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bioRxiv · 10.1101/2022.11.05.515197

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.·Grossmann, M.·Serresi, M.·Cicin-Sain, L.·Gargiulo, G.
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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-/{beta}/{gamma}-, and NF-{kappa}B 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 similar mechanism of action. Thus, this study describes a tool for dissecting antiviral responses to infection and sterile cues, and a rapid approach to other emerging viruses of public health concern in order to discover rational drug combinations.

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Jiang, B., Schmitt, M. J., Rand, U., Company, C., Grossmann, M., Serresi, M., Cicin-Sain, L., Gargiulo, G.. 2022-11-07. Pharmacological modulators of epithelial immunity uncovered by synthetic genetic tracing of SARS-CoV-2 infection responses. https://doi.org/10.1101/2022.11.05.515197

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