With an estimated 100 million symptomatic cases annually, Dengue is well recognised as the most common human arboviral infection globally. A subpopulation of infections exhibits debilitating symptoms of systemic inflammation and vascular leakage, which may be deadly unless monitored closely in hospital. This severe disease is characterised by a cytokine storm, a dysregulated host immune response in which overabundant immune signalling becomes harmful to the host. Dengue treatment is limited to fluid replacement therapy to replace lost blood volume, and Dengue vaccines have had a troubled development that limits public uptake. Novel therapeutic options are urgently needed.
To address this, I have optimised a Dengue mouse model that recapitulates the inflammatory disease observed in humans, where viremia peaks 1-2 days post symptom onset, before symptoms worsen simultaneously with immune activation and viral clearance. Type 1 interferon (IFN)-deficient mice infected with Dengue virus type 2 (DENV2) develop peak viremia at 2 days post-infection followed by weight loss and immune activation up to 4 days post-infection, at which point viremia reaches low or undetectable levels. 26-plex cytokine analysis of infected plasma and spleen samples demonstrated broad immune activation, including key inflammatory cytokines upregulated in human disease such as IL-6, TNF, and IL-1b.
Interestingly, severe Dengue shares many risk factors, immune signatures and inflammatory symptoms with severe COVID-19. Based on the recent progress in understanding cytokine storm in COVID-19, I am now targeting cytokine signalling with clinical-stage anti-inflammatory drugs to treat Dengue in my established mouse model. Preliminary data suggest that broad immunosuppression with Dexamethasone may improve Dengue symptoms, while TNF blockade with etanercept did not mitigate disease outcomes. I am currently determining the efficacy of GM-CSF blockade, and plan to assess Jak inhibition, IL-6 blockade and IL-1b blockade. Collectively, this work will provide crucial information for the development of treatment strategies for moderate/severe Dengue, and my discoveries here may also be applied to the significantly deadlier Dengue/COVID-19 co-infection.