NIHRDataInsights/HRCSData huggingface dataset:
Title: The influence of human immunodeficiency virus and antiretroviral therapy on thymic output in infants and children.
Funder: Wellcome Trust

Abstract: Over 2 million children worldwide are infected with human immunodeficiency virus (HIV) and the majority of these children live in countries with limited healthcare resources. HIV disables the immune system and predisposes HIV-infected children to life-threatening infections. The thymus is a critical component of the immune system and is responsible for generating the T-cells necessary for fighting infections. It is most active in infants and children. How the thymus reacts to HIV-infection or H IV treatment is poorly understood. In this project, we will explore the effect of HIV and ART on thymic function in HIV-infected infants enrolled in the CHER trial and a group of HIV-uninfected infants. Two-thirds of the CHER trial infants received ART immediately and one-third had deferred treatment until clinically indicated. These infants have been followed-up for up to 6 years with 1-3 monthly reviews and blood tests. The findings of this project could help to address many unanswered questions concerning the best ART management strategies to use in HIV-infected children e.g. when to start ART, and when or whether to stop ART. This information could be important for HIV management worldwide.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Genetic and functional mechanisms of susceptibility to mycobacterial infection.
Funder: Wellcome Trust

Abstract: Some people are known to be more susceptible to TB than others. The reasons are partly genetic, but specific genes remain unknown. If we find which genes are responsible for TB susceptibility, we will be able to study what these genes do in the human body, how do they work to protect us and eventually learn how to manipulate their function to stop TB. We will find such genes by comparing variants across the whole human genome between thousands of TB patients and healthy people. Additionally, we will study a microbe, M. tuberculosis, that causes TB in these same patients and will investigate how human genes work to interact with the microbe. Understanding biological mechanisms of susceptibility to TB eventually will help to design better vaccines and drugs and save lives of millions of people that die every year because of TB.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Genetic determinants of host/parasite interactions in African trypanosomiasis.
Funder: Wellcome Trust

Abstract: African sleeping sickness is a neglected disease caused by parasites called trypanosomes that claims the lives of tens of thousands of the poorest people in sub-Saharan Africa. Humans can become infected with trypanosomes if they are bitten by a tsetse fly carrying the parasites. Once infected, humans can go on to develop the disease and many will eventually die. However, it is known that different types of this parasite behave quite differently resulting in a spectrum of disease. For example, a t one end of the scale, there are parasite types that cannot infect humans, while at the other extreme, there are parasite types that infect humans and cause severe disease. There are also differences in the ways in which humans respond to infection - some people develop severe symptoms, while others are able to cure themselves or control disease with mild or no symptoms The aim of this project, therefore, is to identify the parasite factors involved in infecting humans and causing disease, and to understand why some people suffer only mild symptoms while others can die. This information will ultimately help to inform new ways of preventing infection and controlling the disease.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Cytoadherence-mediated pathology in cerebral malaria.
Funder: Wellcome Trust

Abstract: The majority of adults and children admitted to hospital with cerebral malaria die within the first 24 hours despite being given highly effective anti-parasite drugs. My hypothesis is that a significant part of this mortality is due to the presence of red blood cells infected with the malaria parasite sticking in the small blood vessels of the brain. We understand some of the molecular events leading to this process of sequestration, whereby infected red blood cells are withdrawn from circulat ion by sticking to cells lining the blood vessels in various tissues, but not why some parasite variants target the brain and what they do in the cerebral blood vessels to cause severe disease. This work will examine the processes by which parasite infected red blood cells are recruited preferentially to brain blood vessels, rather than other tissues, and define the changes to host cells that this adhesive event causes that might contribute towards disease. By understanding these pathways we h ope to develop fast-acting adjunctive therapies to be used in combination with effective anti-parasite drugs to reduce acute mortality in cerebral malaria.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Evaluation of innovative TB vaccination strategies in preclinical and clinical models.
Funder: Wellcome Trust

Abstract: Tuberculosis kills 2 million people annually. The only vaccine, BCG, protects against severe disease in children but not against lung disease in adults. We urgently need a better vaccine. The current laboratory assays and animal models do not necessarily reflect well what happens in humans, so to test whether the new vaccines actually reduce TB in humans we have to do big clinical trials which take years and are very expensive. We cannot deliberately infect volunteers with TB just to test if th e vaccine works, but we can give them BCG. Any TB vaccine which works against TB should also work against BCG. We plan to test this human BCG challenge model to see if it might work to help evaluate new vaccines. The second part of this proposal is to test ways of making our current new vaccine, MVA85A, better: by adding a second, different vaccine; by adding another protein from TB and by testing if giving a vaccine directly into the lung might be better, as TB mainly infects the lungs. We al ready have regulatory approval to test MVA85A delivered by inhaler directly to the lungs an approach which is used for some licensed flu vaccines.


Research activity codes: 6.1 PHARMACEUTICALS;3.4 VACCINES
Health categories: INFECTION
Title: Hierarchical epidemiology: the spread and persistence of infectious diseases in complex landscapes.
Funder: Wellcome Trust

Abstract: To explain patterns of disease spread and persistence and to develop effective control policies it is vital to understand the process of transmission. For example, particular individuals are often disproportionately responsible for transmission, while landscape characteristics like rivers impede the spread of some diseases. Transmission of rabies can be tracked using contact tracing due to the memorable and discrete nature of infectious bites, providing a uniquely detailed picture of disease spr ead. I will apply statistical models to extensive rabies transmission data to investigate processes governing disease spread and persistence and how these are affected by population structure, physical geography and vaccination effort. Viruses like rabies mutate at such high rates that infection can be tracked between individuals with genetic data. I will develop statistical methodologies for combining spatial and temporal data on rabies cases with viral genetic sequences to reconstruct infect ion pathways. A suite of models will be used to investigate how transmission propagates and results in the spatiotemporal patterns we observe and the impacts of large-scale dog vaccination programs in different settings in Africa and Asia. Alternative control scenarios, outbreak response, and containment strategies will be explored to provide relevant feedback directly to these programs that aim for elimination.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Centre for Immunity, Infection and Evolution.
Funder: Wellcome Trust

Abstract: In the last Century, tremendous progress was made in understanding how pathogens cause disease, escape our immune defences and spread in populations. Nonetheless, new diseases have emerged, such as HIV or avian influenza, and old diseases including malaria, tuberculosis and other neglected tropical diseases have either resurged or generated new problems through their co-infection in vulnerable populations. Although new therapies and approaches to combating these diseases are expected, this hope is threatened by pathogen evolution. This can generate drug resistance, render vaccines ineffective or allow invasion of new hosts and populations. Understanding the processes of evolution provides the best hope to truly maintain the control of infectious organisms To address this we have recently established the Centre for Immunity, Infection and Evolution, bringing together all the necessary specialists, including infection biologists, immunologists, geneticists, mathematical modelers, epi demiologists and evolutionary biologists. Now we perceive a key opportunity to go beyond co-location and initial collaboration, to develop a fully integrated Centre able to reach out to address real world problems and to train a new cadre of multi-skilled interdisciplinary scientists. Our highly successful interdisciplinary approach offers an important opportunity to derive innovative approaches to understand and control infectious disease.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: INFECTION
Title: Finding Solutions to Moral Dilemmas in Ethically Charged Contexts: the case of Paediatric HIV/AIDS research in Developing Country settings.
Funder: Wellcome Trust

Abstract: The proposed research aims to examine the moral features of the solutions arrived at by field-level research actors, to resolve the ethical dilemmas they experience in the conduct of paediatric HIV research. This aim will be addressed by integrating two key approaches: 1. Describes both the dilemmas experienced and the solutions of the field-level research actors to these ethical dilemmas. 2. Critically examines and analyses the moral features of the solutions identified by research-actors a nd their potential applicability in other settings. This research will examine a multi-sited paediatric HIV trial which aims to assess whether purposely interrupting the treatment given to HIV-positive 8-21 year olds has an impact on their condition. The methods used to examine the solutions to challenges experinced in this trial will involve observing the everyday conduct of research, interviewing field-level research actors will involve exploring the solutions in the form of cases ac ross three research sites: the UK, Uganda and Brazil. These locations have different health systems and rates of poverty, mortality and morbidity and comparing the same study across these different settings could produce valuable insights into the ways in which solutions are developed and practiced.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: INFECTION
Title: Unravelling the interplay between dengue virus and the host unfolded protein response and interferon pathways.
Funder: Wellcome Trust

Abstract: Dengue virus, a tropical virus transmitted by mosquitoes, infects 50 million people annually and causes the debilitating and often fatal dengue haemorrhagic fever. The global impact of dengue virus is increasing, yet there are no specific treatments or vaccines. We wish to investigate the poorly understood mechanisms by which dengue virus disrupts the human immune response to cause severe disease. Initially we will use state-of-the-art techniques to identify human proteins that interact with or become altered by a dengue virus protein called NS2B3, which is known to inhibit critical immune pathways in infected immune cells. This will identify human proteins modified by the virus to disrupt our immune defences. We will then perform a detailed analysis of how these proteins contribute to our body's antiviral defence mechanisms against dengue virus and other viral diseases. We currently have a limited understanding of why different dengue virus strains vary in their ability to cause sever e infections, therefore we will investigate whether variation in NS2B3 accounts for some of the differences in disease severity observed in the clinic. We hope this research will lead to improved dengue virus treatments, and that it will improve our understanding of fundamental but poorly understood cellular processes.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: Cryptococcal antigen screening and targeted pre-emptive therapy in patients initiating ART: a prospective cohort study.
Funder: Wellcome Trust

Abstract: Cryptococcal meningitis is a leading cause of death in AIDS patients in the developing world, responsible for upto 500,000 deaths each year. Unfortunately, many patients come late for viral treatment (ART), and many die just before and after starting therapy. Cryptococcal meningitis causes many of these deaths. But many cases of cryptococcal meningitis may be preventable. Routine screening for very early infection, using a blood test (cryptococcal antigen or CRAG), can identify the 10% of pa tients who are at risk of developing cryptococcal meningitis. Once identified, these patients could then be given pre-emptive treatment to prevent them developing severe disease. This has many advantages over the alternative, called prophylaxis, which involves giving all AIDS patients preventative treatment, many of whom may not need it. We will study how effective CRAG screening and targeted pre-emptive treatment is. In addition, a new, easier to use, format of the CRAG screening test will be evaluated. 1000 patients will be screened using the CRAG test before starting ART. Those with a positive result would receive pre-emptive therapy for cryptococcal meningitis. All patients will then be started on standard ART and followed for 1 year to see whether any go on to develop cryptococcal meningitis.


Research activity codes: 5.1 PHARMACEUTICALS;4.4 POPULATION SCREENING
Health categories: INFECTION
Title: Investigating patterns of insecticide resistance in Central African populations of Anopheles funestus a major malaria vector
Funder: Wellcome Trust

Abstract: DDT and dieldrin resistance was recently observed in a Cameroonian An. funestus population. The resistance status to the pyrethroid insecticides, used to treat bednets, is unknown. There are also fears that unless barriers to gene flow exist, these resistances could spread rapidly throughout Cameroon and neighbouring countries such as Gabon and Congo and disrupt malaria control programs in Central Africa. However, little is known about the extent, distribution and mechanisms of insecticide resistance in An. funestus throughout the country and Central Africa. Such information is crucial for a successful implementation and management of control programs against this important malaria vector. Therefore, to improve our ability to control malaria in Central Africa, the aim of this proposal is to characterise insecticide resistance in field populations of An. funestus in this region. The project encompasses three aims: Aim 1 is to assess the susceptibility status of An. funestus populations to main insecticide classes in different regions in Cameroon and neighbouring countries. Aim 2 is to characterise resistance mechanisms in An. funestus populations from Cameroon through target-site detection and microarray. Aim 3 is to assess and predict levels of gene flow between An. funestus populations in Central Africa using microsatellites and DNA sequence polymorphism analysis.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: INFECTION
Title: Scottish Consortium Translational Medicine and Therapeutics Programme: 'Evaluating the effects of neutrophil induced 'damage'-associated molecular patterns in infective lung injury.
Funder: Wellcome Trust

Abstract: Despite advances in antibiotic therapies pneumonia remains a major cause of death worldwide. Neutrophils, central to the body's response to pulmonary pathogens, are recruited to the lung in response to specific pro-inflammatory 'signatures' expressed on the bacterial cell surface. If uncontrolled this process causes damage to lung parenchyma releasing similar inflammatory 'signatures', or DAMPs (damage-associated molecular patterns), initiating a vicious cycle of neutrophil recruitment and activation. We hypothesise that the release of DAMPs serves as a crucial factor in the propagation of non-resolving inflammation through impairment of neutrophil apoptosis and further release of these factors. Through a better understanding of this process, and use of novel imaging modalities in bacterial models of pneumonia, we hope to identify potential translationally relevant therapeutic targets. To this end our key goals are to: 1. Determine the effects of DAMPs released following pulmonary infection. 2. Investigate the contribution of dysregulated neutrophil apoptosis on the generation of DAMPs 3. Determine the effect of neutrophil apoptosis on DAMP production and the resolution of inflammation. 4. Determine the contribution of specific DAMPs to an excessive inflammatory response and the efficacy of various pharmacological interventions. 5. Utilise in vivo optical imaging probes to visualise, and delineate, DAMP-mediated inflammatory processes within the lung.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Ethics, Policy and Practice of Poliomyelitis Vaccination in Orissa: A case study in community, professional and governmental attitudes to mass public health programmes in India.
Funder: Wellcome Trust

Abstract: This interdisciplinary project brings together two experienced academics from different disciplines (history and philosophy) to work together on a project that naturally develops out of their individual past interests. It has three key aims First, to gather relevant empirical evidence about attitudes to poliomyelitis vaccination campaigns in Orissa from three key participant groups: parents, community workers and those involved in the planning and implementation of the campaign (e.g. government officials). Second, to outlineand systematically explore the ethical issues that will arise in relation to the empirical material gathered as part of this project. Third, to develop research capacity in ethics, particularly public health ethics, in a state in India (Orissa) where there is at the moment almost none. This project is only the first of an expected continuing collaboration between the applicants and their institutions.


Research activity codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE;3.4 VACCINES
Health categories: INFECTION
Title: Coordinated use of the hepatitis C virus genome during the virus lifecycle.
Funder: Wellcome Trust

Abstract: Hepatitis C virus is an important human pathogen that infects 170 million people worldwide and in most cases leads to long term liver disease, in some cases this ultimately results in liver cancer or liver failure, necessitating transplant surgery. Although the virus was identified in 1989 it was only recently that it has been possible to grow the virus efficiently in the laboratory. We will exploit this advance to investigate two key stages in the growth of the virus firstly how does the vir us replicate its genetic material, and secondly how is that genetic material built into new viruses? We will also try to understand how these two processes are coordinated we suspect that a virus protein called NS5A plays a key role in this and we will therefore study the function of this protein in more detail. Understanding these processes at a biochemical level will enable us to develop new antiviral compounds that block these stages of virus growth, thus providing valuable new tools for t he treatment of this infection.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: INFECTION
Title: From the Sexual Revolution to the New Plague': A Visual Investigation into Changing Notions of Sexually Transmitted Diseases in Britain, 1961-1992
Funder: Wellcome Trust

Abstract: The project aims to investigate the changing 'meanings' of sexuality through the use of visual imagery and how visual 'practices' were themselves shaped by new theories of media and advertisement. It will examine contemporary concerns relating to STDs and sexual health prompted by local and national authorities in conjunction with the medical profession, medical care organisations, voluntary and charitable networks, and the mass media whilst devising public responses to changing sexual norms and virtues. My project aims to contribute to new approaches in the field of visual culture and medicine that have emerged since the 1990s. It will uncover the strategies, which accounted for the success or failure of sexual health campaigns from the 1960s, the age of the 'sexual revolution' to the 'safer sex' era of the 1980s and highlight how 'awareness' of STDs changed over time to new attitudes towards human sexuality. By investigating changing anxieties regarding sexuality, sexual orientation and sexual behaviour from the 'Permissive' society to the era of the New Right, this project will track how health campaigns informed and reflected changing relationships between gender, sexuality, politics and the medical sciences.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: INFECTION
Title: Application of ribosomal profiling to investigate established and novel translational control phenomena in viruses
Funder: Wellcome Trust

Abstract: Historically, studies of gene expression have measured mRNA abundances rather than rates of protein synthesis. RNA expression profiling techniques, including microarray analysis, have revolutionized our ability to monitor the internal state of cells; however, mRNA and protein levels are often imperfectly correlated, and translational control can have a crucial role in modulating gene expression. In 2009, Ingolia and colleagues described ribosomeprofiling, a technique that provides global analysis of ribosomal footprints on mRNAs, providing new insights into translational control. Together with thelatest advances in deep-sequencing, ribosome profiling can provide a high resolution map of the location of translating and paused ribosomes on the transcriptome at any one time. Ribosomal profiling has since been used to study a variety of translational processes through the definition of ribosomalpause sites, inevitably revealing novel coding sequences. However, profiling is yet to be applied to the study of the regulation of virus gene expression. We will use ribosome profiling to investigate (1) ribosomal pausing at sites


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