Garcia, Gustavo Jr.Irudayam, Joseph IgnatiusJeyachandran, Arjit VijeyDubey, SwatiChang, ChristinaCastillo Cario, SebastianPrice, NateArumugam, SathyaMarquez, Angelica L.Shah, AayushiFanaei, AmirChakravarty, NikhilJoshi, ShantanuSinha, SanjeevFrench, Samuel W.Parcells, Mark S.Ramaiah, ArunachalamArumugaswami, Vaithilingaraja2023-07-192023-07-192023-05-16Garcia, Gustavo, Joseph Ignatius Irudayam, Arjit Vijey Jeyachandran, Swati Dubey, Christina Chang, Sebastian Castillo Cario, Nate Price, et al. “Innate Immune Pathway Modulator Screen Identifies STING Pathway Activation as a Strategy to Inhibit Multiple Families of Arbo and Respiratory Viruses.” Cell Reports Medicine 4, no. 5 (May 16, 2023): 101024. https://doi.org/10.1016/j.xcrm.2023.101024.2666-3791https://udspace.udel.edu/handle/19716/33025This article was originally published in Cell Reports Medicine. The version of record is available at: https://doi.org/10.1016/j.xcrm.2023.101024. © 2023 The Authors.Highlights: • Screen identifies innate immune agonists blocking multiple families of RNA viruses • Dectin-1 and cGAS-STING pathway agonists exhibit broader antiviral activity • STING activator cAIMP blocks ZIKV, WNV, CHIKV, EV-D68, and SARS-CoV-2 infections • cAIMP provides protection against CHIKV-mediated chronic arthritis in mouse model Summary: RNA viruses continue to remain a threat for potential pandemics due to their rapid evolution. Potentiating host antiviral pathways to prevent or limit viral infections is a promising strategy. Thus, by testing a library of innate immune agonists targeting pathogen recognition receptors, we observe that Toll-like receptor 3 (TLR3), stimulator of interferon genes (STING), TLR8, and Dectin-1 ligands inhibit arboviruses, Chikungunya virus (CHIKV), West Nile virus, and Zika virus to varying degrees. STING agonists (cAIMP, diABZI, and 2′,3′-cGAMP) and Dectin-1 agonist scleroglucan demonstrate the most potent, broad-spectrum antiviral function. Furthermore, STING agonists inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and enterovirus-D68 (EV-D68) infection in cardiomyocytes. Transcriptome analysis reveals that cAIMP treatment rescue cells from CHIKV-induced dysregulation of cell repair, immune, and metabolic pathways. In addition, cAIMP provides protection against CHIKV in a chronic CHIKV-arthritis mouse model. Our study describes innate immune signaling circuits crucial for RNA virus replication and identifies broad-spectrum antivirals effective against multiple families of pandemic potential RNA viruses. Graphical abstract available at: https://doi.org/10.1016/j.xcrm.2023.101024en-USArticle