NIHRDataInsights/HRCSData huggingface dataset:
Title: FluPro - a novel flu antiviral.
Funder: Wellcome Trust

Abstract: Influenza ranges from seasonal disease to catastrophic pandemics. Anti-flu measures include vaccines and antivirals. Vaccines have their problems as they act only against the current viruses and are ineffective against new pandemic strains. Further, the new H1N1 pandemic virus will have to be added as a fourth virus to the vaccine. The antivirals Tamiflu and Relenza act against all flu viruses, but there is already widespread resistance to Tamiflu. New measures are urgently needed. Our approach has been to isolate a natural antiviral. We call this protecting virus' or FluPro. The active principle is a small piece of the flu genetic material. This is delivered to the nose by a harmless version of the virus itself so only cells that flu infects get treated. FluPro has been tested in laboratory models where a single intranasal dose completely prevents disease caused by several different (and probably all) flu viruses. Post-infection treatment is also effective. FluPro tricks the infecting virus into making harmless virus (more FluPro) instead of the real thing, so reduces the infection and the spread of infection, and increases the amount of protection. Now we need to do further tests to justify carrying out human trials.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: INFECTION
Title: Wellcome Trust PhD Programme for Clinicians at the University of Dundee.
Funder: Wellcome Trust

Abstract: The incidence of resistance to antimonials, the first line treatment for visceral leishmaniasis, is rising steadily in Bihar, India. 28% of the tubewells in Bihar district are contaminated with arsenic at levels above the WHO recommended guideline. Arsenite has previously been used in laboratory settings to explore mechanisms of drug resistance to antimony. We propose that the arsenic contamination in the ground water in this area may have induced drug resistance in Leishmania donovani to antimonials. Furthermore arsenic's immunosuppressive properties may increase the severity of leishmaniasis and reduce the efficacy of antimonials through suppression of their immunological mechanisms of action. This study aims to explore the relationship between arsenic contamination of groundwater, leishmaniasis and antimonial resistance by answering the following questions. - Is it possible to induce cross resistance to antimonials in vitro by creating an arsenite resistant strain using concentrations of inorganic arsenic present in tube well water in Bihar? - How does the immunotoxicity of chronic exposure in vivo to arsenic affect the host's immune response to Leishmania? - How does the immunotoxicity of chronic exposure to arsenic in vivo affect the efficacy of antimonials?


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Resource centre for genomic epidemiology of malaria.
Funder: Wellcome Trust

Abstract: Our goal is to understand how natural genome variation in human, Plasmodium and Anopheles populations affects the epidemiology and biology of malaria, and to use this knowledge to develop more effective ways of controlling the disease. This requires a concerted effort by many research groups around the world. We propose to establish a resource centre that will support this community effort by: - developing genome technologies and statistical methodologies to underpin global efforts to inv estigate genome variation in human, Plasmodium and Anopheles populations - building informatics systems and open-source web software for integrating and sharing large genetic and epidemiological datasets, to enable malaria researchers around the world to collaborate effectively to investigate how genome variation affects patterns of disease and biological phenotypes - providing scientific leadership in trans-ethnic genome-wide association studies of human resistance to malaria, and in de veloping a global system for monitoring Plasmodium populations by next-generation sequencing.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: INFECTION
Title: An investigation into the regulation of the pro-apoptotic potassium channel, Kv2.1, by the hepatitis C virus NS5A protein.
Funder: Wellcome Trust

Abstract: The World Health Organisation estimates that 170 million people are infected with hepatitis C virus (HCV), with 3-4 million new cases each year. The virus survives in liver cells for many years before leading to disease resulting in both liver failure and cancer. However, we do not yet understand exactly how the virus manages to persist for such a long time. We have shown that a viral protein called NS5A can prevent the death of virus-infected cells, allowing the virus to persist in the liver. NS5A does this by inhibiting a cell protein (called Kv2.1) whose role is to allow the exit of potassium from the cell - this potassium loss would normally trigger cell death by a process called apoptosis. To understand exactly how NS5A blocks Kv2.1 activity we propose to study this at the biochemical and cellular level. This knowledge will be important both for a better understanding of how HCV persists but also in terms of drug development. A drug that blocked the ability of NS5A to inhibi t Kv2.1 would have the potential to prevent the long term persistence of the virus in patients and would therefore be of great clinical benefit.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: The role of CPSF6 in Protecting HIV-1 from Cell Autonomous Innate Immunity
Funder: Wellcome Trust

Abstract: We aim to extend our knowledge of innate immune restriction factors and definethe molecular details of the relationships between restriction factors and their viral encoded targets and antagonists. We aim to test the hypothesis that innate restriction has played a role in limiting the spread of non-pandemic lentiviruses in humans. We will also examine how pandemic HIV-1 M avoids restriction, focusing on tetherin as the most recently discovered and least well defined factor. Our work will consider how HIV-1 avoids triggering innate responses inhuman macrophages as well as seeking novel restriction factors in these cells. We will also examine whether non-primate lentiviruses and herpesviruses are restricted by tetherin


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;3.4 VACCINES
Health categories: INFECTION
Title: Characterisation of host virus interactions.
Funder: Wellcome Trust

Abstract: When viruses enter cells and infect them they meet and interact with a variety of proteins within the cell. Some cellular proteins, called co-factors, get used by the virus and help it infect the cell. Others, called restriction factors, attack the virus and defend the cell. Our work aims to understand how these interactions between the virus and the cell work and how viruses like HIV, the virus that causes AIDS, avoid or antagonise human restriction factors. We propose that comparing viruses th at successfully infect humans with those that do not will be helpful in this work. Importantly, human cells can be made immune to HIV infection by treating them with a protein called interferon. We propose to seek the restriction factors that are induced by interferon and to figure out how they work. We also aim to understand how HIV avoids setting off tripwires that exist within cells and normally trigger infected cells to make interferon and thus restriction factors to protect themselves. We b elieve that understanding how viruses escape restriction factors and how restriction factors work will aid the development of drugs that enhance innate defences and assist effective HIV vaccine design.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;3.4 VACCINES
Health categories: INFECTION
Title: ALPHA: Collaborative network for data analysis in African community-based, longitudinal HIV studies.
Funder: Wellcome Trust

Abstract: The project will maximise the usefulness of data collected by HIV study sites established in nine African communities. These studies have made repeated measurements of the HIV status of people living in well-defined geographical areas; recorded mortality, fertility and migration rates; and described trends in sexual behaviour, family composition and socio-economic consequences of the epidemic. Each site has independently developed its own data collection methods and a specific research agenda. Analyses produced in one study will be replicated using data from the others, showing whether findings are generalisable across different communities or peculiar to specific localities. The collaborative network will train local statisticians working in member studies in advanced analysis techniques, and will communicate research findings to policy makers in each country. In addition, studies will pool their data to generate powerful new information on infection patterns, risks and so cial consequences for national AIDS control programmes and agencies involved in forecasting epidemic spread and designing interventions. Planned studies include: the impacts of HIV on fertility; impact on mobility and mortality of children; description of sexual partnership formation and dissolution; and investigations of the impact of anti-retroviral therapy on mortality and new infection rates.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFECTION
Title: Role of the phase variable cell wall protein CwpV in C.difficile infection.
Funder: Wellcome Trust

Abstract: The bacterium Clostridium difficile can cause very serious infections involving severe diarrhoea which can be fatal. Incidence of infection has increased in recent years, which may be due to new hypervirulent strains . In this project we will investigate the properties of a protein CwpV which we find on the outer coat of the bacterium. The protein is not always on the bacterium; the bacteria can switch production of the protein on and off. This phenomenon, known as phase variation , is often s een in proteins that are important for disease. We will investigate the properties of the CwpV protein and ask if it is involved in helping the bacteria stick to the cells lining the gut. The work will involve biochemical studies and also experiments where hamsters are infected with C. difficile. By comparing animals infected with strains expressing normal levels of CwpV with those not expressing any CwpV, we will discover what role the protein has in disease. The work could have practical benef its in the long term. If we identify an essential process mediated by CwpV, drugs or vaccines could be designed to inhibit this activity and these might be used to treat or prevent C. difficile infection.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: CXCL8 Cleavage by SpyCEP in Invasive Streptococcal Infection.
Funder: Wellcome Trust

Abstract: Streptococcus pyogenes is the cause of severe necrotising fasciitis and is responsible for 400-500 deaths per year in the UK alone. White blood cells that normally fight infection (neutrophils) are prevented from attacking this bacterium, because it produces a unique enzyme that destroys key chemical messengers which recruit neutrophils to infected areas. The enzyme is called SpyCEP and our work has shown that this enzyme makes a big contribution S. pyogenes disease. Indeed, on its own SpyCEP ha s potential to convert a normally harmless bacterium to a killer flesh-eating bacterium. Given that SpyCEP is the key to understanding how S. pyogenes causes flesh eating infections , we now want to determine why that might be. We suspect that SpyCEP has an additional effect on neutrophils. The chemical messengers that normally switch on neutrophils are cut in two by SpyCEP. We believe that the cut chemical messengers fail to send the right signals to neutrophils, and may block the benefic ial effects of any remaining (un-cut) chemical messenger. This means that the neutrophils can no longer kill bacteria. Our hypothesis will be tested in a series of experiments to gain new insight into how S. pyogenes evades our immune response.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Elucidating within-host competition between malaria parasites using mathematical models and Bayesian statistics.
Funder: Wellcome Trust

Abstract: The blood stages of malaria infection determine how sick a person gets and how infectious they become, and consequently blood stage parasites are the target of various drugs and vaccine candidates. Reductionist biomedicine has revealed much about what determines the dynamics of blood stage infection. But while we are rich in details, it has not proved easy to fit mathematical models capable of explaining the patterns we see or predicting what we will see following particular perturbations. Mathe matical models have the virtue of making clear what we do not know and, if they are any good, of generating biological insight and demonstrating the likely effects on patient health, infectiousness and pathogen evolution of different treatment regimes. However, a vast number of mathematical models are consistent with the qualitative understanding of infection process we currently have. The aim of this project is to fit as many models as possible in order to find the ones that explain a very larg e body of data we have accumulated on rodent malaria. From the models that we have left we will be able to further our knowledge of malaria infections, aiding the evaluation of the short and long term consequences of various treatment regimes.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Extrachromosomal elements of Chlamydia: Development of an efficient transformation system for Chlamydia trachomatis.
Funder: Wellcome Trust

Abstract: The capability to manipulate and stably introduce DNA into E.coli heralded the new era of recombinant DNA technology and revolutionised the field of genetics. The technology was based on plasmids and bacteriophages, small circular DNA molecules that can be selected and copied. Although genetic manipulation has been extended to many microorganisms, a few human pathogens, including Chlamydia trachomatis, have remained refractory to this technology. This is because chlamydia, unlike free living vegetative bacteria such as E.coli can only be grown inside cells from animals. Studies have therefore been mainly of a descriptive nature, focussing on traditional cell and biochemical approaches. In this proposal we set out a plan to develop technology that will allow the routine genetic manipulation of C.trachomatis. We have fully characterised the plasmids and bacteriophages of Chlamydia and now propose to use these as a toolkit to develop geneitc manipulation technology for C.trachomatis . We propose to use new technologies that will give access to the specialised cellular compartment used by Chlamydia. Our key objective is to develop a DNA molecule that can be shuttled in and out of C.trachomatis and that will allow us to change the properties of this recalcitrant bacterium.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Optimising transcriptome subtraction technology to identify complicating infections in human hepatitis.
Funder: Wellcome Trust

Abstract: Severe liver disease, often necessitating transplantation, is frequently caused by viral infections. In certain cases where viruses are suspected, no known viruses are found using current diagnostic tests. New genome-era technology now allows us to determine all of the genetic material found in diseased tissue. Normal genes from healthy liver can be subtracted by computation from the list of all the genes found in a diseased liver. Once all of these normal human gene transcripts have been re moved, all of what remains is likely to be foreign. By repeating this process, using a large series of patients, a list of candidate disease-related genes can be identified. Diagnostic tests based on these disease-related genes will be developed to allow the screening of large numbers of healthy people against patients with different types of hepatitis. Ultimately, the screening of large numbers in both healthy and disease groups we will eventually reduce the list to genes from one or two candid ate pathogens. Careful systematic diagnostic assays will then be developed and the new risk factors of severe hepatitis identified allowing better control and treatment of this major global disease.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Optimising antimalarial combination therapies in an area coendemic for vivax and falciparum malaria.
Funder: Wellcome Trust

Abstract: Malaria affects more than quarter of a billion people in Asia, with P. vivax accounting for half of these cases. There is renewed enthusiasm for global efforts to eliminate malaria, but the challenge with P. vivax will be far greater than that for P. falciparum. Furthermore elimination will not be possible if the antimalarial drugs do not work. In the eastern region of Indonesia, strains of P. vivax have emerged which are resistant to conventional treatment with chloroquine. These parasites are now spreading across Asia and South America and undermining malaria control programmes. The research in this fellowship application will be conducted in Papua, Indonesia with the aim of developing the tools necessary to tackle drug resistant vivax malaria. In collaboration with partners from the Indonesian health authorities, we will help to optimise treatment guidelines for vivax and falciparum malaria and then monitor the impact and cost of our recommendations on the health and economics of th e local population.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Development of a PorA/FetA meningococcal vaccine for broad protection against meningococcal disease: progression from pre-clinical studies to Phase I clinical trials in humans.
Funder: Wellcome Trust

Abstract: Meningitis B is the leading cause of bacterial meningitis in the UK, causing 1500-2500 cases each year, and is also the leading infectious cause of death in childhood. Development of a successful vaccine has been hampered by variability in protein molecules on the surface of different strains of the Meningitis B germ which could be used as a vaccine, such that even if the vaccine works against one strain, it does not work against others. However, we have found that combinations of relatively few proteins are commonly associated with the germs that cause most of the disease. Funded by the Wellcome Trust we have been working with two of these proteins, known as PorA and FetA, and found that a combination of just 8 variants of the PorA protein and 4 variants of the FetA protein could protect against 79% of disease isolates circulating in Europe 2000 - 2002. In We have now begun to manufacture this vaccine for testing in humans and will generate additional data in the laboratory to support its future use. If the vaccine produces protective immune responses in humans, it could lead to development of a new strategy to prevent all meningococcal meningitis in children.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: 2nd open access supplement - £1,343
Funder: Wellcome Trust

Abstract: Following on from successful field feasibility trials in Brazil (Wellcome Trust University Translation Award 080961/Z/06/Z) we wish to show that the synthetic sex pheromone of the sandfly vector of VL can be deployed in the field to reduce VL incidence and infectiousness in domestic dogs, the reservoir of VL. Other key goals are to improve the synthesis of the sex pheromone to make it more efficient and reduce to an acceptable degree any impurities in the final product prior to registration. In preliminary field experiments we will compare the effect of two lure-and-kill strategies on numbers of sand flies in and around chicken sheds to determine which is the more lethal and sustainable. In one we will combine synthetic pheromone with Olyset® permethrin impregnated mosquito netting and in the other we will combine synthetic pheromone with ë-cyhalothrin applied as a residual spray. We will then, in an 18 month single-blinded cluster randomised intervention trial in Campo Grande, Mato Grosso do Sul in Brazil, determine the effect of the technology in reducing VL infection and infectiousness of the reservoir (dogs) and thus transmission to humans. We will also develop and implement a commercial strategy in collaboration with interested stakeholders including commercial entities, the Innovative Vector Control Consortium (IVCC), FioCruz and the Brazilian Health Ministry, to ensure the early exploitation of the technology in the event of a successful outcome to the trial.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Why some hosts have high parasite burdens and the implications for the design of sustainable control strategies.
Funder: Wellcome Trust

Abstract: Nematodes are one of the great neglected diseases: they cause disease and death in wildlife, livestock and humans in poor areas of the world. Most individuals harbour few parasites, but a small proportion of most animal populations carry disproportionately high numbers of parasites. The different burdens reflect variation in exposure (larval intake) and variation in the protective immune response mounted by the host. Thus, hosts with high parasite burdens may be unlucky, predisposed, or both. Control methods targeted at the heavily infected can be especially effective in reducing clinical disease and in reducing transmission to other members of the population in this and future generations. Some controls improve the host response (eg selective breeding or nutritional supplementation), whilst others directly reduce average exposure (eg grazing control). Determining the balance between variation in exposure and variation in host response is therefore critical to the selection of c ontrol strategies. Using novel data, new statistical techniques and new understanding of the host response we will build a model that allows the roles of exposure and host response to be distinguished and the best control combinations to be predicted.


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