UK-Indonesian Consortium to Identify Biomarkers Predictive of Dengue Disease Severity.

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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.