Treating the host in Dengue: mediators and pathways of resolution as a new therapeutic paradigm

登革热每年在世界最贫穷地区的128个国家感染约4亿人，但没有适当的治疗方法。根据巴西卫生部的资料，过去10年巴西发生了重大登革热流行病，过去4年报告的病例约为100万例/年（http：//portalsaude.saude.gov.br/index.php/situacao-epidemiologica-dados-dengue）。仅在5月，据报告巴西几个州正在经历一种新的流行病（http：//www.bbc.co.uk/news/world-latin-america-32589268）。虽然严重疾病仅占所有报告病例的约2%，但没有具体的治疗方法，目前无法确定有发生严重疾病风险的患者。高发病率和没有具体的治疗方案相结合，给已经不堪重负的卫生系统带来了巨大的负担。在这项提案中，我们打算研究内源性介质的影响和作用，这些介质可以缓解过度炎症，促进对登革热动力学的解决。为了研究表达谱，以及这些保护性介质的水平如何随时间变化，我们将使用尖端的分析方案（将在英国完成）。为了研究这些介质与人类疾病的相关性，我们将使用患者样本以及实验动物的新模型（将在巴西进行）。后者反映了患者的几项发现，并提供了一个关键的体内环境，以支持识别和将新疗法转化为人类。我们的新方法建议研究登革热感染过程中的炎症过程，更新颖的是内源性组织保护途径可能对感染过程产生的影响（这一领域通常被称为“炎症消退”）。因此，通过这个项目，我们寻求资金来研究登革热的新机制和过程，具有双重目标：1。使用人类样本和动物模型发现登革热的新机制。提供概念验证的结果，“推动”内源性的解决途径可以为登革热提供一种新的治疗途径。这项工作的首要任务是新的概念，即为了对抗与感染相关的过度炎症，我们可以治疗宿主，处理感染因子，从而使它们处于控制之下并有利于它们的处置。

Dengue infects some 400 million people in 128 countries each year in poorest regions of the world, yet proper therapeutic treatment does not exist. According to the Brazilian Ministry of Health, significant dengue epidemics have occurred in the last 10 years in Brazil with around 1 million cases/year reported in the last 4 years (http://portalsaude.saude.gov.br/index.php/situacao-epidemiologica-dados-dengue). Only in May it was reported that several States of Brazil are experiencing a new epidemic (http://www.bbc.co.uk/news/world-latin-america-32589268). Although severe disease accounts for only approximately 2% of all reported cases, no specific treatment is available and it is not possible at present to define patients at risk to develop severe disease. The combination of high incidence and no specific therapeutic options places an enormous burden on already over-stretched health systems.In this proposal we intend to study the impact and roles of endogenous mediators that temper excessive inflammation and promote resolution on the dynamics of Dengue disease. To study profiles of expression, and how the levels of these protective mediators change over time, we will use cutting-edge analytical protocols (to be done in the UK). To study the relevance of these mediators to human disease, we will use patient samples as well as novel models in experimental animals (to be done in Brazil). The latter mirror several findings in patients and provide a crucial in vivo environment to underpin identification and the translation of novel therapies into humans. Our new approach proposes to investigate inflammatory processes during the infection of Dengue and, more novel, the impact that endogenous tissue-protective pathways may have on the course of infection (this area is often referred to as 'resolution of inflammation'). Therefore, with this project we seek funding to study new mechanisms and processes in Dengue with the dual aim:1. Discover novel mechanisms in Dengue using human samples and animal models.2. Provide proof-of-concept results that 'pushing' endogenous pathways of resolution can provide a novel therapeutic avenue for Dengue.The over-arching remit of this work is the novel notion that to combat excessive inflammation associated with infection we could treat the host, to deal with the infectious agents, thus keep them under control and favour their disposal.