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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: Laise, Pasquale (Author) , Stanifer, Megan (Author) , Bosker, Gideon (Author) , Sun, Xiaoyun (Author) , Triana, Sergio (Author) , Doldan, Patricio (Author) , La Manna, Federico (Author) , De Menna, Marta (Author) , Realubit, Ronald B. (Author) , Pampou, Sergey (Author) , Karan, Charles (Author) , Alexandrov, Theodore (Author) , Kruithof-de Julio, Marianna (Author) , Califano, Andrea (Author) , Boulant, Steeve (Author) , Alvarez, Mariano J. (Author)
Format: Article (Journal)
Language:English
Published: 19 July 2022
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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Summary: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.
Item Description:Gesehen am 22.02.2023
Physical Description:Online Resource
ISSN:2399-3642
DOI:10.1038/s42003-022-03663-8

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