Triple-D Targets: The UK-Philippines Dengue Diagnostic and Drug Targets Research Consortium

登革热是人类最重要的蚊媒疾病，在菲律宾不断传播，菲律宾是所有东南亚国家中登革热负担第四大的国家。登革热病毒感染可引起一系列临床疾病，从使人虚弱但自限性的登革热到更严重和可能致命的登革出血热。登革热每2-3年发生一次，对菲律宾的卫生和经济产生重大影响。2008年至2012年期间发生了50多万例确诊病例，其中3000人死亡。尽管大多数登革热病例可以在家中得到治疗，但由于缺乏一种诊断测试来预测那些从轻度疾病发展到严重疾病的人，迫使患者和卫生保健提供者出于“安全目的”寻求住院治疗，从而使已经不堪重负的卫生保健系统饱和。菲律宾和英国学术机构之间的这项合作的总体目标是创建一个最先进的基础设施，以便更好地诊断感染DENV后出现严重疾病的患者。为了实现我们的目标，我们将建立一个特征非常明确的患者样本生物库，这些样本来自随着疾病进展而出现不同结果的登革热患者。我们将使用复杂的方法来观察在菲律宾流行的登革热病毒株，并确定我们可以在血液中检测到的患者RNA或蛋白质的任何变化，这些变化可能与登革热病毒感染相关的严重疾病有关。该方法将具有高通量和非常敏感的特点，因此即使是低水平转录本或蛋白质丰度的变化也将被检测到。我们还将能够检测到病毒微小变化的频率，并调查这些变化是否可能与疾病有关。这项技术将被转让给菲律宾，以便他们能够监测正在该国传播的病毒感染。结果将产生大量数据，这些数据将通过计算方法汇集在一起，这些计算方法要么是可用的，要么是由菲律宾和英国的研究小组开发的。英国合作伙伴在所需的生物信息学工具方面具有特别的经验，并将向菲律宾同行提供这些工具。这些技术和检测DENV突变的技术将通过短期科学交流访问、定期实时网络指导会议以及整个项目的联合讲习班转移到菲律宾。数据集的计算分析将使我们能够识别患者的生物标志物，这将通过额外的样本进行验证。在验证之后，任何生物标志物都可以用于开发诊断测试，以预测那些有发展为严重疾病风险的个体，并监测DENV变异性和检测与发热性疾病相关的其他感染。我们还将确定感染患者的细胞途径，这些途径可以用现有药物靶向，有可能预防严重疾病。总的来说，该项目将极大地支持菲律宾的研究能力建设。至关重要的是，联合王国合作伙伴提供的培训和技术转让将有助于建立一个适用于菲律宾许多其他传染病领域的适应性技术框架。

Dengue is the most important mosquito-borne disease of humans and is constantly spread in the Philippines, which has the 4th largest dengue disease burden of all Southeast Asian countries. 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. Dengue has a major impact on the health and economy of the Philippines as epidemics occur every 2-3 years. Over 500 000 confirmed cases occurred from 2008 - 2012 with > 3000 deaths. 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.The overall objective of this collaboration between academic institutes in the Philippines and the UK is to create a state-of-the-art infrastructure that that will allow better diagnosis of patients who develop severe disease after infection with DENV. In order to achieve our objective we will establish a very well characterised biobank of patient samples, collected from patients with different dengue disease outcomes as the disease progresses. We will use sophisticated methods to look at the strains of DENV that are circulating in the Philippines 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. This technology will be transferred to the Philippines so that they can monitor the virus infections, which are circulating in the country. The results will produce large amounts of data that will be brought together using computational methods, either available or be developed by the Filipino and UK groups. The UK partners have particular experience with the bioinformatics tools needed and will provide these to their Filipino counterparts. These skills and those for detecting mutations in DENV will be transferred to the Philippines through short-term scientific exchange visits, regular real-time cyber-mentoring sessions as well as joint workshops throughout the project. Computational analysis of the datasets will allow us to identify biomarkers in patients, which will be validated with additional samples. After validation, 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 and detect other infections associated with febrile disease. We will also identify cell pathways in infected patients which can be targeted with existing drugs, potentially to prevent severe disease. Overall, the project will significantly support the building of research capacity in the Philippines. 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 the Philippines.