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Pharmacological modulators of epithelial immunity uncovered by synthetic genetic tracing of SARS-CoV-2 infection responses

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Item Type:Article
Title:Pharmacological modulators of epithelial immunity uncovered by synthetic genetic tracing of SARS-CoV-2 infection responses
Creators Name:Jiang, B. and Schmitt, M.J. and Rand, U. and Company, C. and Dramaretska, Y. and Grossmann, M. and Serresi, M. and Cicin-Sain, L. and Gargiulo, G.
Abstract:Epithelial immune responses govern tissue homeostasis and offer drug targets against maladaptation. Here, we report a framework to generate drug discovery–ready reporters of cellular responses to viral infection. We reverse-engineered epithelial cell responses to SARS-CoV-2, the viral agent fueling the ongoing COVID-19 pandemic, and designed synthetic transcriptional reporters whose molecular logic comprises interferon-α/β/γ and NF-κB pathways. Such regulatory potential reflected single-cell data from experimental models to severe COVID-19 patient epithelial cells infected by SARS-CoV-2. SARS-CoV-2, type I interferons, and RIG-I drive reporter activation. Live-cell image–based phenotypic drug screens identified JAK inhibitors and DNA damage inducers as antagonistic modulators of epithelial cell response to interferons, RIG-I stimulation, and SARS-CoV-2. Synergistic or antagonistic modulation of the reporter by drugs underscored their mechanism of action and convergence on endogenous transcriptional programs. Our study describes a tool for dissecting antiviral responses to infection and sterile cues and rapidly discovering rational drug combinations for emerging viruses of concern.
Keywords:COVID-19, Epithelial Cells, Interferon Type I, Pandemics, SARS-CoV-2
Source:Science Advances
Publisher:American Association for the Advancement of Science
Page Range:eadf4975
Date:23 June 2023
Official Publication:https://doi.org/10.1126/sciadv.adf4975
PubMed:View item in PubMed

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