NIHRDataInsights/HRCSData huggingface dataset:
Title: Integrating Infection Prevention into Health Care Delivery
Funder: Medical Research Council

Abstract: The vision in this grant is to develop a translational & applied research and training centre for improving health systems and health care delivery to address the challenge of health care associated infection (HCAI) and antibiotic resistance which are national health priorities. The vision brings together clinical, public health, academic and managerial expertise to drive forward translational research across secondary and primary care. The first objective is to embed infection prevention within NHS management, service delivery and organisational development. The second objective is to apply molecular epidemiology, molecular pathogenesis and rapid diagnostics to patient management, patient pathways and surveillance. Next the grant will investigate the development and utilization of infection surveillance schemes. The fourth objective is to optimize the management of antibiotics in the NHS. The fifth and final objective is to develop multidisciplinary capacity building in infection. The grant takes advantage of the full range of academic skills across diverse departments at Imperial College together with the skills at the Health Protection Agency and epidemiological, data management & behavioural science expertise of the industrial partner, dr Foster Intelligence. This sustainable research programme is designed to foster new leaders in infection research, infection management, in NHS organisational change, in infection surveillance, in antibiotic management both by developing skills of those in post and by training the next generation of personnel required to integrate infection prevention into health care delivery. It will interact with ongoing research initiatives across the Infection Theme at Imperial College to support development of academics interested in the applied molecular epidemiology and molecular pathogenesis of infection. The programme will be managed by a Management Board including senior staff at Imperial College and its associated NHS Trust which includes Prof S. Smith, Chief Executive and Head of the Faculty of Medicine and will be monitored externally via an International Advisory Board.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;8.1 ORGANISATION AND DELIVERY OF SERVICES;2.4 SURVEILLANCE AND DISTRIBUTION;7.3 MANAGEMENT AND DECISION MAKING
Health categories: INFECTION
Title: Molecular bases of tick-borne flavivirus transmission
Funder: Medical Research Council

Abstract: Human epidemics emerge in regions where arboviruses circulate harmlessly between vertebrates and invertebrates. The reasons for the human outbreaks of virus infections are unknown. On the basis of the preliminary studies of tick-borne encephalitis virus (TBEV) we hypothesized that the virulent strains might emerge following the TBEV adaptation to new tick hosts. The TBEV is recognised pathogen with ~14 000 human cases annually. Its circulation in nature is maintained by the transmission from uninfected to infected ticks that co-feed on the same rodent. Two TBEV strains Vs and Hypr although are closely related, in nature transmitted by different tick spp. (I. persulcatus and I. ricinus respectively). Using the infectious clones for these viruses we have engineered a range of Vs/Hypr chimaeras, with substituted individual genes. In tick-transmission experiments we showed that Vs and Hypr are incapable of crossing the tick-spp barrier but Vs/Hypr chimaeras revealed different level of transmission, in 70% dependent on the envelope glycoprotein E and in 30% on the other genome regions. On the other hand, our studies of RNA secondary structures in untranslated regions (UTRs) of flavivirus genomes predicted their significant role in virus adaptation to transmission between vertebrates and invertebrates. In addition to their differences in transmission, the Vs and Hypr show different pathogenic properties; Vs is less virulent in humans (isolated from the recovered patient), cell culture and hamsters, in comparison with Hypr (isolated from fatal case of TBE). The preliminary results with Vs/Hypr chimaeras indicated that polymerase protein NS5 might be responsible for virulent properties of the Hypr, although the precise amino acid involved needs to be determined. In this project, we propose to investigate the precise molecular mechanisms that determine the ability of TBEV to be transmitted between co-feeding ticks, with emphasis on the genetic modifications within the E and NS5 proteins and UTRs. Secondly using Vs/Hypr chimaeric viruses we also intend to identify amino acids that are responsible for different pathogenic characteristics of Vs and Hypr. The microarray assay will be employed to compare cellular genes that are up- and down-regulated by Vs and Hypr and their chimaeras. All together, these data will establish whether or not there is a correlation between genomic domains (RNA or/and protein) responsible for the TBEV tick-transmission and pathogenicity and estimate the role of ticks in the emergence of virus strains with new pathogenic characteristics in nature, a hypothesis that has never been tested experimentally.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: MRC-University of Glasgow Centre for Virus Research
Funder: Medical Research Council

Abstract: The aim of this proposal is to create a leading international hub for virology research (the Centre for Integrated Virology, CIV), harnessing the expertise of the MRC Virology Unit and the University of Glasgow s Institute of Comparative Medicine, along with NHS, government agency and commercial collaborators. The CIV will engage with all aspects from structural and molecular virology, through clinical and veterinary virology to epidemiology and mathematical modelling. Integration with clinical programmes is a crucial element of the CIV?s remit along with enhanced training in clinical virology. Key features of the CIV will be an expanded capacity for horizon scanning for new and emerging viruses and tailored science with the aim of improving the UK?s expertise in these areas. The CIV will serve as the core component of the Integrated Virology Network (IVN), an organisation that includes partners from Health Protection Scotland, the University of St Andrews, the Moredun Research Institute, the East of Scotland Specialist Virology Centre, the National Institute for Medical Research and the Health Protection Agency in Colindale. The IVN will support the CIV s training plans and contribute significantly to information sharing and complementarity of research and control activities.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: INFECTION
Title: Mechanisms within the ESCRT machinery required for HIV-1 budding
Funder: Medical Research Council

Abstract: The last event in the assembly of infectious Human Immunodeficiency Virus (HIV-1) requires a membrane scission event that separates the nascent viral particle from the infected cell. This process is mediated by a late budding activity (L-domain) encoded by a short aminoacid motif (P/SAP) in the structural viral protein gag. It is now established that the HIV-1 L-domain facilitates egress via the recruitment of the Endosomal Complex Required for Transport (ESCRT) machinery. Moreover, there is a growing list of pathogenic human enveloped viruses that also require the ESCRT machinery for replication, namely Ebola virus, Hepatitis B virus, Herpes Simplex Virus type 1, HTLV-1, Lassa virus and Parainfluenza Virus 5. Consequently, the pharmacologic inhibition of the ESCRT machinery may offer a therapeutic opportunity against a broad range of enveloped viruses, but the fact that the ESCRT complexes are primarily involved in essential aspects of cell biology such as endosomal sorting into the Multivesicular Bodies and the resolution of the midbody at the end of cell division raises obvious potential mechanisms of toxicity for future inhibitors of the ESCRT machinery. Therefore, understanding the mechanisms underpinning the functional complexity within the ESCRT machinery and its regulation is not only needed to determine the therapeutic potential of this pathway, but also to further illuminate basic aspects of HIV-1 pathogenesis and cell biology. Thus, the general aim of this research grant application is to define the specific mechanisms within the ESCRT machinery that are required for HIV-1 budding as opposed to the role of this machinery in cytokinesis and endosomal sorting.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Molecular mechanisms of fungal cell wall assembly
Funder: Medical Research Council

Abstract: The fungal cell wall is a dynamic and multi-layered structure, containing a core of crosslinked chitin and glucan. Despite decades of work, there are huge gaps in our knowledge of the enzymes responsible for cell wall synthesis, modification and crosslinking. This is particularly pressing given the significant rise in fatal fungal infections of immunocompromised patients, and thus the need for novel, properly genetically/chemically validated, drug targets. This proposal uses a multidisciplinary approach (covering genetics, biochemistry, structural biology, high throughout screening, synthetic chemistry and cell biology) to significantly advance our understanding of the function, biochemistry, inhibition and genetic/chemical validation of A. fumigatus/C. albicans enzymes involved in fungal cell wall biogenesis. The proposal covers four areas: Cell wall synthesis - with the aims of generating overexpression systems for the membrane enzymes chitin/glucan synthase, determining their crystal structures and probing their mechanisms using novel assays/inhibitors and mutagenesis. UDP-GlcNAc biosynthesis - with the aims of genetically validating this pathway in A. fumigatus, determining the crystal structures for these enzymes to assess exploitable differences with their human orthologues, and discover novel inhibitors through screening approaches. Chitin modification - with the aims of genetically and chemically validating A. fumigatus chitinases and chitin deacetylases as potential drug targets and synthesis/discovery of novel inhibitors. Crosslinking/transglycosylation - with the aims of determining the crystal structures, mechanism and substrate binding of the Gel/Gas and Crh transglycosylases, discover the first ever inhibitors for these enzymes and use these for chemical validation. The output will be: 1) a significant increase in our molecular understanding of fungal cell wall biogenesis enzymes, 2) a collection of novel chemical tools for use by the fungal scientific community, and 3) a springboard for novel antifungal drug discovery by follow-up translational research and/or the pharmaceutical industry.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: The clinical outcomes, response to treatment and epidemic dynamics of HIV-1 in the UK
Funder: Medical Research Council

Abstract: The use of highly active antiretroviral therapy (HAART) has had a major impact on the health of HIV-infected individuals in the developed world and, as a result, life expectations of those infected with HIV have started to approach those seen in the general population. However, treatment paradigms are changing and over the next five years we expect to see changes in the drugs/drug combinations used, the order in which they are sequenced and the CD4 count at which treatment is started. However, the development and transmission of resistant HIV remains a threat to successful treatment. Furthermore, those living with are now older, a greater proportion are women (many of whom are becoming pregnant and receiving treatment to prevent transmission of HIV to their baby) and many are co-infected with viral hepatitis; these factors may complicate the management of those with HIV. In order to plan the need for health-care services and to understand the need for new antiretroviral drugs in HIV-infected persons, it is important to continue to monitor the outcomes of treatment in this population, including the incidence and patterns of drug resistance, and to determine the degree to which the efficacy of future drugs is likely to be compromised by resistance development. The UK Collaborative HIV Cohort (CHIC) Study and UK HIV Drug Resistance Database (UK HDRD) were initiated in 2001 to monitor the uptake and response to HAART among individuals with HIV in the UK, and the development of resistance in these individuals. The main objective of this programme grant application is to continue to follow these two large cohorts (with expansion where possible so that they continue to follow a large and geographically representative group of patients) with the aim of providing timely information on the changing trends over time. In addition, several other questions have arisen which must now be addressed, relating particularly to the use of treatment during pregnancy and the impact of long-term co-infection with hepatitis viruses. Thus, we propose to develop five complementary themes of research (ongoing monitoring of outcomes; understanding the transmission and persistence of resistance; understanding the molecular epidemiology of the UK epidemic; describing the impact on women of antiretroviral treatment received during pregnancy; and describing the impact of co-infection with hepatitis B/C on HIV outcomes). Each theme will include a series of co-ordinated projects covering questions across the broad scientific area.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: N-Myristoyl Transferase as a drug target for anti-malarial therapy
Funder: Medical Research Council

Abstract: There is an urgent need for new anti-malarial drugs and for elimination of the disease these must be active against both Plasmodium falciparum and P. vivax, the two most important human malaria parasites. Such drugs should be effective against both the parasite stage responsible for causing disease and against the sexual blood stage that is essential for transmission. We have identified Plasmodium protein:N-myristoyl transferase (NMT) as a suitable target for such drugs and validated it both genetically and chemically. We aim to develop highly effective inhibitors of NMT that are active against the purified enzyme, and will kill the malaria parasite in vitro and in in vivo. Two existing series of inhibitors will be optimised using medicinal chemistry methods and additional leads will be obtained by screening libraries of compounds. Structural studies on the enzyme and inhibitors will inform this process. Active compounds will be screened against P. falciparum asexual blood stages in vitro using a FACS-based assay to identify and select those most active against this parasite. Selected compounds will also be examined for their ability to inhibit gametocytogenesis. We have developed a transgenic rodent malaria parasite, P. berghei that has the P. falciparum NMT gene inserted into the endogenous NMT locus, and this parasite line will be used to screen the efficacy of compounds in vivo against blood stage parasites, including sexual stages. We propose to further validate this model and develop similar parasites transgenic for the P. vivax enzyme so that the efficacy of the inhibitors against this parasite can be evaluated. We will further develop cell biological assays to confirm on-target effects of NMT inhibitors by examining the properties of particular NMT substrates. At the end of the project we will have produced a number of highly active compounds suitable for further drug development in collaboration with Pharma, and provided a clear understanding of the role for NMT in the biology of the malaria parasite.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: The impact of viral gene expression and cellular signalling upon the control of HCMV latency and reactivation
Funder: Medical Research Council

Abstract: Although primary infection with human Cytomegalovirus (HCMV) is usually asymptomatic in healthy individuals, infection and reactivation of immuno-suppressed AIDS, cancer and transplant patients, causes severe morbidity and mortality. Additionally, infection in utero occurs in approximately 1-2% of all live births and is associated with severe long-term consequences including blindness, deafness and mental retardation. Previous studies on HCMV latency and reactivation suggest that the myeloid lineage is important. HCMV establishes latency in bone-marrow progenitor cells and reactivation is linked with the differentiation state of myeloid cells whereby myeloid cell maturation induces chromatin remodelling of the major lytic (‘reactivation‘) promoter into an active form concomitant with reactivation. However, the apparent contradiction between efficiency of HCMV reactivation in vivo compared with studies in vitro suggests that further, yet undefined, factors augment reactivation in vivo. Firstly, I propose to study the impact of chromatin remodelling of the MIEP during differentiation in the context of inflammatory signalling induced by myeloid cell maturation. Specifically, I intend to identify and characterise signalling pathways involved in reactivation. Broad spectrum chemical inhibitors will be used to identify potential pathways involved and then more detailed analyses using adenoviral vectors to introduce mutant forms of signalling proteins, siRNA technology and more specific inhibitors of points in the pathway will be carried out. These analyses will be performed in an in vitro model that has been used in previously to analyse the molecular mechanisms of HCMV reactivation. Secondly, I propose the further study of a recently identified transcript, UL81-82ast (LUNA), expressed during both lytic and latent infection. Preliminary data suggests that LUNA can disrupt ND10 bodies which maybe due to a potential de-sumoylase activity of the protein. To assess the role of the de-sumoylase function a mutant virus within the putative active site will be characterised for its ability to establish latency and reactivate using the in vitro system. Furthermore, expression of a SUMO protease would allow HCMV to target a number of diverse processes, thus I will perform a yeast 2 hybrid assay and then characterise positive interactions to give further insight into the precise role of this protein during latency, reactivation and lytic infection. It is hoped that these studies will increase our understanding of how HCMV manipulates the host cell environment to so successfully establish both lytic and latent infections, and ultimately lead to the identification of key signalling pathways that promote reactivation providing a target for therapeutic intervention.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Defining the parasitological and immunological basis of cerebral pathology during murine experimental cerebral malaria
Funder: Medical Research Council

Abstract: Cerebral pathology (CM) is a life-threatening consequence of human Plasmodium falciparum infection and a comparable syndrome (experimental CM; ECM) is seen in susceptible strains of mice infected with P. berghei ANKA. Cerebral accumulation of both parasitised erythrocytes (iRBC) and leucocytes has been implicated in the initiation of CM and ECM, but the sequence of events and the relative importance of these two cell types remains unclear. The advent of new tools for high resolution tracking of individual live cells gives us an opportunity, for the first time, to definitively address these shortfalls in our knowledge. I will use dynamic multi-photon imaging of living brains and thick brain sections of malaria-infected mice, combined with transgenic fluorescently-tagged parasites and various fluorescently-tagged leucocyte populations, to examine the intracerebral migration and localisation of iRBC and leucocytes, enabling the elucidation of the cellular and molecular events that direct these pathological events. Intracerebral parasitic accumulation patterns and leucocyte migration and function will be compared during P. berghei ANKA (ECM causing) infection of C57BL/6 (ECM susceptible) and BALB/c (ECM resistant) mice and with P. berghei NK65 (non-ECM promoting parasite strain) infection of C57BL/6 mice to define the basis of cerebral pathology. By integrating imaging techniques with standard immunological approaches (e.g. cell depletion, flow cytometry and real-time PCR) I will determine the phenotype and function of brain infiltrating leucocytes; determining whether specific leucocyte populations (e.g. CD4+ and CD8+ T cells, monocytes) migrate to, and exert effector functions in, specific areas of the brain; and whether this correlates with sites of iRBC sequestration and/or with sites of brain pathology (haemorrhage, oedema, endothelial damage). I will examine whether these responses (homing, sequestration and cytokine production) change during secondary P. berghei ANKA infections (utilising a drug-cure infection model), to investigate the generation of immunological memory to infection and how this alters susceptibility or resistance to ECM. Finally, I will determine whether the leucocyte populations that localise in the brain and contribute to development of ECM differ from the leucocytes that are required to control parasite replication and eliminate the infection. For example, pathogenic lymphocytes may differ from protective populations in their effector function (production of cytokines, lytic molecules, superoxides etc), tissue homing (chemokine receptor expression) or regulation (regulatory receptor expression). Putative biomarkers of protective or pathogenic leucocyte populations will be validated using relevant transgenic or gene knock-out mice.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION