NIHRDataInsights/HRCSData huggingface dataset:
Title: Genetical metabolomics: correlating genotype, metabolotype and phenotype in African trypanosomes
Funder: Wellcome Trust

Abstract: Trypanosoma brucei and related tsetse-transmitted parasites cause significant morbidity and mortality in humans and other animals in sub-Saharan Africa. Thedevastating human disease, African sleeping sickness, threatens millions of people in some of the poorest, most remote areas of the world, and the relatedcattle disease is of huge economic importance. Together these diseases significantly impact on the economy and development of affected countries. There is a desperate need for a deeper understanding of the biology of these parasites, which can then be exploited for the development of novel approachesto combat these diseases. Here I propose to examine the nature of the parasite's metabolism for a number of reasons: (1) there are several unique features of trypanosome metabolism, (2) metabolism can underpin phenotypic variation, (3) currently little is known about how trypanosomes control their metabolism and (4) metabolic pathways can be novel drug targets. The approach I propose is to combine genome-wide forward genetics with metabolomics analysis. This approach will allow me to ascertain how genetic variation


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Investigating the downstream effectors of the cAMP signalling pathway in Trypanosoma brucei as potential drug targets
Funder: Wellcome Trust

Abstract: Current drug treatment options in trypanosomiasis are old, toxic and highly ineffective. Signalling transduction pathways have been shown to have important cellular functions and are therefore good pharmacological targets. The metabolism of cyclic adenosine monophosphate (cAMP) has recently been validated as a drug target in T. brucei. The phosphodiesterase inhibitor CpdA,used in the validation, was fatal to bloodstream forms. However, the downstream effectors of cAMP activity in trypanosomes are unknown. We intend to use reverse genetics, genomics, proteomics and metabolomics to elucidate potential pathways targeted by changes in cellular cAMP levels. Several genes have already been validated as reducing CpdA-sensitivity when knocked down through RNAi and we will study the expression, phosphorylation and localisation of the encoded proteins to understand their role in cAMP-regulated processes. We will try to identify further cellular components of the cAMP pathways by co-immunoprecipitation with these proteins, by comparative proteomics at various cAMP concentrations and by genomic analysis


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Molecular and Cellular Basis of Infection.
Funder: Wellcome Trust

Abstract: EBNA3C is a viral protein expressed in human B cells that have been transformed into lymphoblastoid cell lines (LCL) by infection with Epstein-Barr virus. EBNA3C is encoded by one of three related genes (EBNA3A, EBNA3B and EBNA3C), the products of which function as transcription factors regulating host cell genes. A recent exon microarray experiment in our lab identified a small number of B cell genes whose expression is very substantially altered (up to 60-fold changes were seen) by 'switching on' a conditional EBNA3C encoded by recombinant EBV in LCLs. Several of these genes (eg COBLL1, ADAM28 and ADAMDEC1) are repressed by EBNA3C and at least one gene(AICDA) is activated by EBNA3C. We have found that COBLL1 expression is repressed just as dramatically and with similar kinetics shortly after the infection of primary B cells by EBV - indicating that the conditional EBNA3C cell system is likely to be an accurate model for the processes involved in repression during normal infection of primary B cells. . The aim of this project is to use these genes as model targets of EBNA3C and determine the molecular mechanisms underpinning the epigenetic regulation of transcription associated with this large nuclear viral protein.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Characterisation of the Type Three Secretion System Effector NleG
Funder: Wellcome Trust

Abstract: Enterohaemorrhagic (EHEC) and enteropathogenic (EPEC) Escherichia coli, which share an infection strategy with the mouse-specific pathogen Citrobacter rodentium, colonise the human intestine is conferred by a Type III secretion system that translocates bacterial 'effector' proteins into enterocytes, wherethey subvert cellular pathways and central organelles. The focus of this project is the NleG effectors, which mimic the structure andfunction of eukaryotic RING finger/U-box ubiquitin E3 ligases. While EHEC contains 9 NleG orthologs, EPEC strain E2348/69 and C. rodentium contain one and three homologs respectively. The targets and role in virulence of the NleGs remain unknown. During Bevin's rotation we found that EHEC NleG targets the nucleus, resulting in diminished staining intensity of histone H3, while NleG7 is found diffused in the cytosol. The goals of this project are to: 1. Determine the intracellular trafficking of the NleGs 2. Identify the NleGs' substrate proteins and the role of the NleGs' in cell signalling 3. Determine the impact of the NleGs on nuclear and cytosolic proteins' ubiquitylation and turnover 4. Determine the role of NleGs during infection using in vivo models


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Cholinergic regulation of immunity to parasitic nematode infection
Funder: Wellcome Trust

Abstract: We have recently demonstrated that the M3 muscarinic receptor is important foroptimal induction of Th2 responses and expulsion of the nematode parasite Nippostrongylus brasiliensis after primary and secondary infection. We therefore hypothesize that acetylcholine (ACh) produced by cells of the innateor adaptive immune system promotes responses which are crucial for parasite expulsion. The key goals of this project are to determine the cellular source of ACh which affects immune function, assess the functional consequence of production of ACh and tissue-specific effects during nematode infection, determine the factors which regulate synthesis and release of this mediator, and examine whether immune responsiveness is altered by manipulating endogenous levels of ACh both in vitro and in vivo, the latter in a murine model of allergic airway inflammation. We will also assess the ability of parasite secretory acetylcholinesterases to modulate and polarise immune responses in vitro and in vivo. The development of M3 receptor-selective agonists is currently the goal of many academic and industrial laboratories. This study will determine whether these drugs could also enhance immune function, and thus be applied to a range of pathophysiological conditions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Identifying bacterial regulatory determinants of Mycobacterium marinum-zebrafish infection
Funder: Wellcome Trust

Abstract: The success of Mycobacterium tuberculosis (Mtb), which causes tuberculosis in humans, can be attributed mainly to its ability to establish lifelong, asymptomatic latent infection within the host from which it can reactivate. Two-component signal transduction systems (TCSS), which regulate many physiological processes in bacteria, have been implicated in Mtb virulence buttheir precise roles are unclear. The key goals of the project will be: (1) to use the experimentally tractable, natural infection model provided by the M. marinum-zebrafish system to interrogate the role of TCSS in mycobacterial infection to obtain information relevant to their role in human tuberculosis. This will be achieved by investigating the effect of mutating 11 of the M. marinum TCSS on its pathogenesis in zebrafish infection models and evaluating how this affects interactions with the innate immune system. (2) To investigate the hypoxic nature of zebrafish granulomas using a chemical hypoxia sensor. (3) To investigate the temporal induction of gene expression during infection by constructing TCSS regulon reporters and developing transcriptional profiling methods to study changes in M. marinum gene expression during infection.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Investigating mechanisms of interactions between viral proteins and the cellular endocytic machinery.
Funder: Wellcome Trust

Abstract: CD4 is a crucial immunological receptor of a T helper lymphocyte (Th) and is maintained on the cell surface of the inactive cell via its interaction with Lymphocyte specifickinase (Lck). Upon activation of the lymphocyte, presumably triggered by phosphorylation of the receptor, this interaction is altered and CD4 becomes internalised by clathrin-mediated endocytosis (CME) through its dileucine internalisation motif binding to the AP2 clathrin adaptor complex. It has been shown that Nef, a small accessory protein of HIV-1, decreases cellsurface levels of CD4 in infected Th cells, thus preventing superinfection and facilitating virus release. It has been proposed that Nef achieves this by cross-linking CD4 to AP2 to facilitate CME of the receptor, even when


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Investigation of the mechanisms used by Vaccinia virus protein C6 to modulate the host immune response and contribute to virus virulence.
Funder: Wellcome Trust

Abstract: This project aims to understand the mechanisms used by Vaccinia virus (VACV) protein C6 to modulate the host immune response. Specifically, how C6 inhibits type I interferon (IFN)- induced gene expression, the function of the interaction between C6 and the cellular protein SMARCc1, and the contribution of different C6 interactions to virulence in vivo. The subset of IFN-induced genes whose expression is altered by C6 will firstlybe determined. Key events in the signalling pathway required for the IFN-dependent induction of gene expression will be analysed in the presence of C6 to determine where inhibition by C6 occurs. SMARCc1 is a component of the mammalian SWI/SNF complex involved in chromatin


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Infection, Immunology and Translational Medicine-'Towards the development of auniversal influenza vaccine:Investigation of heterosubtypic humoral and cellular immune responses to influenza induced by vaccincation with viral
Funder: Wellcome Trust

Abstract: Seasonal influenza epidemics and pandemics are associated with a non-trivial mortality, morbidity and carry a heavy socioeconomic burden. Vaccination is still the primary strategy for the prevention and control of influenza despite the limitations of currently licensed vaccines and their requirement of periodic reformulation and annual revaccination of at-risk individuals. A first generation T-cell inducing influenza vaccine developed at the Jenner Institute has demonstrated partial efficacy in a human trial. However, there is further workto be done in terms of targeting other conserved antigenic sites that can efficaciously provide heterosubtypic B cell immunity between multiple strains of influenza. We hypothesise that by targeting both arms of the adaptive immune system through rational vaccine design this could provide the highest level of protection against seasonal and pandemic flu. I will assess this by (i) designing new viral vector vaccines that targetcellular and humoral immunity, (ii) testing appropriate regimens in preclinical studies, (iii) measuring induced immunity to influenza antigens and (iv) delineating the mechanisms of B cell memory induction. As we are interested in assessing the use of these candidate vaccines in combination with or as a booster to seasonal influenza vaccination I will investigate a best in class' regimen including our novel vaccine.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Influence of host genetics and Mycobacterium tuberculosis strain variation on macrophage function and TB clinical outcome.
Funder: Wellcome Trust

Abstract: We currently do not understand the factors which determine if a person can resist TB infection and disease, or will develop the severest forms of the disease. It is likely differences between peoples immune systems and differences between the bacteria both play a role. Our hypothesis is that differences in peoples immune cells determine how they respond to infection with different types of TB bacteria and ultimately if the immune cells kill the bacteria, or the bacteria thrive and cause disease in the lungs, or in the worst cases, spread to other parts of body, causing more severe disease. This fellowship will investigate: 1. Whether variation in genes of cells responsible for bacterial killing (called macrophages), contribute to people developing different types of TB. 2. How differences in the killing capacity of macrophages affect the disease. 3. Whether different strains of TB bacteria are better at evading the immune system of an individual and are therefore more likely to spread to other parts of the body outside the lungs. Together, these findings will help to obtain a comprehensive understanding of how human genetics macrophage killing ability and TB strain contribute to the development of different clinical forms of TB.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Assessment of the neutralising ability and infection enhancement properties of monoclonal antibodies to Dengue virus.
Funder: Wellcome Trust

Abstract: Dengue is a viral disease that is spread by mosquitoes in tropical and sub-tropical regions worldwide. There are estimated to be 50-100 million infections every year. five percent of people with dengue develop severe disease. These patients can develop very low blood pressure, bleeding and fluid in the lungs. There are currently no medicines to treat dengue and no vaccines to prevent infection. There are four different types of dengue and unfortunately, infection with one type does not protect a gainst getting another type of dengue. Indeed, the second time a person gets dengue, they are more likely to develop severe disease. This is thought to be a result of the body's immune response failing to kill the virus on the second infection effectively, and instead causing a large amount of inflammation. It is the inflammation that causes the severe disease. This has made developing a vaccine difficult. In this project, I will use the blood from patients recovering from dengue infection an d assess its ability to kill virus and cause the dangerous inflammation. I am hoping to find parts of the immune response that would make a good vaccine by killing virus effectively without the negative effects of inflammation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: The Role of DDX5 and DDX17 in the HIV-1 Life Cycle.
Funder: Wellcome Trust

Abstract: New drugs are urgently required to treat AIDS. There appears to be no vaccine imminently available and 40 million people are already infected. We know HIV grows inside certain cells and uses some of the cells proteins for its own purposes to help make new viruses. We have identified a number of these proteins which the cell can survive without, but the virus cannot. If we can block them from helping the virus we will stop new infectious viruses being produced. We want to understand this interact ion better so we can design inhibitors to develop into new drugs. Ultimately we will screen drug libraries (as we have done for other HIV viral RNA/protein interactions in collaboration with the Department of Chemistry) to seek new treatments for AIDS.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Structural investigation of the Hepatitis C Virus capsid assembly
Funder: Wellcome Trust

Abstract: Hepatitis C Virus infection can cause chronic liver pathologies such as cirrhosis and hepatocellular carcinoma. With at least 130 million people infected world wide, the drive to understand and treat this virus is pressing. The core protein is responsible for the formation of the capsid that protects the viral genome. However very little is known about the structural information of the capsid. This project aims to elucidate the three-dimensional structure of the capsid by electron microscopy and X-ray crystallography. Further biophysical characterisation of the capsid will help to further our understanding of the molecular details of this medically relevant virus. The project then aims to discover and characterise novel inhibitors of assembly as a potential antiviral therapy.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Combating Infectious Disease: Computational Approaches in Translational Science (CIDCATS) - 'Exploring a novel mechanism for antibacterial action in biofilms'
Funder: Wellcome Trust

Abstract: This project has two main strands. The first strand of activity is the application of computational methods (homology modelling, protein folding / threading) to develop a structural understanding of the mechanism of action ofan enzyme and to identify selective inhibitors of the protein activity by virtual screening or fragment-based methods. The initial target protein is a novel deacetylase (IcaB) which has been identified on the cell surface of Staphylococcus epidermidis and is implicated in biofilm development. The computational work will complement ongoing structural studies of the protein. The second strand of work is to develop methods for characterising real and virtual libraries of fragments, designed to provide novel three-dimensional shapes and chemistries.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Combating Infectious Disease: Computational Approaches in Translational Science (CIDCATS) - 'Application of plasma technology for the elimination of intracellular infections in vitro'
Funder: Wellcome Trust

Abstract: Currently, limited approaches are available to treat infections due to inherent and acquired resistance to existing drugs. Ionised gas or "plasma", the fourth state of matter, is of interest for biomedicine for the production of reactive species, electrons, ions and UV light. Plasmas have been demonstrated to have antimicrobial properties. They can eliminate free-living microorganisms in a time- and dose-dependent fashion; however, it is unknown whether they could clear intracellular infections without damaging the eukaryotic host cell. In this project, the student will address the hypothesis that an atmospheric pressure dielectric barrier discharge (AP-DBD) plasma jet can eliminate intracellular pathogens in macrophages without affecting the integrity and viability of the host cell. This will be a proof-of-principle study using intracellular growth within a macrophage of the bacterial pathogen Salmonella enterica in vitro as a model. We will define parameters for reproducible plasma treatment with AP-DBD plasma jet and will identify the main biological


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: INFECTION
Title: Combating Infectious Disease: Computational Approaches in Translational Science (CIDCATS) - 'Modelling RNA regulatory networks in infectious disease'
Funder: Wellcome Trust

Abstract: The strength and duration of the innate immune response is regulated at the post-transcriptional level by miRNAs. miR-132 has been previously shown to suppress the anti-viral response. Interestingly, a miR-132 predicted target is ARGONAUTE-2 (AGO2), a protein involved in miRNA biogenesis and function. These findings create an opportunity to investigate the interaction between miR-132 and AGO2 in the context of the innate immune response. We aim to study the effect of miR-132 on the functional activity of AGO2 in an experiment-and-modelling coupled approach by (a) measuring the abundance of relevant components of the miR-132/AGO2 interaction system in vitro and ex vivo, and (b) building an agent-based model (ABM) of the interaction in the context of viral infection and the immune response.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Combating Infectious Disease: Computational Approaches in Translational Science 'Investigation of Chlamydia trachomatis PmpD and OmcB proteins as candidate vaccine immunogens and adhesins using structural and invivo techniqu
Funder: Wellcome Trust

Abstract: Chlamydia trachomatis, an obligate intracellular bacterium, is the leading cause of preventable blindness worldwide, affecting between 300-500 million people, and is also the most common sexually transmitted disease with over 90 million new cases reported annually. Development of a vaccine has not been prioritized, probably due to the availability of antibiotics to treat the disease, difficulties in culture and genetic manipulation, and a limited understanding of the factors involved in host cell binding. The project aims to investigate two proteins as candidate vaccine immunogens, which are also implicated in chlamydial epithelial cell attachment - polymorphic membrane protein D (PmpD) and outer membrane complex B protein (OmcB). Initially, expression, purification and structure determination of the proteins will be carried out using X-ray crystallography to elucidate the nature of potential antigenic fragments. These in vitro and in silico approaches will be complemented by in vivo studies on C57BL/6 mice using identified recombinant PmpD and OmcB subunits as vaccine immunogens. Co-crystallisation experiments with PmpD and OmcB recombinant proteins and their putative ligands will be carried out to elucidate binding mechanisms that may facilitate the design of novel blocking agents and inhibitors.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Combating Infectious Disease: Computational Approaches in Translational Science (CIDCATS) - 'Templated self-assembly of nanocontainers with applications in virology and drug delivery
Funder: Wellcome Trust

Abstract: This PhD project will address the development of a self-assembly kinetic modelfor ssRNA viruses incorporating the cooperative roles of genomic RNA. Potential synthetic nanocontainers will be then designed that mimic viral capsids: for which the cargo assists encapsidation. A major component will comprise investigation of the roles of packaging signals in ensuring robustness of assembly, and assessment of the impact of ostensible antiviral strategies targeting these signals.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION