HDAC1-3 inhibition increases SARS-CoV-2 replication and productive infection in lung mesothelial and epithelial cells
Copyright © 2023 Trionfetti, Alonzi, Bontempi, Terri, Battistelli, Montaldo, Repele, Rotili, Valente, Zwergel, Matusali, Maggi, Goletti, Tripodi, Mai and Strippoli..
Background: Despite the significant progress achieved in understanding the pathology and clinical management of SARS-CoV-2 infection, still pathogenic and clinical issues need to be clarified. Treatment with modulators of epigenetic targets, i.e., epidrugs, is a current therapeutic option in several cancers and could represent an approach in the therapy of viral diseases.
Results: Aim of this study was the analysis of the role of histone deacetylase (HDAC) inhibition in the modulation of SARS-CoV-2 infection of mesothelial cells (MCs).MeT5A cells, a pleura MC line, were pre-treated with different specific class I and IIb HDAC inhibitors. Unexpectedly, treatment with HDAC1-3 inhibitors significantly increased ACE2/TMPRSS2 expression, suggesting a role in favoring SARS-CoV-2 infection. We focused our analysis on the most potent ACE2/TMPRSS2 inducer among the inhibitors analysed, MS-275, a HDAC1-3 inhibitor. ACE2/TMPRSS2 expression was validated by Western Blot (WB) and immunofluorescence. The involvement of HDAC inhibition in receptor induction was confirmed by HDAC1/HDAC2 silencing. In accordance to the ACE2/TMPRSS2 expression data, MS-275 increased SARS-CoV-2 replication and virus propagation in Vero E6 cells.Notably, MS-275 was able to increase ACE2/TMPRSS2 expression and SARS-CoV-2 production, although to a lesser extent, also in the lung adenocarcinoma cell line Calu-3 cells.Mechanistically, treatment with MS-275 increased H3 and H4 histone acetylation at ACE2/TMPRSS2 promoters, increasing their transcription.
Conclusion: This study highlights a previously unrecognized effect of HDAC1-3 inhibition in increasing SARS-CoV-2 cell entry, replication and productive infection correlating with increased expression of ACE2 and TMPRSS2. These data, while adding basic insight into COVID-19 pathogenesis, warn for the use of HDAC inhibitors in SARS-CoV-2 patients.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
|---|---|
| Enthalten in: |
Frontiers in cellular and infection microbiology - 13(2023) vom: 01., Seite 1257683 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Trionfetti, Flavia [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 03.01.2024 Date Revised 21.02.2024 published: Electronic-eCollection Citation Status MEDLINE |
|---|
| doi: |
10.3389/fcimb.2023.1257683 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM366532197 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM366532197 | ||
| 003 | DE-627 | ||
| 005 | 20240222232245.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240108s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.3389/fcimb.2023.1257683 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1302.xml |
| 035 | |a (DE-627)NLM366532197 | ||
| 035 | |a (NLM)38162580 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Trionfetti, Flavia |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a HDAC1-3 inhibition increases SARS-CoV-2 replication and productive infection in lung mesothelial and epithelial cells |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 03.01.2024 | ||
| 500 | |a Date Revised 21.02.2024 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Trionfetti, Alonzi, Bontempi, Terri, Battistelli, Montaldo, Repele, Rotili, Valente, Zwergel, Matusali, Maggi, Goletti, Tripodi, Mai and Strippoli. | ||
| 520 | |a Background: Despite the significant progress achieved in understanding the pathology and clinical management of SARS-CoV-2 infection, still pathogenic and clinical issues need to be clarified. Treatment with modulators of epigenetic targets, i.e., epidrugs, is a current therapeutic option in several cancers and could represent an approach in the therapy of viral diseases | ||
| 520 | |a Results: Aim of this study was the analysis of the role of histone deacetylase (HDAC) inhibition in the modulation of SARS-CoV-2 infection of mesothelial cells (MCs).MeT5A cells, a pleura MC line, were pre-treated with different specific class I and IIb HDAC inhibitors. Unexpectedly, treatment with HDAC1-3 inhibitors significantly increased ACE2/TMPRSS2 expression, suggesting a role in favoring SARS-CoV-2 infection. We focused our analysis on the most potent ACE2/TMPRSS2 inducer among the inhibitors analysed, MS-275, a HDAC1-3 inhibitor. ACE2/TMPRSS2 expression was validated by Western Blot (WB) and immunofluorescence. The involvement of HDAC inhibition in receptor induction was confirmed by HDAC1/HDAC2 silencing. In accordance to the ACE2/TMPRSS2 expression data, MS-275 increased SARS-CoV-2 replication and virus propagation in Vero E6 cells.Notably, MS-275 was able to increase ACE2/TMPRSS2 expression and SARS-CoV-2 production, although to a lesser extent, also in the lung adenocarcinoma cell line Calu-3 cells.Mechanistically, treatment with MS-275 increased H3 and H4 histone acetylation at ACE2/TMPRSS2 promoters, increasing their transcription | ||
| 520 | |a Conclusion: This study highlights a previously unrecognized effect of HDAC1-3 inhibition in increasing SARS-CoV-2 cell entry, replication and productive infection correlating with increased expression of ACE2 and TMPRSS2. These data, while adding basic insight into COVID-19 pathogenesis, warn for the use of HDAC inhibitors in SARS-CoV-2 patients | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a ACE2 regulation | |
| 650 | 4 | |a HDAC (histone deacetylase) | |
| 650 | 4 | |a SARS-CoV-2 | |
| 650 | 4 | |a TMPRSS2 expression | |
| 650 | 4 | |a epidrugs | |
| 650 | 4 | |a mesothelial cells | |
| 650 | 4 | |a pleura | |
| 650 | 4 | |a viral infection and replication | |
| 650 | 7 | |a entinostat |2 NLM | |
| 650 | 7 | |a 1ZNY4FKK9H |2 NLM | |
| 650 | 7 | |a Angiotensin-Converting Enzyme 2 |2 NLM | |
| 650 | 7 | |a EC 3.4.17.23 |2 NLM | |
| 650 | 7 | |a Histone Deacetylase Inhibitors |2 NLM | |
| 650 | 7 | |a HDAC1 protein, human |2 NLM | |
| 650 | 7 | |a EC 3.5.1.98 |2 NLM | |
| 650 | 7 | |a Histone Deacetylase 1 |2 NLM | |
| 650 | 7 | |a EC 3.5.1.98 |2 NLM | |
| 700 | 1 | |a Alonzi, Tonino |e verfasserin |4 aut | |
| 700 | 1 | |a Bontempi, Giulio |e verfasserin |4 aut | |
| 700 | 1 | |a Terri, Michela |e verfasserin |4 aut | |
| 700 | 1 | |a Battistelli, Cecilia |e verfasserin |4 aut | |
| 700 | 1 | |a Montaldo, Claudia |e verfasserin |4 aut | |
| 700 | 1 | |a Repele, Federica |e verfasserin |4 aut | |
| 700 | 1 | |a Rotili, Dante |e verfasserin |4 aut | |
| 700 | 1 | |a Valente, Sergio |e verfasserin |4 aut | |
| 700 | 1 | |a Zwergel, Clemens |e verfasserin |4 aut | |
| 700 | 1 | |a Matusali, Giulia |e verfasserin |4 aut | |
| 700 | 1 | |a Maggi, Fabrizio |e verfasserin |4 aut | |
| 700 | 1 | |a Goletti, Delia |e verfasserin |4 aut | |
| 700 | 1 | |a Tripodi, Marco |e verfasserin |4 aut | |
| 700 | 1 | |a Mai, Antonello |e verfasserin |4 aut | |
| 700 | 1 | |a Strippoli, Raffaele |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Frontiers in cellular and infection microbiology |d 2011 |g 13(2023) vom: 01., Seite 1257683 |w (DE-627)NLM220414289 |x 2235-2988 |7 nnns |
| 773 | 1 | 8 | |g volume:13 |g year:2023 |g day:01 |g pages:1257683 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.3389/fcimb.2023.1257683 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 13 |j 2023 |b 01 |h 1257683 | ||