Dengue is the most common mosquito-borne viral infection, and the causative agent of many epidemics annually across the globe. Some infections present with debilitating symptoms of systemic inflammation and vascular leakage, which can prove deadly unless closely managed in hospital. Such disease is characterised by a cytokine storm: an abnormal host immune response in which overabundant immune signalling contributes to host pathology. Treatment is limited to fluid replacement therapy to replace lost blood volume, and Dengue vaccines have proven controversial. As Dengue continues to expand globally, novel therapeutic options are urgently needed.
To address this, I’ve optimized a Dengue mouse model to recapitulate the inflammatory symptoms seen in humans, where moderate/severe disease coincides with potent immune activation. Type I interferon (IFN)-deficient mice infected with Dengue virus type 2 (DENV2) lose weight loss until 4-5 days post-infection, at which point viral load becomes low or undetectable and mice recover by 9 days post-infection. 25/26 cytokines tested were upregulated in infected mouse plasma, including key inflammatory agents observed in human Dengue such as IL-6, TNF and IL-1b.
Interestingly, Dengue shares many risk factors and inflammatory signatures with COVID-19. During the COVID-19 pandemic, many clinical trials were performed to identify effective treatments against COVID-19-mediated cytokine storm. Some of these strategies targeted features that are known to be significant in severe Dengue, so I am now testing whether they translate effectively to treating in my Dengue mouse model. TNF-depleting monoclonal antibody significantly reduced Dengue-induced weight loss independent of viral load, while Dexamethasone, Baricitinib and monoclonal antibodies against IL6R, IL1b or GMCSF had no effect on weight loss. We are now analysing the mechanism of action of anti-TNF against Dengue in these mice. This work will provide crucial insight into therapeutic strategies against Dengue, and results may translate to the significantly deadlier Dengue/COVID-19 coinfection.