Journal Article

DKFZ-2022-01708

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A model for network-based identification and pharmacological targeting of aberrant, replication-permissive transcriptional programs induced by viral infection.

Laise, P. ; Stanifer, M. L. ; Bosker, G. ; Sun, X. ; Triana, S. ; Doldan, P.DKFZ* ; La Manna, F. ; De Menna, M. ; Realubit, R. B. ; Pampou, S. ; Karan, C. ; Alexandrov, T. ; Kruithof-de Julio, M. ; Califano, A. ; Boulant, S.DKFZ* ; Alvarez, M. J.

2022
Springer Nature London

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Please use a persistent id in citations: doi:10.1038/s42003-022-03663-8

Abstract: 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.

Keyword(s): COVID-19: drug therapy (MeSH) ; Humans (MeSH) ; SARS-CoV-2 (MeSH) ; Transcriptome (MeSH) ; Virus Diseases (MeSH) ; Virus Replication (MeSH)

Note: Research Group “Cellular Polarity and ViralInfection”, German Cancer Research Center (DKFZ), Heidelberg, Germany.

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Contributing Institute(s):

1. NWG Infection and Immune Sensing Dynamics (F140)

Research Program(s):

1. 316 - Infektionen, Entzündung und Krebs (POF4-316) (POF4-316)

Appears in the scientific report 2022

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