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第四大登革热疾病负担。感染登革病毒（DENV）会引起一系列临床疾病，从使人衰弱但自限性的登革热到更严重且可能致命的登革出血热。登革热对菲律宾的健康和经济产生重大影响，因为每2-3年发生一次流行病。2008年至2012年期间发生了50多万例确诊病例，死亡人数超过3000人。虽然大多数登革热病例可以在家中管理，但缺乏诊断测试来预测那些从轻度发展到严重疾病的个体，迫使患者和医疗保健提供者出于“安全目的”寻求住院治疗，饱和已经不堪重负的医疗保健系统。菲律宾和英国学术机构之间的这种合作的总体目标是创造一个国家的-这将有助于更好地诊断感染DENV后发展为严重疾病的患者。为了实现我们的目标，我们将建立一个非常具有特征的患者样本生物库，这些样本是随着疾病的进展从具有不同登革热疾病结果的患者中收集的。我们将使用复杂的方法来观察在菲律宾传播的DENV菌株，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DENV感染相关的严重疾病有关。该方法将是高通量和非常灵敏的，使得即使是低水平转录物或蛋白质丰度的变化也将被检测到。我们还将能够检测病毒微小变化的频率，并调查这些变化是否与疾病有关。这项技术将被转移到菲律宾，以便他们能够监测在该国传播的病毒感染。结果将产生大量数据，这些数据将使用菲律宾和英国小组现有或开发的计算方法汇集在一起。联合王国的合作伙伴在所需的生物信息学工具方面具有特别的经验，并将向菲律宾的合作伙伴提供这些工具。这些技能和检测DENV突变的技能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期间的联合研讨会转移到菲律宾。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。经过验证后，任何生物标志物都可以用于开发诊断测试，以预测那些有进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通路，这些通路可以用现有药物靶向，从而有可能预防严重疾病。总体而言，该项目将大力支持菲律宾的研究能力建设。至关重要的是，英国合作伙伴提供的培训和技术转让将有助于建立一个适应性强的技术框架，该框架也与菲律宾许多其他传染病领域有关。

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.