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

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.

Experimental work is unveiling a novel therapeutic opportunity for treating bacterial and viral infection: targeting the host in order to augment its ability to 'deal' with the infective agent. To achieve this, we propose to exploit the biology of the Resolution of Inflammation investigating the properties of pro-resolving mediators (Annexin A1, lipoxins and resolvins). These are known to augment myeloid cell phagocytosis and killing function to avoid excessive cell activation that would lead to self-harm. This approach works in models of sepsis, influenza and bacteremia. Here we will focus on Dengue fever in view of: 1)its epidemic nature in Brazil with massive number of patients and ensuing impact on society, both from a health and economic perspective; 2)the lack of any therapeutic treatment, except for fluid replenishment; 3)the current inability to identify patients who will develop severe dengue which may be lethal.

We will address the hypothesis that inadequate engagement of pro-resolving mediators contributes to the excessive inflammatory response observed in patients with the most severe forms of dengue infection. The specific aims of our integrated and translational project are:

Aim 1. Define expression levels of pro-resolving mediators in dengue patients
Aim 2. Define expression relevance of anti-inflammatory/pro-resolution mediators in experimental models of dengue infection in mice.

This project will generate new knowledge in the pathogenesis of dengue allowing the identification of novel biomarkers for patient stratification and informing of novel therapeutic targets for future development and commercialization. Proof-of-concept pharmacological experiments with molecules identified in the pro-resolving screening will also be performed, paving the way to future translational investigations. As such this partnership will deliver novel science as well as practical IP-protectable strategic approaches for the clinical management of dengue.

This project aims to define fundamental anti-inflammatory processes that become dysregulated in Dengue with a particular focus on protective pathways that can be operative in the patients. As such this work can open new avenues to identify and distinguish between patients affected by Classical Dengue (where diseases resolves spontaneously within 7-10 days) and Severe Dengue (where disease is severe and protracted and can lead to death; ~5-10% of patients). The project will identify new (bio)markers for stratification and inform new potential therapeutic avenues. Ultimately, this could lead to improved patient care and outcomes for patients with Severe Dengue, including reduced mortality, better use of healthcare resources and economic savings in poor countries.

Benefit to Society.

This project will benefit society in multiple ways. The epidemic and unpredictable nature of Dengue (see http://www.bbc.co.uk/news/world-latin-america-32589268 for a recent commentary on the current outburst of Dengue in Brazil) confirms the timeliness of this proposal.

Patient Benefit: This work will benefit patients through identification of those more susceptible to developing Severe Dengue so that they can be better managed and this could save lives. In fact, biomarkers of severity may help in defining this patient population which will benefit the most from intensive treatment and hospitalisation. They could also be selected for participation in clinical trials of new dengue-specific therapeutics. Such patient stratification has the potential to improve the efficiency and outputs of future clinical trials as the trials would be focused on the most severely affected patients.

Society Benefit: Thanks to the links with clinicians of Prof Teixeira and Santiago, there is an operative path for translating our novel work on Dengue into potential diagnostic and therapeutic tools leading to improved treatments for patients and overall public health. At the same time, better clinical management of Dengue through improved identification of high risk patients will have an impact on national health systems in poor countries with reduction of costs associated with intensive treatment and hospitalisation.

General Public Benefit: The general public will benefit from an increase in the understanding of Dengue infection and how it can be managed, especially in view of the current Dengue epidemic that Brazil is experiencing.


Benefit to the Economy.

The possibility to develop novel biomimetics would attract the interest of pharmaceutical companies and we will investigate the potential commercial exploitation of the research outcomes. While these benefits will not be achievable during the duration of this project, this proposal holds strong potential to contribute to the economy and wealth of the UK and Brazil providing in this manner a legacy that could come to fruition post-project.

The project also offers the opportunity to train highly skilled researchers with exposure to interdisciplinary fields in both UK and Brazil, augmenting in this manner the competitiveness of the two Countries.

On a longer scale, the possibility to develop a treatment for Dengue would benefit the Brazilian (and other countries affected by Dengue) economy also in several indirect ways. Loss of productivity and premature deaths are some of the indirect costs associated to Dengue. In addition, while it is hard to exactly quantify the impact of Dengue on tourism, official and media warnings during Dengue epidemics have a negative impact, damaging those regions whose economy relies on tourism.