NIHRDataInsights/HRCSData huggingface dataset:
Title: Deciphering nanoscale interactions at the virus-host interface
Funder: Medical Research Council

Abstract: Viral diseases represent one of the world’s highest social-economic burdens. Increased global trade and travel, climate change resulting in shifting viral vectors, and emergence of new and often deadly viruses, necessitates development of new research, diagnostic, and therapeutic tools to combat coming pandemic and epidemic infections. For this, a thorough understanding of the basic lifecycle of viruses and the cellular factors and functions required for viral replication is needed. In turn, as obligatory, intracellular parasites, viruses exploit cellular processes such as signalling, membrane trafficking, molecular sorting, etc. Thus viruses provide a valuable tool to study multiple aspects of normal cell function. Our group is interested in deciphering the complex interactions between Poxviruses and their host cells. For these studies we combine cellular, molecular, and virological techniques with state-of-the-art technologies such as automated small compound and image-based cell- and virus-targeting siRNA screening, advanced proteomics, live cell-, electron-, and superresolution microscopy technologies. Using this combined approach we look to uncovering novel mechanisms by which poxviruses subjugate host cell functions to facilitate productive replication. Particular focus is placed on investigating how poxviruses manipulate host cell endocytic machinery to their advantage1-3, unraveling the complex protein nanoarchitecture of poxvirus particles and their intracellular disassembly and assembly4, and determining the mechanisms by which these viruses modulate the host response to infection prior to viral gene expression5. Not only will these studies provide a more detailed understanding of the cell biology of poxvirus infection, we have to opportunity to uncover novel functions of cellular factors. Additionally, this work has the potential to uncover general strategies used by viruses to subjugate their host cells and by extension the possibility to develop cell-targeting, broad-spectrum antiviral agents.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Viral Hepatitis
Funder: Medical Research Council

Abstract: HCV will remain a serious healthcare burden for the foreseeable future and despite attempts at intervention, new infections will persist, particularly in the 'people who inject drugs' (PWID) group. Emergence of antiviral resistance that could be transmitted in the community, and the impact of the inherent diversity within and between HCV genotypes on patient treatment are crucial challenges. In addition, virus evolution occurs in a genetically diverse host background, ultimately shaping response to infection. Fundamental questions on the contribution of host factors to pathogenesis and their role in determining the outcome of DAA therapy need to be addressed for those who fail to clear virus. Our core objective is to tackle viral evolution and host response as interconnected issues. We have developed initiatives and expertise which are central to our plans. To translate our research findings for clinical benefit, we will capitalize on HCV Research UK as a unique resource for clinical data and samples and utilize next generation sequencing (NGS) and bioinformatics pipelines to determine the evolution of viral resistance in those who do not respond to therapy. In addition, creation of gene knockouts by CRISPR technology combined with single cell sequencing will be pivotal for understanding the contribution of host factors as drivers of viral diversity, including DAA-resistance. Our future programme thus encompasses clinical to fundamental research, populations to single cells, incorporating in vivo, in vitro and in silico dimensions. In the same vein, we set out a strategic plan for the rational design of a HCV vaccine from our studies on neutralising antibodies. Virus eradication will not succeed through antiviral therapy alone due to lack of availability and cost, and resistance may be problematic. Our aim is to isolate unique antibodies from niche patient cohorts from HCV Research UK that are otherwise difficult to access. Again, our objectives are rooted in extensive expertise allied to the benefits of core-funded sequencing platforms and cognate bioinformatics expertise. Moreover, the collaborative network established with a range of disciplines will energise the plans and bring unique ideas to confront the obstacles preventing vaccine development.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Clinical and Veterinary Virology
Funder: Medical Research Council

Abstract: One of our strategic aims is to continue to link CVR research programmes with clinical and public health problems. In the last quinquennium, we recruited a Senior Clinical Lecturer and NHS Honorary Consultant in Infectious Diseases (Emma Thomson) who has been instrumental in bridging the traditional strengths in fundamental virology at the CVR with clinics (both locally and in London) as well as liaising with public health bodies both nationally (PHE and HPS) and internationally (WHO). We have recently appointed from 1st October 2016 another NHS Honorary Senior Clinical Lecturer/Honorary Consultant on a 50:50 funded position between the CVR and NHS (post and associated funding already approved by NHS). This post will link the CVR with the NHS West of Scotland Specialist Virology Centre (WOSSVC), which is the diagnostic laboratory for viral infections serving the Greater Glasgow and Clyde NHS Board. It is the largest NHS Diagnostic Virology Department in Scotland, providing specialist virological services to 75% of the Scottish population. Hence, the CVR will have a strong foothold both in the Brownlee Centre for Infectious and Communicable Diseases (Thomson) and the WOSSVC (new appointee). This will ideally position the CVR to translate fundamental research programmes into diagnostic and clinical practice. At the same time the presence of active practitioners embedded within clinical and diagnostic NHS departments will facilitate access to clinical data and samples, helping to shape our future strategy for addressing critical health issues arising from viral infection.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Viral Genomics and Bioinformatics
Funder: Medical Research Council

Abstract: Massive advances in the technologies associated with high-throughput sequencing, computational biology and genomic analysis have revolutionised research throughout biomedicine, including virology. As a result, our ability to detect and characterise viruses now has a depth and scope that lacks precedent, and the opportunities to advance our understanding of viral infections are immense. Sequencing and analysing multiple full genomes of important viruses will increase our understanding of diversity and evolution at local, national and global levels. This will lead to a much quicker appreciation of the epidemiology of viral diseases and to the robust linking of viral genotype to phenotype in terms of disease severity, transmissibility and potential to cross species barriers. The Viral Genomics and Bioinformatics (VG&B) programme already underpins the CVR programmes planned for the next quinquennium, and in addition reaches out to selected researchers nationally and internationally. As a high-end collaborative facility, VG&B plans are embedded within the individual CVR programmes. The VG&B programme is also an OIE Collaborating Centre for Viral Genomics and Bioinformatics. Our vision is to position the VG&B programme as an international, highly collaborative hub of excellence, with the technological infrastructure and critical mass of expertise necessary for underpinning the CVR research programmes, serving the UK virology community, and interacting with the NHS, national and inter-governmental public health bodies, and international research communities.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Intrinsic Immunity
Funder: Medical Research Council

Abstract: The post-translational modification (PTM) of proteins by ubiquitin and ubiquitin-like (UBL) polypeptides regulates many fundamental aspects of cell biology, including multiple facets relating to host immunity. Viruses have therefore evolved mechanisms to utilise or suppress these PTM pathways to overcome host immune defence mechanisms during infection, thereby promoting their replication and spread. Understanding the biochemical interplay between viral and host factors which utilise these pathways will therefore lead to new insights into the regulation of host immunity, processes which restrict the replication of many clinically important viruses. This programme aims to define the biochemistry of key viral host-cell interactions that utilise ubiquitin and SUMO PTM pathways to influence the outcome of host immunity during herpesvirus infection, using HSV-1 as a model system. By defining the biochemistry of these interactions we aim to: significantly advance our understanding of the signalling mechanisms that mediate the cellular restriction of herpesviruses and the establishment of viral latency; uncover fundamental principles relating to the regulation of ubiquitin and SUMO ligases that mediate key aspects of cellular immunity during HSV-1 infection; develop methodologies suitable for the identification of viral ubiquitin ligase inhibitors using ICP0 as a model ligase. This programme will add significant value to the MRC, CVR, and its associated research partners through the delivery of an interdisciplinary and internationally competitive programme of research. This programme will strengthen the study of ubiquitin and ubiquitin-related pathways within the CVR in other virus systems, including influenza A virus (IAV), Hepatitis C Virus (HCV), and selected arboviruses, through the dissemination of research reagents and expert knowledge. Our goal is to define the functional significance and host-cell regulation of these important PTM pathways during infection, thereby revealing fundamental insight into the biochemical mechanisms that influence the outcome of viral infection and pathogenesis


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Arthropod-borne infections
Funder: Medical Research Council

Abstract: Urbanisation, agricultural practices, mass transportation and changing interactions between humans and their environment create unprecedentend opportunities for viruses to emerge and spread globally among human populations. Many emerging viruses are transmitted to vertebrate hosts, including humans by arthropod vectors, such as mosquitoes. “Arboviruses” can replicate in both vertebrates and arthropods and thus overcome a diverse array of hostile antiviral responses from species in very different taxa. Our understanding of the antiviral responses in vertebrates far exceeds that of arthropod vectors such as the mosquito Ae. aegypti. Studies on the fundamental processes governing insect vector immune responses to arboviral infections will increase our understanding of vector “competence” (i.e. the ability of insect vectors to transmit certain arboviruses) and facilitate the development of novel control measures. We will focus on the identification and characterisation of interaction partners of proteins involved in two key RNAi pathways: the exogenous small interfering (si) RNA and PIWI-interacting (pi)RNA pathways. These studies will use viruses like Zika and Chikungunya and the roles and effects of these RNAi pathways and interaction partners will be further analysed in vivo at insect vector tissue and organism level. Studies on arboviruses and other emerging viruses will also be conducted in collaboration with the Uganda Virus Research Institute in Uganda, where several emergent viruses with epidemic potential have been identified (including yellow fever, Zika, Semliki Forrest, Ebola and Marburg viruses). We aim to identify viruses and other pathogens causing febrile illness in 3 geographically distinct regions of Uganda (North West, Central and South West districts). Specifically, we will study samples from the Acute Febrile Illness cohort (AFI) – a large UVRI/CDC cohort of patients presenting to health centres with fever, of which 17% remained undiagnosed despite comprehensive diagnostic testing.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFECTION
Title: Respiratory infections
Funder: Medical Research Council

Abstract: Multiple viruses are responsible for respiratory infections and co-infections causing a variety of disease outcomes that range from a mild cold to life-threatening viral pneumonia. Occasionally, respiratory viruses result in emerging infections such as the swine-origin influenza A virus (that caused the 2009 pandemic) or the severe acute respiratory syndrome coronavirus that caused an extended outbreak in several countries in early 2000s. Molecular diagnostic assays are routinely used in the UK healthcare system and they can simultaneously test for the presence of multiple viruses. Databases with results from such diagnostic tests represent a rich source of information that can reveal insight into the epidemiology of viral respiratory infections in the patient population. Respiratory viruses are generally studied as single entities and not as a community. Since they are obligate intracellular pathogens that infect a well-defined ecological niche (the human respiratory tract), studying them as a community is a logical approach to capture the impact of their complex interactions on their infection dynamics. We propose to study the infection dynamics of a group of respiratory viruses in a large and well-defined population over an extended period of time. We will analyse the long-term trends in viral respiratory infections using information on diagnostic test results (and associated metadata) of the Greater Glasgow and Clyde Health Board (GGCHB, the largest Health Board in Scotland) patient population. We will sequence a large number of viruses from clinical specimens to determine their complete genomes, study their evolutionary dynamics and to identify mutations that might be associated with changes in their phenotype (virulence, seasonality, age group distribution, etc.). We will use mathematical and statistical models to infer interactions among viruses at the patient level and their impact at the epidemiological scale. Finally, we will develop bioinformatics tools to facilitate the future use of complex sequence data in diagnostic laboratories and public health bodies.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Other infectious diseases of global public health significance
Funder: Medical Research Council

Abstract: Antimicrobial resistance, viral hepatitis and infections with pandemic potential place a major burden on human health. Our research focusses on: 1) Antibiotic-resistance – which increases morbidity/mortality for the individual and has huge public health implications. Our research aims to i) demonstrate in well-conducted trials that narrower spectrum antibiotics do not lead to poorer clinical outcomes; ii) assess the role of shorter antibiotic courses as a mechanism to reduce antibiotic selection pressure (CAP-IT) and the utility of short course dual antibiotics to effect more rapid bacterial kill in bacterial sepsis syndromes with high morbidity and mortality (ARREST); iii) investigate the role of old, now rarely used narrower spectrum antibiotics and/or repurpose existing narrower spectrum antibiotics as alternatives to broad spectrum antibiotics; iv) investigate novel point-of-care biomarkers to more clearly distinguish bacterial from viral infection and avoid using antibiotics inappropriately. 2) Viral hepatitides, in particular hepatitis C where a number of very potent, low toxicity oral direct acting antivirals (DAA) are able to cure >90% of patients with just 12-24 weeks of treatment. This offers the chance of global elimination because treatment could be shifted to the community and the brevity of the treatment means hard-to-reach populations could be treated successfully. There is a major caveat, in that these DAA are very expensive and hence not universally available, and moreover, do not prevent re-infection. We aim to explore a strategy of treating immediately vs. deferring in those with minimal liver disease to better understand the clinical benefits of treatment; a second study exploring the utility of even shorter DAA courses is also planned. 3) Emergent infections with pandemic potential. The 2009 influenza pandemic, only 6 years after the SARS coronavirus outbreak in 2003, served to illustrate the importance of a world-wide rapid-response infrastructure ready for future pandemics. MRC CTU as part of the INSIGHT network, established two observational studies in influenza, in the hospital (FLU003 Plus) and out-patient (FLU002 Plus) settings in direct response to this pandemic. These studies, along with the genetic substudy (INSIGHT-004) aim to inform on the longitudinal changes in clinical presentation of differing influenza strains, understand influenza strain drift/shift, antiviral resistance and the genetics that underpin poorer outcomes. We are now trialling a passive immunotherapy (FLU-IVIG) for those severely ill and hospitalised with influenza. This represents a novel treatment, which if found to be effective is likely to be developed into a commercialised polyclonal antibody product.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Paediatric and adolescent infections
Funder: Medical Research Council

Abstract: This integrated programme of complementary randomised trials, cohorts and pharmacovigilance studies aims to address questions about medicines and other interventions relevant to the most frequent and serious infectious diseases affecting children worldwide, in particular HIV, tuberculosis, malaria and sepsis. This is important because infectious diseases still dominate as causes of childhood mortality and morbidity and disproportionately affect children in sub-Saharan Africa. The programme has a large international component in Europe, North and South America, Thailand and Africa, and is at the forefront of both national and international research in paediatric infectious diseases. The most appropriate research study designs are used for each specific question, not repeating all studies done in adults but using research in adults to identify where questions may be different or likely have different answers in children. Recognising the relative paucity of research in children, multiple complementary questions are addressed in factorial trials wherever possible to increase the evidence base for clinical management, and add value to the original investment in setting up and running the trial. Substudies investigating aspects such as pharmacokinetics, immunology, virology, and adherence are also included alongside trials wherever possible, as are additional analyses of trial data in an observational framework. High quality additional long-term data can also be collected in trial extensions by linking to cohorts. However, not all questions regarding the optimal management and treatment of HIV-infected children can be answered by randomised trials, because many cannot be framed as an implementable intervention. Data from cohort studies are used to answer these population-level questions of major relevance to children, adolescents and their families. Our future plans are • to continue to address clinically relevant questions in paediatric infectious diseases through appropriate research designs, and • to ensure that results are incorporated into national and international management guidelines and policy, and then into clinical practice, including through additional operational research if relevant. Several randomised trials in HIV and tuberculosis are funded and in advanced planning phases. Ongoing analyses within cohorts and cohort collaborations led by the group are addressing a wide range of contextual topics that can be generalised to the treatment and care of the wider population of HIV-infected children and young people. A large programme of pharmacovigilance studies continues to provide important long-term safety data to the European Medicines Agency on newly licensed antiretroviral drugs for children.


Research activity codes: 3.4 VACCINES;2.4 SURVEILLANCE AND DISTRIBUTION;6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Tuberculosis Treatment Trials
Funder: Medical Research Council

Abstract: Outline the overall aim and importance of the research, the specific research objectives, plan and methodology, including experimental design Address any clinical and translational research issues, specific goals/plans for medical/public health exploitation/applications, and refer to any IPR implications (see Guidance Notes). In 1993 the WHO declared TB a global emergency. Despite this, TB remains a considerable cause of mortality and morbidity, with 8.6 million new TB cases and 1.3 million TB deaths in 2012. TB kills more adults than any other infectious disease with 5000 people dying from the disease every day globally. Effective short course treatment for drug-sensitive TB was developed by the MRC TB & Chest Diseases Unit in the 1970s and 80s. However, many patients fail to complete treatment, drug-resistance is on the increase and there is an urgent need for new drugs. Since the formation of the MRC Clinical Trials Unit in 1998 a programme of trials has been initiated in collaboration with a number of international organisations. Initially the focus has been on shortening and/or simplifying the treatment of drug-sensitive TB, assessing in non-inferiority designs alternatives to the standard 6-month regimen. Most recently two trials assessing the role of fluoroquinolones in treatment shortening have been assessed. Additional questions addressing this question are currently being conducted or planned including a strategy trial of ultra short course chemotherapy and trials in children. The Multi-Arm Multi-Stage (MAMS) trial design was developed in the MRC CTU and allows for early stopping of poorly performing arms in a multi-arm trial. We designed a Phase IIB TB trial with a MAMS design which recently reported results and are planning to implement the design in future trials. The treatment of drug-resistant TB, in particular multi-drug resistant disease, has a very poor evidence base and a large multi-centre phase III trial, the first ever to be conducted, is evaluating regimens which are considerably shorter than the recommended WHO standard of care. Two of these regimens include the newly licensed drug bedaquiline.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION