGBS cases, and from this, work out what their antibody level would have been in their cord blood. If so, we can reduce significantly (by half) the number of cord blood samples we need to collect. We will test this possibility in the first part of the study. To maximise the efficiency of the study, and minimise the costs, we will embed our study in a large, already funded study which is looking at different ways of screening for GBS (the GBS3 Trial).

  • Funder: UKRI Project Code: MR/P019978/2
    Funder Contribution: 275,886 GBP
    Partners: SGUL

    Tuberculosis (TB) causes over 1.5 million deaths each year and there is increasing resistance to antibiotics used to treat the disease. There are few new anti-TB drugs, and new approaches to treating patients are required. In TB the immune system is overactive, and inflammation damages the lung tissues. This is a complex process involving a range of our own immune cells. Understanding this process better should help to identify opportunities to develop new treatments that reduce inflammation and tissue damage. There is evidence that platelets, cells in the blood that are usually associated with blood clotting, are also important in regulating the immune system. They have been shown to be important in many different diseases that involve inflammation including cancer and arthritis, but very little is known about their role and their importance in TB. Background work for this project shows that platelets increase levels of markers of inflammation that are produced by cells of the immune system when they are infected with TB. I also found that patients with TB have higher concentrations of platelet-derived factors in their blood compared to healthy controls, and these levels decreased when the patients were given TB treatment. The main idea behind my research, which is that platelets are important in regulating the human immune system's response to tuberculosis, is supported by these results. My project has 2 parts: 1. I shall study the effect of platelets on production of markers of inflammation by monocytes, which are cells of the human immune system. Using techniques I have used in my previous work, I will obtain monocytes and platelets from blood taken from healthy donors. I will measure inflammatory markers produced by monocytes with and without platelets following TB infection, as well as measuring gene expression from these cells using a technique called qPCR. I will look at how platelets may affect the immune cells including studying the importance of direct contact between the platelets and the immune cells as a way of regulating inflammation and TB bacterial growth. 2. I shall then focus on the clinical importance of platelet activation in patients with TB before, during, and after anti-TB treatment. I will examine targets suggested by the work above to confirm that their effects can be demonstrated in patients as well as in cells in laboratory experiments. I shall recruit 120 adult TB patients (drug-sensitive disease only) and the same number of age- and sex-matched healthy controls. All subjects will be HIV-negative. I will collect clinical and X-ray data about the patients and any scarring left by infection with tuberculosis. Patients will have a test called spirometry to measure lung function. This will be done for TB patients at the end of their treatment, and in healthy controls for comparison. 30mls blood will be taken from patients before treatment, after 14 and 56 days, and at the end of treatment. The blood will be used to measure platelet activation and some will be frozen at -70C for later measurement of platelet factors, and the remainder used to obtain platelet and white blood cell counts. Some patients will have a procedure called a bronchoscopy as part of their clinical care. Fluid from the lungs will be obtained from these patients, and the cells and fluid tested for evidence of platelet activity. Together, these results will allow me to understand what is happening in terms of platelets and the immune response in TB patients. In summary, this project will produce data about the role of platelets in TB. This is a new and exciting area that might affect TB treatment in the future. It will also provide me with an excellent clinical and laboratory science training that I need to progress as a clinical academic.