Open Access

REVIEW

Emerging viral infections: role of flavivirus NS1-mediated rewiring of PRR signaling

Matteo Ferraresi¹, Giulia Pezzi¹, Silvia Beltrami¹, Giorgia Cianci¹, Gloria Maini¹, Alessia Liboni², Marcello Baroni³, Daria Bortolotti^1,*, Giovanna Schiuma^1,*, Sabrina Rizzo^1,#, Giovanni Strazzabosco^1,#

1 Department of Environmental and Prevention Sciences, University of Ferrara, Ferrara, Italy
2 Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, Ferrara, Italy
3 Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy

* Corresponding Authors: Daria Bortolotti. Email: ; Giovanna Schiuma. Email:
# These authors contributed equally to this work

European Cytokine Network 2026, 37(2), 41-53. https://doi.org/10.32604/ecn.2026.083049

Received 27 March 2026; Accepted 29 May 2026; Issue published 30 June 2026

Abstract

Flaviviruses, including Dengue, West Nile, Zika, and Japanese encephalitis viruses, are arthropod-borne RNA viruses that pose an increasing global health threat. This review summarizes the role of nonstructural protein 1 (NS1), a multifunctional glycoprotein found in intracellular and secreted forms, as a key regulator of innate immunity. NS1 modulates several pattern recognition receptor pathways, including TLRs, RLRs, SR-B1-related mechanisms, and inflammasome platforms, thereby altering cytokine and interferon responses. Its effects are virus- and context-dependent. WNV NS1 inhibits TLR3/TRIF signaling, reducing IRF3 activation, type I interferon production, and interferon-stimulated gene expression. In contrast, DENV NS1 is linked to inflammatory signaling, particularly through TLR4. At the cytosolic level, NS1 from DENV, WNV, and ZIKV disrupts RIG-I/MDA5–MAVS signaling and weakens IFN-β induction. NS1 also affects inflammasome pathways: DENV promotes IL-1β release through a CD14-dependent mechanism, ZIKV suppresses cGAS-mediated antiviral signaling, and JEV promotes NLRP3 inflammasome assembly. Overall, NS1 selectively dampens interferon-mediated antiviral defenses while sustaining or enhancing inflammation, contributing to endothelial dysfunction, neuroinflammation, and severe disease.

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Keywords

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