Abstract
Dengue is the most prevalent and rapidly transmitted mosquito-borne viral disease of humans. One of the fundamental innate immune responses to viral infections includes the processing and release of pro-inflammatory cytokines such as interleukin (IL-1β and IL-18) through the activation of inflammasome. Dengue virus stimulates the Nod-like receptor (NLRP3-specific inflammasome), however, the specific mechanism(s) by which dengue virus activates the NLRP3 inflammasome is unknown. In this study, we investigated the activation of the NLRP3 inflammasome in endothelial cells (HMEC-1) following dengue virus infection. Our results showed that dengue infection as well as the NS2A and NS2B protein expression increase the NLRP3 inflammasome activation, and further apoptosis-associated speck-like protein containing caspase recruitment domain (ASC) oligomerization, and IL-1β secretion through caspase-1 activation. Specifically, we have demonstrated that NS2A and NS2B, two proteins of dengue virus that behave as putative viroporins, were sufficient to stimulate the NLRP3 inflammasome complex in lipopolysaccharide (LPS)-primed endothelial cells. In summary, our observations provide insight into the dengue-induced inflammatory response mechanism and highlight the importance of DENV-2 NS2A and NS2B proteins in activation of the NLRP3 inflammasome during dengue virus infection.
Highlights
Dengue Virus (DENV) is a positive-sense single-stranded RNA virus from the Flaviviridae family
Our data reveal the physiopathologic relevance of the NLRP3 inflammasome during DENV-2 infection, which may provide therapeutic targets along these pathways for novel anti-DENV-2 treatment
We found that DENV2 triggered NLRP3 activation in endothelial cells (HMEC-1)
Summary
Dengue Virus (DENV) is a positive-sense single-stranded RNA virus from the Flaviviridae family. Dengue is caused by any of the four serotypes DENV-1 to DENV-4. The interleukin IL-1β plays a crucial role in the cytokine storm during dengue infection [5, 6]. It is Dengue Non-Structural Proteins Activate Inflammasome an extremely potent cytokine that is regulated and induced by dengue-infected macrophages and monocytes [6,7,8]. The pro-inflammatory cytokine IL-1β has been shown to play a crucial role in increasing the deregulation of hemostasis and thrombosis during DENV infection [4, 6, 9]. Caspase-1 activation is regulated by a second independent stimulus such as the “inflammasome,” a multi-protein complex assembled upon activation [10]
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