UK - Department for Business, Energy and Industrial Strategy
UK-Indonesian Consortium to Identify Biomarkers Predictive of Dengue Disease Severity.
Project Data Last Updated: 27/08/2020
IATI Identifier: GB-GOV-13-FUND--Newton-MR_P017509_1
Dengue is the most important mosquito-borne disease of humans. Indonesia bears the largest dengue disease burden and economic cost in Southeast Asia. The incidence of dengue haemorrhagic fever has increased dramatically in Indonesia from 0.05/100000 individuals in 1968 to ~35-40/100000 in 2013. Infection with dengue virus (DENV) causes a spectrum of clinical illnesses, ranging from dengue fever, a debilitating but self-limited condition, to the more severe and potentially fatal dengue haemorrhagic fever, but the factors contributing to differential disease severity are not entirely understood. Although most dengue cases could be managed at home, the lack of a diagnostic test to predict those individuals who progress from mild to severe disease forces patients and healthcare providers to seek hospital admissions for "safety purposes", saturating an already overwhelmed healthcare system. Our OVERALL OBJECTIVE, by adopting an integrated analysis of peripheral blood from patients who have well-defined clinical outcomes, is to correlate disease severity with a) DENV genetic diversity or other co-morbidity factors (e.g. co-infection), b) host transcriptomic and proteomic changes and c) alterations in platelet function and endothelial activation and permeability. In order to achieve our objective we will analyse a very well characterised biobank of patient samples, collected both retrospectively and prospectively from patients with different dengue disease outcomes as the disease progresses. We will use sophisticated methods to look at the strains of DENV and other arthropod-borne viruses (such as chikungunya and Zika virus) that are circulating in Indonesia and also identify any changes in patient RNA or proteins which we can detect in blood that might be linked to serious disease associated with DENV infection. The methods will be both high throughput and very sensitive so that even changes in the abundance of low-level transcripts or proteins will be detected. We will also be able to detect the frequency of minor changes in the virus and investigate whether these may be linked to disease. Using complementary approaches we will also examine a) platelet number and function in patient blood samples and b) the ability of patient serum from different disease outcomes to mediate changes in endothelial permeability using in vitro assays. The results will produce large amounts of data that will be brought together using computational methods, either available or to be developed by the UK partners. The UK partners have particular experience with the bioinformatics tools needed and will provide these to their Indonesian counterparts through short-term scientific exchange visits throughout the project. Computational analysis of the datasets will allow us to identify biomarkers in patients, which will be verified using prospectively collected samples. After verification, any biomarkers can then be used to develop diagnostic tests to predict those individuals at risk of progressing to severe disease and to monitor DENV variability. In addition, our metagenomic analysis will also assess whether other arboviruses such as chikungunya and Zika virus, whose status in Indonesia is unknown, may have been misdiagnosed as dengue infection. Overall, the project will significantly support the building of research capacity in Indonesia. Critically, the training and technology transfer provided by the UK partners will help to establish an adaptable technological framework that is also relevant to many other infectious disease areas in Indonesia.Objectives
Our OVERALL OBJECTIVE, by adopting an integrated analysis of peripheral blood from Indonesian patients who have well-defined clinical outcomes, is to correlate dengue disease severity with i) dengue virus genetic diversity or other co-morbidity factors (e.g. co-infection) using metagenomic analysis, ii) host transcriptomic and proteomic changes and iii) platelet function and the presence of mediators of endothelial permeability. Our integrated data analysis will allow us to identify candidate viral and host biomarkers that predict progression to severe dengue disease, which will be verified using prospectively collected samples. In addition, our metagenomic analysis will also assess whether other arboviruses such as chikungunya and Zika virus, whose status in Indonesia is unknown, may have been misdiagnosed as dengue infection. To achieve our overall objective, we propose two parallel but closely integrated activities that are built within a collaborative framework and research infrastructure. The core activities are: A) Research and B) Training. Research: The project has 5 specific research aims: i) To use retrospectively and prospectively collected blood and serum from patients sampled at different times after hospital admission (during the febrile, critical and recovery phases) with well characterised clinical outcomes (febrile illness non-dengue, dengue +/- warning signs and severe dengue disease) to undertake a global unbiased metagenomic, transcriptomic and proteomic ('omics) analysis. ii) To analyse platelet function in the prospectively collected samples and determine the effects of patient serum on endothelial cell permeability using an in vitro model. iii) To develop a collaborative bioinformatic framework that integrates clinical, 'omics and biochemical and immunological data. iv) To use the integrated datasets to identify candidate nucleic acid and protein biomarkers for prognostic diagnosis of dengue severity and verify the biomarkers using prospectively collected clinical samples. v) To determine the contribution of circulating arboviruses in Indonesia to dengue and other febrile diseases. Training: The research plan will be achieved using a series of interconnected work packages distributed between the UK and Indonesian researchers. The expertise of the researchers at the University of Bristol (UoB) and University of Glasgow (UoG) in high-throughput 'omics along with any integrated bioinformatic and statistical analysis tools will be transferred to the Indonesian partners at the Universities of Indonesia (UI), Padjadjaran (UP) and Jenderal Soedirman (JS) through short-term scientific exchange visits, and joint workshops throughout the project. This will significantly support the Indonesian research capacity enhancement program. Critically, the training will help to establish an adaptable technological framework that is relevant to many other infectious disease areas in Indonesia.
|Extending:||UK Research & Innovation|
|Funding:||UK - Department for Business, Energy and Industrial Strategy|
|Implementing:||University of Bristol|
Sectors groups as a percentage of country budgets according to the Development Assistance Committee's classifications.
A comparison across six financial years of forecast spend and the total amount of money spent on the project to date.