Investigating the role of inflammasome activation by dengue virus non-structural protein 1 during dengue infection.

Abstract

Abstract Dengue virus (DENV), consisting of serotypes 1–4, is the most medically important flavivirus, causing an estimated 50–100 million dengue cases globally every year. Most symptomatic DENV infections present as an acute febrile illness; however, severe complications include vascular leakage leading to hemorrhage and hypovolemic shock. DENV non-structural protein 1 (NS1) is secreted from infected cells and has been implicated as a major driver of dengue pathogenesis, activating immune cells and acting directly on endothelial barriers, causing them to become pathologically hyperpermeable. While recent work has delved into the mechanisms behind the endothelial cell-intrinsic pathway of DENV NS1-induced vascular leak, much less is known about how DENV NS1 interacts with immune cells and what role this activation plays in DENV infection. We have discovered that DENV NS1 can trigger activation of the inflammasome, a family of cytosolic innate immune sensors that react to danger-associated molecular patterns. DENV NS1 induces the release of the pro-inflammatory cytokine IL-1β in human and murine monocytes in a caspase-1 dependent manner that is independent of NLRP3. Additionally, we found that caspase-1-deficient, but not NLRP3-deficient, mice are more susceptible to infection in a murine model of DENV infection. These results indicate that the inflammasome acts as a sensor of the DENV viral toxin NS1 and plays a protective role during DENV infections This work was supported by NIAID/NIH grant R01 AI24493 (E.H.)