%0 Journal Article
%A Laise, Pasquale
%A Stanifer, Megan L
%A Bosker, Gideon
%A Sun, Xiaoyun
%A Triana, Sergio
%A Doldan, Patricio
%A La Manna, Federico
%A De Menna, Marta
%A Realubit, Ronald B
%A Pampou, Sergey
%A Karan, Charles
%A Alexandrov, Theodore
%A Kruithof-de Julio, Marianna
%A Califano, Andrea
%A Boulant, Steeve
%A Alvarez, Mariano J
%T A model for network-based identification and pharmacological targeting of aberrant, replication-permissive transcriptional programs induced by viral infection.
%J Communications biology
%V 5
%N 1
%@ 2399-3642
%C London
%I Springer Nature
%M DKFZ-2022-01708
%P 714
%D 2022
%Z Research Group “Cellular Polarity and ViralInfection”, German Cancer Research Center (DKFZ), Heidelberg, Germany.
%X 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.
%K COVID-19: drug therapy
%K Humans
%K SARS-CoV-2
%K Transcriptome
%K Virus Diseases
%K Virus Replication
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:35854100
%2 pmc:PMC9296638
%R 10.1038/s42003-022-03663-8
%U https://inrepo02.dkfz.de/record/180984