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

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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.