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Pharmacological modulators of epithelial immunity uncovered by synthetic genetic tracing of SARS-CoV-2 infection responses
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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10284557/ https://www.ncbi.nlm.nih.gov/pubmed/37343108 http://dx.doi.org/10.1126/sciadv.adf4975 |
Sumario: | 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. |
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