A model for network-based identification and pharmacological targeting of aberrant, replication-permissive transcriptional programs induced by viral infection
© 2022. The Author(s)..
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.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:5 |
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| Enthalten in: |
Communications biology - 5(2022), 1 vom: 19. Juli, Seite 714 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Laise, Pasquale [VerfasserIn] |
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| Links: |
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| Themen: |
Journal Article |
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| Anmerkungen: |
Date Completed 21.07.2022 Date Revised 07.12.2022 published: Electronic UpdateOf: Res Sq. 2022 Feb 04;:. - PMID 35132404 Citation Status MEDLINE |
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| doi: |
10.1038/s42003-022-03663-8 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM343742020 |
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| 245 | 1 | 2 | |a A model for network-based identification and pharmacological targeting of aberrant, replication-permissive transcriptional programs induced by viral infection |
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| 500 | |a Date Revised 07.12.2022 | ||
| 500 | |a published: Electronic | ||
| 500 | |a UpdateOf: Res Sq. 2022 Feb 04;:. - PMID 35132404 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022. The Author(s). | ||
| 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 700 | 1 | |a Stanifer, Megan L |e verfasserin |4 aut | |
| 700 | 1 | |a Bosker, Gideon |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Xiaoyun |e verfasserin |4 aut | |
| 700 | 1 | |a Triana, Sergio |e verfasserin |4 aut | |
| 700 | 1 | |a Doldan, Patricio |e verfasserin |4 aut | |
| 700 | 1 | |a La Manna, Federico |e verfasserin |4 aut | |
| 700 | 1 | |a De Menna, Marta |e verfasserin |4 aut | |
| 700 | 1 | |a Realubit, Ronald B |e verfasserin |4 aut | |
| 700 | 1 | |a Pampou, Sergey |e verfasserin |4 aut | |
| 700 | 1 | |a Karan, Charles |e verfasserin |4 aut | |
| 700 | 1 | |a Alexandrov, Theodore |e verfasserin |4 aut | |
| 700 | 1 | |a Kruithof-de Julio, Marianna |e verfasserin |4 aut | |
| 700 | 1 | |a Califano, Andrea |e verfasserin |4 aut | |
| 700 | 1 | |a Boulant, Steeve |e verfasserin |4 aut | |
| 700 | 1 | |a Alvarez, Mariano J |e verfasserin |4 aut | |
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