A model for network-based identification and pharmacological targeting of aberrant, replication-permissive transcriptional programs induced by viral infection
SARS-CoV-2 hijacks the host cell transcriptional machinery to induce a phenotypic state amenable to its replication. Here we show that analysis of Master Regulator proteins representing mechanistic determinants of the gene expression signature induced by SARS-CoV-2 in infected cells revealed coordin...
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| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
19 July 2022
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| In: |
Communications biology
Year: 2022, Volume: 5, Pages: 1-12 |
| ISSN: | 2399-3642 |
| DOI: | 10.1038/s42003-022-03663-8 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s42003-022-03663-8 Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s42003-022-03663-8 
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| Author Notes: | Pasquale Laise, Megan L. Stanifer, Gideon Bosker, Xiaoyun Sun, Sergio Triana, Patricio Doldan, Federico La Manna, Marta De Menna, Ronald B. Realubit, Sergey Pampou, Charles Karan, Theodore Alexandrov, Marianna Kruithof-de Julio, Andrea Califano, Steeve Boulant & Mariano J. Alvarez |
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| 520 | |a SARS-CoV-2 hijacks the host cell transcriptional machinery to induce a phenotypic state amenable to its replication. Here we show that analysis of Master Regulator proteins representing mechanistic determinants of the gene expression signature induced by SARS-CoV-2 in infected cells revealed coordinated inactivation of Master Regulators enriched in physical interactions with SARS-CoV-2 proteins, suggesting their mechanistic role in maintaining a host cell state refractory to virus replication. To test their functional relevance, we measured SARS-CoV-2 replication in epithelial cells treated with drugs predicted to activate the entire repertoire of repressed Master Regulators, based on their experimentally elucidated, context-specific mechanism of action. Overall, 15 of the 18 drugs predicted to be effective by this methodology induced significant reduction of SARS-CoV-2 replication, without affecting cell viability. This model for host-directed pharmacological therapy is fully generalizable and can be deployed to identify drugs targeting host cell-based Master Regulator signatures induced by virtually any pathogen. | ||
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