Home > Publications database > A model for network-based identification and pharmacological targeting of aberrant, replication-permissive transcriptional programs induced by viral infection. > print

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024 7 _ |a 10.1038/s42003-022-03663-8
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082 _ _ |a 570
100 1 _ |a Laise, Pasquale
|b 0
245 _ _ |a A model for network-based identification and pharmacological targeting of aberrant, replication-permissive transcriptional programs induced by viral infection.
260 _ _ |a London
|c 2022
|b Springer Nature
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500 _ _ |a Research Group “Cellular Polarity and ViralInfection”, German Cancer Research Center (DKFZ), Heidelberg, Germany.
520 _ _ |a 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.
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588 _ _ |a Dataset connected to CrossRef, PubMed, , Journals: inrepo02.dkfz.de
650 _ 2 |a COVID-19: drug therapy
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a SARS-CoV-2
|2 MeSH
650 _ 2 |a Transcriptome
|2 MeSH
650 _ 2 |a Virus Diseases
|2 MeSH
650 _ 2 |a Virus Replication
|2 MeSH
700 1 _ |a Stanifer, Megan L
|b 1
700 1 _ |a Bosker, Gideon
|b 2
700 1 _ |a Sun, Xiaoyun
|b 3
700 1 _ |a Triana, Sergio
|b 4
700 1 _ |a Doldan, Patricio
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700 1 _ |a La Manna, Federico
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700 1 _ |a De Menna, Marta
|b 7
700 1 _ |a Realubit, Ronald B
|b 8
700 1 _ |a Pampou, Sergey
|b 9
700 1 _ |a Karan, Charles
|b 10
700 1 _ |a Alexandrov, Theodore
|b 11
700 1 _ |a Kruithof-de Julio, Marianna
|0 0000-0002-6085-7706
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700 1 _ |a Califano, Andrea
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700 1 _ |a Boulant, Steeve
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700 1 _ |a Alvarez, Mariano J
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773 _ _ |a 10.1038/s42003-022-03663-8
|g Vol. 5, no. 1, p. 714
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