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 (2022). A model for network-based identification and pharmacological targeting of aberrant, replication-permissive transcriptional programs induced by viral infection. Communications biology, 5(1), p. 714. Springer Nature 10.1038/s42003-022-03663-8
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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 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 Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Urologie 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Urologie 04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Urology |
UniBE Contributor: |
La Manna, Federico, De Menna, Marta, Kruithof-de Julio, Marianna |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
2399-3642 |
Publisher: |
Springer Nature |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
25 Jul 2022 13:44 |
Last Modified: |
05 Dec 2022 16:22 |
Publisher DOI: |
10.1038/s42003-022-03663-8 |
PubMed ID: |
35854100 |
BORIS DOI: |
10.48350/171475 |
URI: |
https://boris.unibe.ch/id/eprint/171475 |
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