A Model for Network-Based Identification and Pharmacological Targeting of Aberrant, Replication-Permissive Transcriptional Programs Induced by Viral Infection
Abstract Precise characterization and targeting of host cell transcriptional machinery hijacked by viral infection remains challenging. Here, we show that SARS-CoV-2 hijacks the host cell transcriptional machinery to induce a phenotypic state amenable to its replication. Specifically, analysis of Master Regulator (MR) proteins representing mechanistic determinants of the gene expression signature induced by SARS-CoV-2 in infected cells revealed coordinated inactivation of MRs 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 MRs, based on their experimentally elucidated, context-specific mechanism of action. Overall, >80% of 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 MR signatures induced by virtually any pathogen..
| Medienart: |
|
|---|
Preprint| Erscheinungsjahr: |
2022 |
|---|---|
| Erschienen: |
2022 |
| Enthalten in: |
ResearchSquare.com - (2022) vom: 29. Juli Zur Gesamtaufnahme - year:2022 |
|---|
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Laise, Pasquale [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
|---|
| doi: |
10.21203/rs.3.rs-1287631/v1 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
XRA03516087X |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | XRA03516087X | ||
| 003 | DE-627 | ||
| 005 | 20230429181753.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 220205s2022 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.21203/rs.3.rs-1287631/v1 |2 doi | |
| 035 | |a (DE-627)XRA03516087X | ||
| 035 | |a (ResearchSquare)10.21203/rs.3.rs-1287631/v1 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Laise, Pasquale |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a A Model for Network-Based Identification and Pharmacological Targeting of Aberrant, Replication-Permissive Transcriptional Programs Induced by Viral Infection |
| 264 | 1 | |c 2022 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a Abstract Precise characterization and targeting of host cell transcriptional machinery hijacked by viral infection remains challenging. Here, we show that SARS-CoV-2 hijacks the host cell transcriptional machinery to induce a phenotypic state amenable to its replication. Specifically, analysis of Master Regulator (MR) proteins representing mechanistic determinants of the gene expression signature induced by SARS-CoV-2 in infected cells revealed coordinated inactivation of MRs 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 MRs, based on their experimentally elucidated, context-specific mechanism of action. Overall, >80% of 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 MR signatures induced by virtually any pathogen. | ||
| 650 | 4 | |a Biology |7 (dpeaa)DE-84 | |
| 650 | 4 | |a 570 |7 (dpeaa)DE-84 | |
| 700 | 1 | |a Stanifer, Megan |e verfasserin |4 aut | |
| 700 | 1 | |a Bosker, Gideon |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Xiaoyun |e verfasserin |4 aut | |
| 700 | 1 | |a Triana, Sergio |e verfasserin |4 aut | |
| 700 | 1 | |a Doldan, Patricio |e verfasserin |4 aut | |
| 700 | 1 | |a Manna, Federico La |e verfasserin |4 aut | |
| 700 | 1 | |a De Menna, Marta |e verfasserin |4 aut | |
| 700 | 1 | |a Realubit, Ronald |e verfasserin |4 aut | |
| 700 | 1 | |a Pampou, Sergey |e verfasserin |4 aut | |
| 700 | 1 | |a Karan, Charles |e verfasserin |4 aut | |
| 700 | 1 | |a Alexandrov, Theodore |e verfasserin |4 aut | |
| 700 | 1 | |a Julio, Marianna Kruithof-de |e verfasserin |4 aut | |
| 700 | 1 | |a Califano, Andrea |e verfasserin |4 aut | |
| 700 | 1 | |a Boulant, Steeve |e verfasserin |4 aut | |
| 700 | 1 | |a Alvarez, Mariano |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t ResearchSquare.com |g (2022) vom: 29. Juli |
| 773 | 1 | 8 | |g year:2022 |g day:29 |g month:07 |
| 856 | 4 | 0 | |u https://doi.org/10.1038/s42003-022-03663-8 |z lizenzpflichtig |3 Volltext |
| 856 | 4 | 0 | |u http://dx.doi.org/10.21203/rs.3.rs-1287631/v1 |z kostenfrei |3 Volltext |
| 912 | |a GBV_XRA | ||
| 912 | |a SSG-OLC-PHA | ||
| 951 | |a AR | ||
| 952 | |j 2022 |b 29 |c 07 | ||