TY  - JOUR
AU  - Laise, Pasquale
AU  - Stanifer, Megan L
AU  - Bosker, Gideon
AU  - Sun, Xiaoyun
AU  - Triana, Sergio
AU  - Doldan, Patricio
AU  - La Manna, Federico
AU  - De Menna, Marta
AU  - Realubit, Ronald B
AU  - Pampou, Sergey
AU  - Karan, Charles
AU  - Alexandrov, Theodore
AU  - Kruithof-de Julio, Marianna
AU  - Califano, Andrea
AU  - Boulant, Steeve
AU  - Alvarez, Mariano J
TI  - A model for network-based identification and pharmacological targeting of aberrant, replication-permissive transcriptional programs induced by viral infection.
JO  - Communications biology
VL  - 5
IS  - 1
SN  - 2399-3642
CY  - London
PB  - Springer Nature
M1  - DKFZ-2022-01708
SP  - 714
PY  - 2022
N1  - Research Group “Cellular Polarity and ViralInfection”, German Cancer Research Center (DKFZ), Heidelberg, Germany.
AB  - 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.
KW  - COVID-19: drug therapy
KW  - Humans
KW  - SARS-CoV-2
KW  - Transcriptome
KW  - Virus Diseases
KW  - Virus Replication
LB  - PUB:(DE-HGF)16
C6  - pmid:35854100
C2  - pmc:PMC9296638
DO  - DOI:10.1038/s42003-022-03663-8
UR  - https://inrepo02.dkfz.de/record/180984
ER  -