Browsing by Author "Dubey, Swati"
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Item Innate immune pathway modulator screen identifies STING pathway activation as a strategy to inhibit multiple families of arbo and respiratory viruses(Cell Reports Medicine, 2023-05-16) Garcia, Gustavo Jr.; Irudayam, Joseph Ignatius; Jeyachandran, Arjit Vijey; Dubey, Swati; Chang, Christina; Castillo Cario, Sebastian; Price, Nate; Arumugam, Sathya; Marquez, Angelica L.; Shah, Aayushi; Fanaei, Amir; Chakravarty, Nikhil; Joshi, Shantanu; Sinha, Sanjeev; French, Samuel W.; Parcells, Mark S.; Ramaiah, Arunachalam; Arumugaswami, VaithilingarajaHighlights: • 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.2023.101024