NIHRDataInsights/HRCSData huggingface dataset:
Title: Molecular mechanisms of TCR signal initiation, propagation and regulation determining T cell fate.
Funder: Wellcome Trust

Abstract: T lymphocytes are at the centre of the immune system to rid our body of infectious pathogens. This is dramatically emphasised by AIDS, in which some T lymphocytes are destroyed by HIV. T lymphocytes receive signals from incoming bacteria, viruses and parasite to rapidly destroy them, while avoiding erroneous attacks of the same immune system to body tissues, which might provoke an auto-immunity disease. Both infections and autoimmunity may severely affect well-being of those afflicted by these diseases and impose a heavy burden on health resources. Progress in understanding precisely the underlying mechanisms of human immunity makes vaccins work more effectively and design of novel therapies prevent or cure triggering of auto-immunity (e.g., diabetes, multiple sclerosis). During the past twenty years the research of my laboratory has contributed to discover several elemental components of the signalling machinery through which T lymphocytes are alerted and command adequate respons es to eliminate the invading infectous agent or, if defective, provoque auto-immunity. This reaserch has helped and will continue finding better and more adequate therapies not only to infections and autoimmunity but also improve organ transplantation and fight against cancer.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;3.4 VACCINES
Health categories: INFECTION
Title: Identifying the contribution of the prevalent, diverse, phage-derived gtr operons to O-antigen modification and Salmonella diversity, virulence and persistence.
Funder: Wellcome Trust

Abstract: The bacterium Salmonella enterica is a common cause of food poisoning in the developed world, which is usually a self-limiting disease consisting mainly of diarrhoea and vomiting (gastroenteritis). Salmonella however consists of genetically related but slightly different bacterial serovars that each have slightly different infectious traits, and some variants lead to more serious (systemic) disease ending in death. Thus, Salmonella infections lead to significant economic and health care costs , and health concerns for humans and live stock. To combat the occurrence of these infections by developing a vaccine or eradicating these bacteria from the food chain, or even to trace outbreaks of infection, requires a great understanding of this bacterium and how it interacts with they environment and its human and animal hosts. This includes how strains evolve, how it persists in the animal reservoir, how they spreads between hosts, and why the host immune system fails to eradicate Salmone lla strains. In this project a group of proteins will be analyzed that appear to facilitate the success of Salmonella by modifying the bacterial surface. How these proteins work, what they do exactly and why they are so important will be examined.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: The molecular basis of parasitism in the nematode Strongyloides ratti.
Funder: Wellcome Trust

Abstract: Nematode worms live inside the guts of people. A quarter of all people, mostly in the developing world, have worms There are drugs that can be used to kill these worms, but these drugs are becoming less effective the more that they are used. In the future new drugs need to be discovered. Nematode worms that live in the guts of people have evolved special tricks to live in such an odd environment. The work we are doing is trying to discover these tricks, especially what molecules they use to do this. We will do this by using a nematode worm that has a stage that lives in guts and another stage that lives in the soil. We will compare these two forms - any molecules that are the same in these two forms are molecules it takes to be a worm. But, molecules that only the gut worm uses must be behind one of the tricks it uses to live in guts. By knowing the molecules that the worms use to live inside people's guts, then in the future drugs that stop these molecules working might be able to kill these worms, but be safe to people.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Equipment only grant for Mass Spectrometers for proteomics, lipidomics and focused metabolomics research.
Funder: Wellcome Trust

Abstract: Biomedical research programmes at St Andrews University have attracted over 26 million of grant funding in the last five years, including 12.5 million from the Wellcome Trust. A further 5 million of Wellcome Trust funding was awarded towards a new 13 million building to expand biomedical research at St Andrews. A significant proportion of our research focuses on combating infectious disease, whose threat is expected to increase with more international travel and trade, transmission events fr om animal hosts, climate change effecting disease distribution and the development of drug-resistant diseases. For example, St Andrews scientists are looking for differences between many medically important pathogens and humans that can be exploited to develop urgently required new drugs against neglected diseases. They are also gaining a greater understanding of what happens when a virus infects people, what molecular interactions are occurring, and how this affects the severity of the dis ease, allowing novel approaches to drug discovery processes. Sophisticated modern mass spectrometers are important tools for studying these diseases at the molecular level. We can look at individual components of a biochemical process and, by analysing the pattern of the signals produced, interpret the data to provide insights into the disease process.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: INFECTION
Title: Coupling Influenza Genetic and Epidemiological Data through Mathematical Modelling.
Funder: Wellcome Trust

Abstract: To control an outbreak, we need to understand how transmission occurs. For example, is transmission fuelled by school children, who may have less immunity and more social contacts? To answer such questions, we need to reconstruct an 'infection tree' that shows who infects whom. This is usually done using data collected by doctors tracing the contacts that infected people have had when ill. This is extremely time consuming and could be potentially replaced by tracking the way the virus changes wh en passing from an individual to another. These changes act as a 'memory' of the chain of transmission followed by the viruses. Using this information, we can study how the virus evolves while growing inside the body and when passing to another individual. For this, we use new techniques that tell us not just the usual genetic fingerprints of the viruses inside an individual, but can also identify viral strains with a slightly different fingerprint due to copying errors. This will allow us to better understand the way the diversity of viruses is created and conserved, and to build computer models simulating how viruses evolve and are transmitted in a population.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Wolbachia as a defence against RNA viruses in insects.
Funder: Wellcome Trust

Abstract: Insects such as mosquitoes transmit some of the most important viral diseases of humans, animals and plants. Furthermore, viruses have been blamed for the decline of some beneficial insects such as honey bees. It was recently discovered that when fruit flies are infected with a bacterium called Wolbachia they become resistant to viruses. If this bacterium is transferred into mosquitoes, it can also prevent them from transmitting the virus that causes dengue fever in humans. This is important bec ause if Wolbachia was introduced into natural populations of insects, it might block the transmission of diseases by mosquitoes or protect beneficial insects from infection. This project will investigate how Wolbachia protects insects against viruses. We will study which step of the viral life cycle is affected by Wolbachia, which genes are involved in the protection against viruses, and whether viruses evolve to escape the effects of Wolbachia. Our results will be important for attempts to use Wolbachia to prevent disease transmission, and may suggest ways to increase the antiviral effects of Wolbachia. They will also provide insights into how the most diverse group of animals on earth, the insects, protect themselves against infection.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Defining the role of kynurenine pathway metabolites in the inflammatory response to trypanosome invasion of the CNS.
Funder: Wellcome Trust

Abstract: Human African trypanosomiasis (HAT), also known as sleeping sickness, is a devastating disease caused by parasites called trypanosomes. If untreated, or inadequately treated, the disease is always fatal. HAT occurs in 37 countries in sub-Saharan Africa, 60 million people are at risk from the disease, and it kills many thousands of people every year. The disease occurs in two stages-the early stage in which the trypanosomes multiply in the patient's bloodstream, and then the late stage in which t he parasites cross the blood-brain barrier (BBB) and invade the central nervous system (CNS), often causing a fatal inflammatory reaction in the brain. But the most commonly used drug (melarsoprol) for treating CNS disease actually 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 better drugs. This project will use an established rodent model of sleeping sickness to investigate wheth er a key metabolic pathway, called the kynurenine pathway, plays a major role in determining the passage of trypanosomes across the BBB leading to severe inflammation within the brain. These studies should significantly increase our potential to treat sleeping sickness with fewer toxic effects.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Functional analysis of the Plasmodium falciparum cGMP-dependent protein kinase.
Funder: Wellcome Trust

Abstract: Malaria kills approximately 1 million people each year. The parasite which causes the most lethal form of malaria - Plasmodium falciparum has developed resistance to previously effective drugs. There are also reports that the treatment of choice (ACTs) is taking longer to cure people in some parts of the world. It is essential that the anti-malarial drug discovery pipeline is productive. To produce effective drugs we need a detailed understanding of how the malaria parasite works at the molecu lar level; which of its biochemical pathways are important for its survival and are these sufficiently different from their human counterparts to be targeted safely by drugs? Our proposal is aimed at gaining a detailed understanding of a particular pathway in the malaria parasite the cGMP signalling pathway and specifically its main player: PfPKG. We have found that if we block the activity of PfPKG (a protein kinase) with inhibitors, malaria parasites are not able to escape from human red b lood cells to either cause disease or mediate transmission to mosquitoes. We have made progress in finding out how inhibition of PfPKG blocks parasite development, but in this proposal we want to elucidate the precise molecular details.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Protection against intestinal helminth infection: Role of the novel intestinal mucin MUC5AC .
Funder: Wellcome Trust

Abstract: Although often considered exotic, infections of both man and animals by roundworm parasites that live in the intestinal tract is extremely common and accounts for a considerable health burden to people (especially in the developing world) and animals (especially domesticated animals). Unfortunately, we are still unclear as to how our defence system clears these large parasites from the body. Mucus is believed to protect us from a variety of infectious agents (viruses, bacteria) that invade parts of the body such as our lungs, our intestines and genital tracts. The mucus is different at these different body sites and is specifically designed to fight the infections it encounters there. We have recently made a very surprising discovery that a mucin (an important component of the mucus) that is normally only ever found in the lungs, eye or stomach actually helps fight roundworm infection in the intestine. This was completely unexpected. We hope to discover exactly how this mucin called Muc5ac does this. This will help us develop new types of drug that can control these infections as we already know that resistance to drugs currently used to treat roundworm infection is rife in domestic animals and emerging in people.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Structure and Function of the phospholipase/sphingomyelinase PlcHR from P. aeruginosa.
Funder: Wellcome Trust

Abstract: The opportunistic pathogen Pseudomonas aeruginosa causes chronic infections of the respiratory system in cyctic fibrosis (CF) sufferers resulting in severe inflammation and permanent lung tissue damage. In spite of the development of improved treatments over the last years, these secondary infections remain the major cause of fatality in CF patients. In addition, P. aeruginosa is responsible for acute infections in immuno-compromised patients (i.e. people undergoing cancer chemotherapy) and pati ents with large, open wounds leading to wide-spread, life-threatening infections. We propose to investigate one of the major secreted virulence factors, a protein complex designated PlcHR. This complex has been shown to play a crucial role in pathogen-host interactions and infection. We will determine the enzymatic mechanism and the structural basis of biological action using a combination of biophysical and biochemical techniques including utilizing an exclusively designed novel library of c hemical compounds. Our studies will provide fundamental information required to improves existing therapies. In addition, the hits from our compound libraries will provide a starting point to develop novel specific inhibitors.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: The role of pneumolysin in the pathogenesis of Streptococcus pneumoniae infection and as a vaccine adjuvant.
Funder: Wellcome Trust

Abstract: Pneumolysin is a key virulence factor and damages host cells by forming pores in cell membranes. At low concentrations the toxin is also a powerful immune modulator and can enhance immunogenicity of other proteins. We have developed a non-toxic toxoid version of pneumolysin that retains its adjuvant activity. We will determine the effects of the toxin on pathogenesis of infection using animal models and in vitro assays and investigate the mechanism of adjuvant activity of the toxin. We will char acterize the effect of the purified toxin and toxoid both in vivo by use in vaccination studies and in vitro by effects on cytokine production by immune cells. There is evidence to suggest that the toxin is involved in the production of IL-17 that in turn affects neutrophil recruitment and clearance of the organism. IL-17 production in response to toxin from T-cells and the importance of this interaction will be determined in IL-17 knockout mice. The toxin has also interacts with Toll like recep tor 4 (TLR-4). The parts of the toxin involved in this interaction will be determined by mutagenesis approaches. The importance of TLR-4 will be determined by use of TLR-4 knockout mice and macrophages derived from these mice.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;3.4 VACCINES
Health categories: INFECTION
Title: An integrated screening strategy to develop inhibitors of Trypanosoma brucei RNA editing ligase 1.
Funder: Wellcome Trust

Abstract: Public health in developing countries suffers from devastating infectious diseases - one of the reasons for the so-called poverty trap . Many of these disease affect mainly the poor and have largely been neglected for drug development by the pharmaceutical industry. Among the most important neglected diseases are those caused by trypanosomatid parasites. Combined, African trypanosomes and various Leishmania species infect more than 2 million people every year. Around 16 million people are alr eady infected with American trypanosomes. Available drugs are often difficult to administer and have severe side effects but, if left untreated, human African trypanosomiasis ( sleeping sickness ) and visceral leishmaniasis are fatal. Better drugs are desperately needed. One promising approach in drug development is to identify a unique parasite enzyme and to then inhibit this enzyme with a drug. The enzyme s absence in humans will help avoid side effects. We previously identified such a uniq ue enzyme, RNA editing ligase , and showed that survival of the sleeping sickness parasite depends on it. In this application we propose to use computational as well as biochemical approaches to find strong inhibitors of this enzyme. Our hope is that such chemicals can then be developed into better drugs against diseases caused by trypanosomes.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Defining the population at risk of Plasmodium knowlesi malaria to complete thehuman malaria baseline in Asia
Funder: Wellcome Trust

Abstract: This proposal will allow the estimation of the global population at risk and disease burden of P. vivax malaria. Five themes support these central goals. (1) Unstable transmission mapping needs to be radically improved to support hybridisation of traditional burden estimation techniques with geostatistical methods in these lower transmission but highly populous areas. (2) Stable transmission mapping must also be achieved and a large proportion of the proposal concerns the development of new Baye sian MBG cartographic procedures to provide continuous endemicity surfaces for P. vivax. (3) Clinical incidence mapping in areas of unstable and stable transmission will also be conducted to allow objective determination of the most precise method of burden estimation for each nation. (4) G6PD prevalence mapping is also required and, when combined in a Bayesian decision-support framework with the new P. vivax endemicity maps, will enable statistical evidenced-based primaquine treatment policy in both control and elimination contexts. (5) Basic reproductive number under control (Rc) mapping to support elimination cartography, will require substantial development of available mathematical models for P. vivax transmission. The biology of P. vivax, including its ability to relapse from liver stages, has consequences for mapping, burden estimation and modelling that will require innovative solutions.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;4.4 POPULATION SCREENING
Health categories: INFECTION
Title: Defining the population at risk and burden of disease of Plasmodium vivax malaria.
Funder: Wellcome Trust

Abstract: New work has highlighted the public health importance of the Plasmodium vivax malaria parasite. Developing the science to map the disease and measure its burden worldwide is the main goal of this SRF renewal. The work will prioritize five areas. (1) Improving mapping techniques and accuracy in areas of relatively low risk, where the majority of the population at risk reside. (2) Developing new endemicity mapping techniques for those areas where the parasite is transmitted throughout the year and is a greater medical problem. (3) Developing methods to transform these maps into local numbers of cases for efficient health care planning. (4) Combining these incidence risk maps with maps of the prevalence of a genetic condition (G6PD deficiency) is then needed, to quantify the probability of such individuals suffering potentially life threatening reactions, following treatment with the only liver-stage curative drug available, primaquine. (5) Combining new mathematical models with these map s will then enable the mapping of a measure of the capacity for disease growth under current levels of control, which is essential to the control and elimination strategies for P. vivax, particularly in Asia. The biology of P. vivax makes all of this work a tremendous scientific challenge.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;4.4 POPULATION SCREENING
Health categories: INFECTION
Title: Wolbachia as a tool for the control of mosquito-borne disease.
Funder: Wellcome Trust

Abstract: Tropical diseases transmitted by mosquitoes, particularly malaria and dengue, represent some of the world s most serious public health problems It has recently been shown that the presence of certain strains of bacteria called Wolbachia, that live inside mosquito cells, can inhibit or completely block the development of malaria parasites or dengue viruses, and can switch on the mosquito s immune system; some of these immune genes are known to affect malaria parasite development. Wolbachia can a lso spread through mosquito populations by manipulating their reproduction, so they can provide a very attractive new disease control system. This project seeks to stimulate and optimize the development of Wolbachia-based disease control strategies by better understanding the mechanisms that underpin the pathogen inhibition interactions and the manipulation of reproduction by Wolbachia, and better understanding how insect immunity affects interactions between Wolbachia and its mosquito host.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFECTION
Title: Mechanisms and clinical relevance of GM-CSF s capacity to reverse C5a-mediated impairment of phagocytosis by neutrophils.
Funder: Wellcome Trust

Abstract: Patients in the intensive care unit (ICU) are at high risk of developing hospital infections. White blood cells (neutrophils) that destroy bugs work less efficiently in such patients. We can make these cells work again by adding a chemical (called GM-CSF) in the lab, but we don t know how GM-CSF works or whether it might help in real patients. This proposal addresses these issues. When GM-CSF works, it probably turns on chemical signals inside the white blood cell, which tell the cell to ea t bugs more efficiently. I shall determine which chemical signals are turned on by GM-CSF. This will tell us how GM-CSF is working, and should suggest ways of developing new treatments to improve white cell function. I shall also study white blood cells from other patients who receive GM-CSF as part of their medical care. I shall determine whether GM-CSF makes white blood cells eat bugs more efficiently. If it does, the proposal would naturally lead on to clinical trials aiming to see if GM-C SF can prevent hospital infections in the ICU.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION