NIHRDataInsights/HRCSData huggingface dataset:
Title: Epidemiology of Human Influenza in Vietnam.
Funder: Wellcome Trust

Abstract: Influenza (the flu ) is a respiratory disease that kills hundreds of thousands of people worldwide every year. Flu epidemics in colder climates occur in the wintertime, and the virus is able to come back every year because it is constantly evolving to escape our immune defenses. Every 20 or 30 years, influenza causes massive global outbreaks, known as pandemics, when a new influenza strain enters the human population. The last of these started in March 2009, and although it was quite mild, p andemics have the potential to be widespread and extremely lethal. It is generally believed that seasonal flu and pandemic flu originate in Asia, but not enough supporting data have been collected to determine this conclusively. During the course of this fellowship, I will investigate how influenza viruses circulate in Vietnam through a combination of community- and hospital-based studies. This will help us understand (1) how many people in Vietnam are infected with flu every year and how s evere these infections are, (2) whether flu epidemics, as experienced in colder climates, can indeed originate in Vietnam or Southeast Asia, and (3) how a policy of influenza vaccination in Vietnam would affect flu transmission in Vietnam and globally.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFECTION
Title: Tools for the elimination of blinding trachoma.
Funder: Wellcome Trust

Abstract: Trachoma, caused by a bacterial infection, is the most important infectious cause of blindness. The control strategy relies in part on annual oral antibiotics treatment of whole districts wherever the disease is common. Decisions on antibiotic deployment are based on the proportion of children who have evidence of eyelid inflammation, but inflammation can persist for years after clearance of infection. As a result, some populations continue to be given antibiotics annually for years after inf ection has disappeared, wasting health workers time, antibiotics, and money, and unnecessarily increasing the risk that other microbes will develop antibiotic resistance. It is currently difficult to recommend that antibiotic guidelines be changed because we dont know much about the effect of population-level antibiotic use on the proportion of people who are infected. I aim to: 1. develop and validate a method for determining the bacterial load in trachoma 2. develop and test a method for detecting presence of bacterial transmission in a population 3. study the impact of antibiotic treatment on district-level prevalence, intensity, and transmission of ocular C. trachomatis; and (2) determine the critical predictors of MDA success 4. explore why eyelid inflammation persists in a population after infection has disappeared.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: Host location by expophagic African malaria vectors
Funder: Wellcome Trust

Abstract: The study will focus in outdoor host location behaviour in Anopheles spp. mosquitoes, and the overall goal is to identify patterns of behaviour that might be exploited for efficicent and safe delivery of insecticides and other checmicals, or that might provide opportunities to develop entirely novel tools to target these species. We will investigate the simple hypothesis that Afrotropcal anophelinese have inherent and therefore measurable and predictable patterns of behaviour when orientating toward human and bovine hosts. We will undertake a series of investigations to analyse the behaviour of different species of mosquites as they orient to or land on bait animal or human hosts, outdoors. We will use infra-red video camera technology, newly developed by ourselves in another porject, to record and analyse these behavioural patterns. The goal is the identification of key points in time and space during bloodfeeding, that are vunerable to intervention. Ultimately, we hope that effective tools developed on the basis of the fundings from this research might enable effective control of outdoor malaria transmission.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Age structure of populations of tsetse flies under control pressure
Funder: Wellcome Trust

Abstract: If not treated Sleeping sickness is an inevitably fatal disease of humans. Itaffects the poorest members of society on the poorest continent in the world. Treatment is difficult and dangerous to the patient. The latter stages of the disease are still often treated with the drug Melarsoprol whose toxicity directly leads to the death of up to 10% of the patients receiving it and where up to 30% of treatments can fail because of resistance to the drug. New means of sleeping sickness control are urgently needed. Our bigger aim is to make tsetse control an affordable option in sleeping sickness foci - this currently is not the case. This fellowship aims to look at one of the means of doing that. In brief it takes tsetse flies 20 or more days to mature an infection with the trypanosomes causing sleeping sickness. Only after this are they able to transmit the disease. Consequently if you reduce the averageage of flies in the population you will affect transmission even if you do notkill all flies. The fellowship will provide the candidate with high quality training within a well structured, well financed programme staffed by an internationally recognised workforce.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: INFECTION
Title: Development of effective rift valley fever vaccines for use in sheep and humans.
Funder: Wellcome Trust

Abstract: Rift Valley fever (RVF) is a mosquito-borne viral zoonosis that invariably causes death of newborn lambs and abortion in pregnant ewes. Human disease follows close contact with infected animal tissue and body fluids and is characterized by a mild febrile illness that occasionally progresses to a life-threatening haemorrhagic syndrome. No licensed vaccine is available forhuman use and that used in livestock is not safe for use in pregnant animals. Thus, the proposed research aims to develop a recombinant viral-vectored vaccine for use in sheep and humans. The RVF viral glycoproteins, Gn and Gc, that are targets of neutralizing antibodies, will beinserted into modified vaccinia virus Ankara (MVA) and a simian adenovirus (ChAdOx1) vector. These


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: Decoding the influenza A virus polymerase-promoter complex
Funder: Wellcome Trust

Abstract: Influenza virus is a constant burden on our healthcare and poses, together with the limited supply of anti-influenza treatments, the constant mutation of the virus, and its tendency to cause regular global outbreaks, a severe threat to our economy. It is therefore crucial to develop novel strategies to control the virus. One avenue that may lead to these is a better understanding of the molecular mechanisms that influenza employs to multiply and express its genetic information. Current evidence suggests that a central, so-called polymerase-RNA complex drives these essential viral activities, but, in spite of its importance, how this complex works is still far from understood. In this study, we will therefore use highly sensitive methods to study the activities of this enzyme in purified form and in living cells. This approach will reveal new insights into the activity of the influenza A polymerase-RNA complex and may thus provide new targets for anti-influenza drug development.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Mechanisms of interferon-alpha induced block to HIV replication (INTAPHIR).
Funder: Wellcome Trust

Abstract: Interferons are molecules produced when the body senses viral infection and induce a general antiviral state. When interferon is given to HIV-infected patients not taking anti-HIV treatment the amount of virus in their blood usually decreases. Little is known about the mechanism involved but laboratory experiments suggest that as yet undiscovered factors are directly inhibiting viral replication in cells after interferon stimulation. We plan to take samples from patients co-infected with HI V and HCV who are given interferon treatment to clear HCV infection. Using a technology that allows us to look at all the genes that are turned on (expressed) by interferon in patients' cells we will compare genes expressed in patients who have strong anti-HIV responses, with patients who have a poor response and see which genes are causing this difference. In patients who have already suppressed HIV replication with HIV-specific drugs we will investigate if adding interferon to their drug regi men has any effect on the low level of virus that can still be found in their blood and on the amount of virus in their cells. If interferon has any effect this may lead to considering the use of this type of therapy to eradicate HIV infection.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: INFECTION
Title: The social impact of HIV self-testing: reconstructing knowledge and re-framing risks associated with HIV prevention.
Funder: Wellcome Trust

Abstract: HIV counselling and testing (HCT) is important because it provides a route to accessing treatment which is integral to HIV prevention strategies. There is a range of HCT options available in sub-Saharan Africa (SSA) including opt-out, hospital-based testing, voluntary counselling and testing services and home-based approaches at community-level. Despite this the number of individuals who have tested remains less than optimal. These gaps are often due to conflicts between desire for confidenti ality and need for convenience. Policy is slowly moving towards introducing HIV self-testing (HST) amongst Health Care Workers (HCW) but it also has huge potential to address testing gaps at community level and previous research has shown high levels of acceptability. Opponents express concerns about the potential for coercive testing and whether access to regular and repeat testing may encourage increases in risky behaviour amongst those who test negative. This research will explore how acces s to a novel HST technology will impact socially on individuals and families and provide the evidence to ensure that future policy decisions are informed and scale-up counselling strategies developed to increase equitable and ethical access to knowledge of HIV status through a range of HCT options.


Research activity codes: 4.3 INFLUENCES AND IMPACT
Health categories: INFECTION
Title: The contribution of the SIC to the pathogenesis of invasive group A streptococcal infections.
Funder: Wellcome Trust

Abstract: Group A streptococcus (GAS) may be carried asymptomatically in the throat. However, it may also lead to a range of severe illnesses, including infection in childbirth and problems following infection, depending on genetic factors in the human host as well as the ability of the bacterium to overcome the immune system. Almost half the cases of severe disease are caused by one type of GAS, known as M1, which makes a toxin called SIC that can stick to several human proteins involved in immune respon ses, inhibiting their function. The main goal of this project is to investigate the interaction of M1 GAS SIC with part of the immune system: the complement cascade, in order to understand how GAS can overcome the immune system. The specific aims are to investigate: (1) whether SIC binds to a variety of host immune system proteins, (2) how SIC production helps GAS overcome the immune system in mouse models and, (3) whether the interaction of SIC with the complement system is the most important a spect of its activity. There are very few studies that have examined the effects of SIC production in severe infections, and this project aims to address this knowledge gap.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: The role in ESX-1, a novel protein secretion system, in Staphylococcus aureus virulence.
Funder: Wellcome Trust

Abstract: Staphylococcus aureus is a bacterium present in the nose and on the skin of healthy people. The immune system normally prevents carriage of S. aureus from turning into infection. When the natural defences fail, however, S. aureus can cause severe lung, skin and other infections. In recent years, methicillin-resistant Staphylococcus aureus (MRSA) strains have emerged and can cause rapidly fatal infections. These infections are extremely difficult to treat because they are resistant to mos t current antibiotics. It is essential that we develop new antibiotics against S. aureus infections. This project will investigate a recently discovered secretion system called ESX-1 that the bacteria use to cause disease. Strains of S. aureus lacking this system cause much less severe infections. We therefore believe that ESX-1 is a potential target for the development of new antibiotics. To investigate this further, we will use mutated strains of S. aureus lacking components of the ESX-1 s ystem to determine which components of the system are critical to cause infection. We will use state of the art scientific techniques to discover which factors are secreted by the ESX-1 system. Finally we aim to develop drugs to inhibit the ESX-1 system as new antibiotic treatments for S.aureus infections.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Prostaglandins as potential biomarkers and therapeutic targets in critical illness-associated immune dysfunction.
Funder: Wellcome Trust

Abstract: Hospital-acquired infections (HAI) occur in 5% of UK hospital admissions annually, 5000 individuals dying as a result. Critically ill patients suffer the highest burden often secondary to less aggressive drug-resistant bacteria. The reason for this predisposition is not known. The process of inflammation is found in all critical illness. I have found initial evidence that prostaglandin (PG) E2, a chemical that profoundly inhibits the immune system from killing bacteria, is elevated in critically ill individuals. In laboratory tests this effect can be reversed with commonly available drugs such as ibuprofen, potentially offering a means of decreasing susceptibility to HAI. The proposed research seeks to build on these findings. I hope to better characterise the PG profile in patients with severe pneumonia, and in an established murine model of susceptibility to infection. I intend to correlate PG concentration with key clinical outcomes, including risk of HAI and death. The ability of common cyclooxygenase-inhibitors (NSAIDs) or novel selective agents to reduce the PG burden, improve bacterial clearance and reduce susceptibility to infection and its associated mortality will be tested. I hope to identify immunosuppressive PGs as a means of predicting adverse events and, if causally associated, a novel therapeutic target.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION
Title: The European Malaria Reagent Repository.
Funder: Wellcome Trust

Abstract: Over the last 50 years, globally recognised research in Edinburgh has produced the largest and most diverse bank of malaria parasite-specific reagents, worldwide. This includes parasite isolates spanning the human malarias and rodent models, parasite antigens, recombinant proteins, diagnostic products, antibodies, and hybridoma cell lines. We will create the European Malaria Reagent Repository which is dedicated to the development and curation of these reagents. Specifically, we will: (i) rep lenish and renew reagents currently archived and those generated in the future; (ii) comprehensively annotate reagents and their uses in an online database; (iii) increase the accessibility of materials to academic and commercial researchers; (iv) improve expertise in the use of reagents in malaria-endemic countries; and (v) generate a commercially viable, self-sustaining resource the through income generated by supplying reagents upon request for academic and commercial uses. Our project will s ecure the future of malaria reagents and our comprehensive annotation will maximise their utility across the global infectious disease community. We have laid the foundations for our repository by developing the database to archive reagents and the website from which they can be sourced, demonstrating that the oldest archived materials can be revived and renewed, and parameterising the business plan for self-sustainability.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: INFECTION
Title: Integrated bioinformatics resources for kinetoplastid pathogens.
Funder: Wellcome Trust

Abstract: Access to genomic-scale datasets has revolutionized the molecular and cell biology of protozoan pathogens, advancing basic and applied research on these organisms, including the development of potential therapeutics. The aim of this proposal is to fully integrate established kinetoplastid databases, addressing key areas that currently limit the utility of these resources, so as to provide a global resource that enables and accelerates research into trypanosomatid parasites. The key objective s are to: 1. Annotate and curate high priority data, focusing on reference genomes, poorly-annotated species and the incorporation of expert knowledge from the community. 2. Develop and implement rapid (semi-automated) annotation pipelines to accommodate the large number of kinetoplastid genome sequences now emerging. 3. Expand the scale and diversity of functional genomics datasets supported by TriTrypDB, incorporating data from population diversity, transcriptomic, proteomic, and metabo lomic analyses that were produced by Wellcome Trust-supported researchers and the wider national and international research communities. 4. Ensure full coordination of GeneDB (www.genedb.org) activities with the NIH/NIAID-funded Eukaryotic Pathogen Genome Database (EuPathDB.org), and harmonise with other relevant pathogen databases. This strategic proposal is a crucial step in the global effort to ensure long-term stability of the highly successful kinetoplastid database resources.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: INFECTION
Title: MiPGR - The Microbial Population Genomics Resource.
Funder: Wellcome Trust

Abstract: The speed and scale with which we can now generate the genome sequences of isolates of bacterial pathogens is remarkable and the technology is being widely taken up by the basic microbiology, clinical microbiology and public health communities. At present, the new genome data are hard to access as they are not available in a user-friendly format and there is an urgent need to provide an international database that hosts the genome sequences from the rapidly growing numbers of isolates of diffe rent bacterial pathogens. We have developed a web application that is modeled on the MLST databases that we host and which, via an open-access website, can store the genome data of large numbers of isolates of each pathogen species (core genome, accessory genes and metadata for each isolate), with linked analysis tools for molecular epidemiology and evolution. Our web application is already being used by our collaborators at the Sanger Institute to store and analyse their genome data and we se ek funds to further develop it so it can be made available on-line (initially for Staphylococcus aureus and Streptococcus pneumoniae genomes) and to maintain, expand and curate this essential population genomic resource.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: INFECTION
Title: A First-in-Human Phase I Clinical Trial for the Novel Clostridium difficile Antibiotic SMT19969.
Funder: Wellcome Trust

Abstract: The bacterium Clostridium difficile is often a harmless resident of the human intestine with levels kept in check by the complex community of other microorganisms resident in the gut. However, following disruption to the healthy balance of the gut flora it can cause a potentially fatal infection of the colon. Recent years have seen a dramatic increase in both the number of cases and severity of C. difficile infection (CDI) and the disease is now firmly established as a significant healthcare issue. Current therapy options are limited and of sub-optimal efficacy with up to 30% of patients experiencing at least one additional episode of CDI following initial treatment. The primary goal of this proposal is to complete a first-in-human (FIH) Phase I clinical trial on SMT19969 which is a novel antibiotic specifically targeted to the treatment of CDI that is expected to significantly reduce rates of recurrent disease. In addition to basic safety and tolerability data in man, an extensive package of additional scientific data will be generated that will support high levels of efficacy being achieved in CDI patients.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Structural studies of the human metapneumovirus nucleocapsid and associated polymerase components.
Funder: Wellcome Trust

Abstract: Human metapneumovirus (hMPV) is a recently discovered human pathogen that is amajor cause of lower respiratory tract infections in children. The negative-sense RNA genome of this virus is encapsidated in form of a helical nucleocapsid by the nucleoprotein (N). This structure acts as the template forviral RNA synthesis and as platform for the assembly of the viral replicase components M2-1, P and the large polymerase protein L. The proposed research endeavours a reconstitution of recombinant hMPV nucleocapsids with components of the replication machinery followed by a structural characterisation of the resulting complexes by electron microscopy. In addition, individual componentsand sub-complexes will be studied at atomic resolution detail via x-ray crystallography. Data obtained from in-vitro generated assemblies will be validated by comparison with corresponding structures of in-tact viral particles. A full structural understanding of how the replication components of hMPV assemble onto the nucleocapsid combined with atomistic details of individual interactions may form the basis for the design of antiviral therapeutics targeted against viral replication and transcription.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION