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 (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

[img]
Preview
Text
s42003-022-03663-8.pdf - Published Version
Available under License Creative Commons: Attribution (CC-BY).

Download (1MB) | Preview

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)

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 and 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:

31 Jul 2022 01:58

Publisher DOI:

10.1038/s42003-022-03663-8

PubMed ID:

35854100

BORIS DOI:

10.48350/171475

URI:

https://boris.unibe.ch/id/eprint/171475

Actions (login required)

Edit item Edit item
Provide Feedback