Dengue virus envelope protein domain III induces pro-inflammatory signature and triggers activation of inflammasome.

Dengue virus poses a considerable clinical problem, with the four closely related serotypes of dengue virus (DENV) infecting around 50-100 million people per year world-wide. The drastic increase in the dengue infection could be partly attributed to geographic expansion of the vector due to increasing urbanization, unavailability of specific antiviral therapies, licensed dengue vaccine, and poor understanding of the host immune responses. It has been reported that the immune-dominant envelope protein (E protein) domain III region (EDIII) of DENV is one of the most potent vaccine candidates because of its ability to trigger host immunity by inducing production of protective neutralizing antibodies. However, its role in the modulation of innate inflammatory responses hitherto remains unexplored. Herein, we demonstrate that EDIII protein of DENV induces pro-inflammatory signature by inducing production of inflammatory cytokines such as IL-1β and TNF-α in THP-1 cells through NF-κB pathway. Also, we observed increase in the maturation of IL-1β, which was found to be associated with increased ROS production and potassium efflux. Further, our findings reveal that the IL-1β production by EDIII protein is mediated through caspase-1 and NLRP3 inflammasome activation. In conclusion this study unearths the role of DENV EDIII protein in modulating innate inflammatory responses, which might provide possible mechanism of pathogenesis and open-up new avenues for the development of therapeutics against DENV.