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

Jiang, B.; Schmitt, M.J.; Rand, U.; Company, C.; Dramaretska, Y.; Grossmann, M.; Serresi, M.; Cicin-Sain, L.; Gargiulo, G.

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., Schmitt, M.J., Rand, U., Company, C., Dramaretska, Y., Grossmann, M., Serresi, M., 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
ISSN:	2375-2548
Publisher:	American Association for the Advancement of Science
Volume:	9
Number:	25
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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