A model for network-based identification and pharmacological targeting of aberrant, replication-permissive transcriptional programs induced by viral infection

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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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Autores principales: Laise, Pasquale, Stanifer, Megan L., Bosker, Gideon, Sun, Xiaoyun, Triana, Sergio, Doldan, Patricio, La Manna, Federico, De Menna, Marta, Realubit, Ronald B., Pampou, Sergey, Karan, Charles, Alexandrov, Theodore, Kruithof-de Julio, Marianna, Califano, Andrea, Boulant, Steeve, Alvarez, Mariano J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9296638/
https://www.ncbi.nlm.nih.gov/pubmed/35854100
http://dx.doi.org/10.1038/s42003-022-03663-8
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author Laise, Pasquale
Stanifer, Megan L.
Bosker, Gideon
Sun, Xiaoyun
Triana, Sergio
Doldan, Patricio
La Manna, Federico
De Menna, Marta
Realubit, Ronald B.
Pampou, Sergey
Karan, Charles
Alexandrov, Theodore
Kruithof-de Julio, Marianna
Califano, Andrea
Boulant, Steeve
Alvarez, Mariano J.
author_facet Laise, Pasquale
Stanifer, Megan L.
Bosker, Gideon
Sun, Xiaoyun
Triana, Sergio
Doldan, Patricio
La Manna, Federico
De Menna, Marta
Realubit, Ronald B.
Pampou, Sergey
Karan, Charles
Alexandrov, Theodore
Kruithof-de Julio, Marianna
Califano, Andrea
Boulant, Steeve
Alvarez, Mariano J.
author_sort Laise, Pasquale
collection PubMed
description 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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spelling pubmed-92966382022-07-21 A model for network-based identification and pharmacological targeting of aberrant, replication-permissive transcriptional programs induced by viral infection Laise, Pasquale Stanifer, Megan L. Bosker, Gideon Sun, Xiaoyun Triana, Sergio Doldan, Patricio La Manna, Federico De Menna, Marta Realubit, Ronald B. Pampou, Sergey Karan, Charles Alexandrov, Theodore Kruithof-de Julio, Marianna Califano, Andrea Boulant, Steeve Alvarez, Mariano J. Commun Biol Article 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. Nature Publishing Group UK 2022-07-19 /pmc/articles/PMC9296638/ /pubmed/35854100 http://dx.doi.org/10.1038/s42003-022-03663-8 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Laise, Pasquale
Stanifer, Megan L.
Bosker, Gideon
Sun, Xiaoyun
Triana, Sergio
Doldan, Patricio
La Manna, Federico
De Menna, Marta
Realubit, Ronald B.
Pampou, Sergey
Karan, Charles
Alexandrov, Theodore
Kruithof-de Julio, Marianna
Califano, Andrea
Boulant, Steeve
Alvarez, Mariano J.
A model for network-based identification and pharmacological targeting of aberrant, replication-permissive transcriptional programs induced by viral infection
title A model for network-based identification and pharmacological targeting of aberrant, replication-permissive transcriptional programs induced by viral infection
title_full A model for network-based identification and pharmacological targeting of aberrant, replication-permissive transcriptional programs induced by viral infection
title_fullStr A model for network-based identification and pharmacological targeting of aberrant, replication-permissive transcriptional programs induced by viral infection
title_full_unstemmed A model for network-based identification and pharmacological targeting of aberrant, replication-permissive transcriptional programs induced by viral infection
title_short A model for network-based identification and pharmacological targeting of aberrant, replication-permissive transcriptional programs induced by viral infection
title_sort model for network-based identification and pharmacological targeting of aberrant, replication-permissive transcriptional programs induced by viral infection
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9296638/
https://www.ncbi.nlm.nih.gov/pubmed/35854100
http://dx.doi.org/10.1038/s42003-022-03663-8
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