NIHRDataInsights/HRCSData huggingface dataset:
Title: Field trials of synthetic sandfly sex pheromone to reduce human visceral leishmaniasis transmission
Funder: Wellcome Trust

Abstract: Although visceral leishmaniasis is a major vector-borne disease of humans and dogs there are few options for sustainable control. Female sand flies take blood from infected hosts (attracted to them by the combined host smell and male sand fly produced sex pheromone) and transmit the infection to new hosts. Sand fly control is limited to insecticide treatment of animal shelters, an action that kills male sand flies, interrupts mating behaviour and results in females feeding elsewhere on unprotect ed hosts. It thus increases rather than reduces the risk of transmission. We have synthetized the male sand fly pheromone, and demonstrated that when placed near insecticide, a disproportionate number of females are attracted and killed. We are conducting a trial in Brazil to demonstrate that this lure-and-kill approach (the product) will reduce transmission, by measuring the effect the product has on infection in dogs. The objective of the current proposal is to strengthen the product efficacy and regulatory data for potential adoption by the Brazilian Ministry of Health. Following the recommendations of an international scientific committee, we propose (i) to test if the product could reduce infection in humans, and (ii) to describe more completely its chemical, biological and ecological properties.


Research activity codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health categories: INFECTION
Title: Optimizing the herpesvirus-specific CD8 T-cell response by targeting the IL-10 receptor pathway.
Funder: Wellcome Trust

Abstract: Human cytomegalovirus (HCMV) is a common virus that usually does not cause any symptoms However, individuals with poorly functioning immune systems fail to control this virus resulting in disease which may be fatal; for example, transplant patients receiving drugs that suppress the immune system. CD8 T-cells are important antiviral immune cells that limit HCMV. Their transfer into HCMV-infected patients is a promising strategy to help manage life-long HCMV infection to prevent disease. Unfortun ately, an immune protein called interleukin-10 (IL-10), can suppress CD8 T-cells. I propose that blocking the action of IL-10 will enable rapid growth of effective antiviral CD8 T-cells for use in T-cell transfer therapy. I will test this by growing and assessing the function of HCMV-specific CD8 T-cells, both with and without blocking IL-10. Work includes using novel methods for large-scale generation, essential for cell transfer therapy. I will also use a mouse model of CMV infection to examin e whether growing CD8 T-cells in the absence of IL-10 improves control of virus infection after transfer into immune-suppressed, virus-infected hosts. These studies will assess the effectiveness of IL-10 blockade in the generation of potent antiviral T-cells for adoptive cell therapy and treatment of HCMV-infected individuals.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: INFECTION
Title: The effect of pneumolysin-induced histone posttranslational modifications on the innate response of macrophages to Streptococcus pneumoniae
Funder: Wellcome Trust

Abstract: Streptococcus pneumoniae is a major cause of severe bacterial disease. It contains factors, which help it cause disease; of these the toxin pneumolysin is critical in helping it escape the body's defences. One of the first lines of defence against bacteria is the macrophage, the resident immune cell found in tissues but how pneumolysin inhibits macrophages is unclear. The ability to transcribe our genetic code into proteins is regulated by factors including chemical changes to histone protei ns, around which DNA is wound. These changes to histones are emerging as important causes of human disease but it is unclear if they arise during acute bacterial infection and influence our body's response to infection. I will examine whether the toxin pneumolysin causes modifications to histones, the modifications that arise and determine which immune genes are effected. The histone modifications will be manipulated to determine how they influence the macrophages response to S. pneumoniae infec tion. I will also determine if the histone changes persist in macrophages and whether they can be transmitted to future generations, using mouse models of infection. This project will provide new insights into how bacteria cause disease and potentially suggest new approaches to combat these infections.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Childhood pneumococcal pneumonia in Nepal: novel immunodiagnostic methods and transcriptomic investigation of pathophysiology
Funder: Wellcome Trust

Abstract: 1.3 million children <5 years of age die from pneumonia annually worldwide, with the bacterium Streptococcus pneumoniae (pneumococcus) responsible for half of these deaths, despite increasing uptake of vaccines against pneumococcus. However, diagnosis of pneumococcal pneumonia is difficult and inaccurate. We also lack a clear understanding of why many children carry pneumococcus in their nose and throat and are healthy, and yet some develop disease. I aim to assess new diagnostics for, and d escribe the pathophysiology of, pneumococal pneumonia in children prospectively enrolled at Patan Hospital, Kathmandu, Nepal. This is an area with high burden of pneumococcal pneumonia and planned pneumococcal vaccination from autumn 2014. I will characterise children with pneumonia according to standardised clinical and laboratory methods. I will then look at antibody secretion from immune cells to components of the pneumococcal cell wall as a diagnostic test, and calculate the proportion o f pneumonia secondary to pneumococcus. To understand the pathophysiology of pneumococcal pneumonia, we will measure and analyse the changes in gene expression between healthy children and children with pneumococcal pneumonia. This project would facilitate my training in various methods and develop new diagnostic tools in an important clinical context.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Innate immune governance of the fate of inflammatory monocytes in tuberculosis.
Funder: Wellcome Trust

Abstract: I aim to increase our understanding of protective immune responses to Tuberculosis (TB), that may help us can develop new strategies to overcome this diease. I will focus on the role of one type of immune cell, called monocytes. These accumulate at the site of disease and mature into cells called macrophages, which can engulf and kill the microbes that cause TB, called Mycobacterium tuberculosis (Mtb). Differences in the way monocytes mature to macrophages may influence the outcome of infection with Mtb. In this fellowship application, I will test the theory that disease causing strains of Mtb influence monocyte maturation in such a way that diminishes the ability of the resulting macrophages to control infection. Then I will focus on the role of a specific surface component of monocytes and macrophages called TLR2, which is known to recognize Mtb. I will test whether blocking TLR2 experimentally will also influence monocyte maturation in such a way that favours survival and growth of Mtb. Finally, I will test whether the gene expression patterns that are associated with monocyte maturation in my model of tuberculosis is replicated in macrophages from the respiratory tract of patients with active tuberculosis disease.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Pathogenesis of Crimean-Congo Haemorrhagic Fever (CCHF) - interaction of immune response, viral load and clinical course.
Funder: Wellcome Trust

Abstract: Crimean-Congo haemorrhagic fever (CCHF) is a viral infection transmitted to humans mainly through tick bites. It is present in a number of countries worldwide and has a significant mortality (10-30%). The way in which the virus overcomes natural human defences is poorly understood, and it is suspected that an exaggerated human immune response may cause some of the severe effects. This research will study CCHF in adult patients in Turkey. The key goals are: 1. To measure the levels of CCHF virus in blood and urine samples and to determine if this correlates with the severity of the infection. 2. To investigate the body's immune response to CCHF related to severity and outcome of the infection. 3. To investigate whether an over active immune response may play a role in severe CCHF cases, with a similar mechanism to that seen in other severe infections. Although there is no proven drug treatment for CCHF, through this research we will have a better understanding of how the diseas e acts in humans and a platform to design future studies. It will also provide international academic and laboratory collaboration, and strengthen laboratory capability.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Elucidation of the roles of PTN and ISG15 in RSV cytopathogenesis: possible biomarkers of severe disease?.
Funder: Wellcome Trust

Abstract: Respiratory syncytial virus (RSV) causes bronchiolitis, a serious lung infection in infants. There is no vaccine to prevent or drug to treat this illness. How RSV causes disease remains a mystery. When RSV infection occurs, cells lining the airways respond by producing proteins/ chemicals to fight the infection. Infants born prematurely are much more vulnerable to severe illness and death following RSV infection. I believe the infectionfighting response in infants born prematurely is less effect ive, which may explain why they are more vulnerable to severe RSV disease. The research team at Queens University Belfast have developed the means to grow airway cells that look and behave as they would in infants.The team has identified that children who get milder symptoms with RSV infection may have more of certain infection-fighting proteins in their airways than those who get very sick. By growing cells from normal and premature infants at birth and one-year-old and then infecting these cel ls with RSV, I will identify the difference in production of these infection-fighting chemicals by the airway cells. I believe this information will help us find ways to boost the ability of preterm/young infants airways to fight RSV infections through future research.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION
Title: Accelerated Clinical Evaluation of a Monovalent Vectored Ebola vaccine
Funder: Wellcome Trust

Abstract: An outbreak of Ebola in West Africa has spread from Guinea to several countries and presents a continuing threat. WHO have declared this an international public health emergency. The current proposal aims to test the most suitable potential vaccine candidate for Ebola in humans for the first time, in the UK and West Africa, in parallel with collaborators at NIH, to determine its safety and immunogenicity. Successful completion of these trialsin 2014 would provide WHO with the option of deploying this vaccine early in 2015.


Research activity codes: 3.4 VACCINES
Health categories: INFECTION
Title: China s AIDS NGOs: A Vehicle of Norm Changes?.
Funder: Wellcome Trust

Abstract: This proposed project aims to examine a non-biomedical, social means to fighting the spread of HIV/AIDS in China. That is, mitigating stigmatization against the people living with the disease through the efforts of Chinese non-governmental organizations (NGOs) to diffuse the international norms proscribing stigmatization into the country. This project asks why HIV-related stigmatization is serious in China and whether AIDS NGOs there can play a positive role in bringing about norm change to mitigate stigmatization.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: INFECTION
Title: Emergency Evaluation of Treatments for Ebola Virus Disease
Funder: Wellcome Trust

Abstract: We aim to establish a clinical trials platform in two or more Ebola Virus Disease (EVD) treatment centres in West Africa through which the efficacy and safety of un-registered therapeutic products can be rapidly assessed in patients with EVD. Therapeutic options will be evaluated in a standardised format that is consistent with ethical standards and the delivery of patient care in challenging conditions, and will provide data for potential regulatory approval. Following a run-in' observational stage, the initial pragmatic intervention study design is an openlabel, non-randomised trial with sequential enrolment and analysis of subjects and with historic and contemporaneous controls. Multiple products will be assessed separately using a standardised methodology. The trial is designed to distinguish as rapidly as possible between three situations: (a) the treatment is very effective, (b) the treatment is promising and (c) the treatment is ineffective. The platform will be established and operationalized in the near term using two agents studied in series or parallel (depending on availability). The selection of the initial agent for evaluation will be decided within the next two weeks, as additional data become available. The medium term objective is to provide a platform for the evaluation of three therapeutic classes with different modes of antiviral action: neutralising antibodies (e.g. ZMapp, convalescent plasma); RNA inhibitor molecules (e.g. TKM-100802/AVI-7537); other antivirals (e.g. Brincidofovir).


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFECTION
Title: Strategic Alliance Funding: MRC Weatherall Institute of Molecular Medicine (WIMM) at the University of Oxford 22-27
Funder: Medical Research Council

Abstract: Strategic Alliance Funding: MRC Weatherall Institute of Molecular Medicine (WIMM) at the University of Oxford


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.4 METHODOLOGIES AND MEASUREMENTS
Health categories: INFECTION;BLOOD;CARDIOVASCULAR;STROKE
Title: Targeting transfer RNA-derived fragments during KSHV infection
Funder: Medical Research Council

Abstract: Non-coding RNAs (ncRNAs) play diverse roles in a multitude of cellular processes, functioning as critical regulators of gene expression. This is reinforced by ncRNA dysregulation being implicated in the development and progression of a wide range of human diseases. We have exciting data demonstrating that the oncogenic herpesvirus, KSHV, manipulates a recently identified class of ncRNAs, termed transfer RNA-derived small RNA fragments (tRFs), to enhance its own replication. We provide evidence that KSHV specifically dysregulates two distinct tRF subgroups, namely 3'-tRFs and i-tRFs. Notably, reversing KSHV-mediated tRF dysregulation is detrimental for KSHV lytic replication, which may provide a novel antiviral strategy. We will examine the role of these two distinct tRF subsets in virus replication. Firstly examining the role of downregulated 3'-tRFs in regulating mRNA levels in a similar fashion to miRNAs. Secondly, we will assess the role of upregulated i-tRFs as RNA binding protein (RBP) sponges. The role of these target mRNAs and RBPs will then be further investigated in the context of virus replication. In addition, we will examine virus-induced mechanisms which lead to tRF dysregulation during infection, particularly focussing on KSHV-mediated manipulation of RNA modifying enzymes. Finally, we will assess and optimise the best approach to reverse tRF dysregulation in KSHV producer cell lines and a 3D tumour model. This project will therefore determine how KSHV-mediated manipulation of tRFs can regulate gene expression and identify novel mechanisms of how tRF biogenesis is regulated during infection. It will also assess whether reversing tRF levels is a viable antiviral therapeutic approach. Together it will provide valuable information on tRFs as emerging regulators of gene expression with diverse biological functions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION;CANCER AND NEOPLASMS
Title: MiTAG- Microwave treatment for anogenital disease.
Funder: Chief Scientist Office, Scotland

Abstract: Anogenital precancerous lesions can be difficult and painful to treat and treatment can be associated with complications. For example, >1% of people experience genital warts, which are treated with cryotherapy and creams which sting and can cause inflammation. Cervical pre cancers are also common (13,000 new cases per annum in Scotland) and are treated by excision, sometimes leading to subsequent bleeding and increased risk of preterm birth. These conditions are caused by human papillomaviruses (HPVs). Our collaborators, Emblation Limited, a Scottish medical device manufacturer (http://www.emblation.com/), developed a microwave “pen” that can clear HPV-associated diseases just by mild heating of the tissue. Work using well-proven laboratory models of anogenital pre cancers and genital warts is necessary before progressing to a clinical trial. We will test how microwaving affects living tissues and ask if microwaving stops the HPV virus growing in the tissues. An important part of this project will be to understand if and how microwaving can activate antiviral immunity against the anogenital-infective HPVs. In the end, microwave treatment could be an innovative, acceptable and non-painful means to treat anogenital disease. This would benefit patients by providing better-tolerated treatment devoid of after effects and benefit clinicians by reducing clinic time and resources.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: INFECTION;CANCER AND NEOPLASMS
Title: Characterising the Role of IN Binding Partners in HTLV Infection and Integration
Funder: Wellcome Trust

Abstract: Human T-cell lymphotropic virus type 1 (HTLV-1) is a virus that can cause a range of debilitating and often fatal diseases including neurological disorders and an aggressive form cancer. There exists no successful therapy to treat these diseases, therefore research into mechanisms of the viral lifecycle is crucial. For the virus to replicate efficiently it must integrate a DNA copy of its RNA genome into host DNA using the viral enzyme integrase. Integration site selection is not random but is influenced by interaction with host proteins. The correlation between the site of integration, production of virus, and disease occurrence indicates the integration site as a point of interest. We have identified a number of host proteins that could (directly or indirectly) be involved in targeting the HTLV-1 pre-integration complex to the site of integration. Using a combination of lentiviral shRNA mediated knock-down and expression of chimeric proteins we will investigate whether proteins that co-purify with HTLV-1 IN affect infectivity and integration. Understanding these mechanisms is a step towards identifying potential drug targets to prevent HTLV-1 infection.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION;CANCER AND NEOPLASMS
Title: Investigating Bacterial Colibactin Expression and its Effects on Tumour Formation
Funder: Wellcome Trust

Abstract: Colorectal cancer is the third most common cause of tumours worldwide. Evidence suggests that bacteria residing in the gut play a role in the onset of this disease, with research showing links between diet, the bacteria living in our gut and the overall health of the individual. Patients suffering from disorders of the gut are routinely given probiotics, cultures of health-promoting bacteria that colonise the host’s gut, outcompeting harmful bacteria and restoring a healthy microbial population within the intestine. One probiotic bacteria, Escherichia coli, has been shown to have antibiotic and anti-inflammatory properties, but research also suggests that these bacteria can release harmful toxins that damage intestinal cells, initiating the development of colorectal cancer. I aim to investigate how specific dietary components affect the expression of probiotic toxins in a way that reduces tumour development. I will use molecular biology techniques to work out how components of the diet affect gene expression of the toxin in probiotic strains, and I will use mouse models to study tumour development in living organisms. In the future, I hope that coupling administration of probiotics with specific dietary components could reduce the risks of developing colorectal cancer and become an effective therapeutic approach.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFECTION;CANCER AND NEOPLASMS
Title: Investigating and developing dietary therapeutics to modulate the gut microbiota to prevent and treat breast cancer
Funder: Wellcome Trust

Abstract: The gut microbiome holds the largest number of microorganisms in the body, responsible for producing a wide array of metabolites and modulating numerous physiological functions. Not only has the gut microbiome been studied to adapt responses in distant organs, but gut microbial perturbations may also be associated with breast cancer risk and progression. We therefore propose that dietary supplementation to improve the gut microbiome could slow tumour initiation and progression. I aim to utilise probiotic combined with prebiotic supplementation in breast cancer mouse models to define a cancer-protective microbiota. To evaluate any anti-cancer mechanisms of probiotics and plant-derived prebiotics, I will use techniques, such as flow cytometry, immunohistochemistry and immunoassays, to assess immune function systemically and in tumour microenvironments. By monitoring any alterations in metabolic output of the microbiota, using NMR and mass spectrometry, I aim to identify if the mechanisms are metabolite driven. It is also vital to profile microbial populations by whole genome sequencing and link back to metabolite profiles. These studies will help to understand how the gut microbiota links to breast cancer initiation and progression and aim to develop dietary interventions which could be used as part of preventative and therapeutic strategies.


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