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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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