The inflammasome pathway is activated by dengue virus non-structural protein 1 and is protective during dengue virus infection

Dengue virus (DENV) is a medically important flavivirus causing an estimated 50-100 million dengue cases annually, some of whom progress to severe disease. DENV non-structural protein 1 (NS1) is secreted from infected cells and has been implicated as a major driver of dengue pathogenesis by inducing endothelial barrier dysfunction. However, less is known about how DENV NS1 interacts with immune cells and what role these interactions play. Here we report that DENV NS1 can trigger activation of inflammasomes, a family of cytosolic innate immune sensors that respond to infectious and noxious stimuli, in mouse and human macrophages. DENV NS1 induces the release of IL-1 beta in a caspase-1 dependent manner. Additionally, we find that DENV NS1-induced inflammasome activation is independent of the NLRP3, Pyrin, and AIM2 inflammasome pathways, but requires CD14. Intriguingly, DENV NS1-induced inflammasome activation does not induce pyroptosis and rapid cell death; instead, macrophages maintain cellular viability while releasing IL-1 beta. Lastly, we show that caspase-1/11-deficient, but not NLRP3-deficient, mice are more susceptible to lethal DENV infection. Together, these results indicate that the inflammasome pathway acts as a sensor of DENV NS1 and plays a protective role during infection. Dengue, caused by dengue virus (DENV), is the most prevalent mosquito-transmitted disease in humans and a significant public health issue worldwide. DENV nonstructural protein 1 (NS1) has been shown to contribute to dengue pathogenesis through the induction of endothelial barrier dysfunction, resulting in hyperpermeability and vascular leak-a key feature of severe dengue disease. DENV NS1 has also been shown to activate innate immune cells; however, the exact mechanisms and consequences of this interaction are unclear. Here we show that DENV NS1 triggers activation of the inflammasome pathway-a family of cytosolic innate immune sensors-in mouse and human macrophages. We find that DENV NS1-induced inflammasome activation is independent of the NLRP3 inflammasome but dependent on caspase-1 and CD14. We also find that, in a mouse model of DENV disease, caspase-1/11-deficient mice succumb to infection at higher rates compared to caspase-1/11-functional mice, whereas NLRP3 deficiency had no effect on survival. Altogether, our study demonstrates that the inflammasome pathway acts as a sensor of DENV NS1 and contributes to protective responses during DENV infection, potentially identifying the inflammasome pathway as a therapeutic target.