Targeting androgen regulation of TMPRSS2 and ACE2 as a therapeutic strategy to combat COVID-19
Summary: Epidemiological data showing increased severity and mortality of COVID-19 in men suggests a potential role for androgen in SARS-CoV-2 infection. Here, we present evidence for the transcriptional regulation of SARS-CoV-2 host cell receptor ACE2 and TMPRSS2 by androgen in mouse and human cell...
Main Authors: | , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2021-03-01
|
Series: | iScience |
Subjects: | |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004221002224 |
id |
doaj-5d33409195584a248853fc15987a68ba |
---|---|
record_format |
Article |
spelling |
doaj-5d33409195584a248853fc15987a68ba2021-03-22T12:52:19ZengElsevieriScience2589-00422021-03-01243102254Targeting androgen regulation of TMPRSS2 and ACE2 as a therapeutic strategy to combat COVID-19Qu Deng0Reyaz ur Rasool1Ronnie M. Russell2Ramakrishnan Natesan3Irfan A. Asangani4Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA 19104, USADepartment of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA 19104, USADepartment of Microbiology, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA 19104, USADepartment of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA 19104, USADepartment of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA 19104, USA; Department of Cancer Biology, Abramson Family Cancer Research Institute, Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, BRBII/III, Philadelphia, PA 19104, USA; Corresponding authorSummary: Epidemiological data showing increased severity and mortality of COVID-19 in men suggests a potential role for androgen in SARS-CoV-2 infection. Here, we present evidence for the transcriptional regulation of SARS-CoV-2 host cell receptor ACE2 and TMPRSS2 by androgen in mouse and human cells. Additionally, we demonstrate the endogenous interaction between TMPRSS2 and ACE2 in human cells and validate ACE2 as a TMPRSS2 substrate. Furthermore, camostat—a TMPRSS2 inhibitor—blocked the cleavage of pseudotype SARS-CoV-2 surface Spike without disrupting TMPRSS2-ACE2 interaction, thus providing evidence for the first time of a direct role of TMPRSS2 in priming the SARS-CoV-2 Spike, required for viral fusion to the host cell. Importantly, androgen-deprivation, anti-androgens, or camostat attenuated the SARS-CoV-2 S-mediated cellular entry. Together, our data provide a strong rationale for clinical evaluations of TMPRSS2 inhibitors and androgen-deprivation therapy/androgen receptor antagonists alone or in combination with antiviral drugs as early as clinically possible to prevent COVID-19 progression.http://www.sciencedirect.com/science/article/pii/S2589004221002224Biological SciencesMolecular BiologyVirology |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Qu Deng Reyaz ur Rasool Ronnie M. Russell Ramakrishnan Natesan Irfan A. Asangani |
spellingShingle |
Qu Deng Reyaz ur Rasool Ronnie M. Russell Ramakrishnan Natesan Irfan A. Asangani Targeting androgen regulation of TMPRSS2 and ACE2 as a therapeutic strategy to combat COVID-19 iScience Biological Sciences Molecular Biology Virology |
author_facet |
Qu Deng Reyaz ur Rasool Ronnie M. Russell Ramakrishnan Natesan Irfan A. Asangani |
author_sort |
Qu Deng |
title |
Targeting androgen regulation of TMPRSS2 and ACE2 as a therapeutic strategy to combat COVID-19 |
title_short |
Targeting androgen regulation of TMPRSS2 and ACE2 as a therapeutic strategy to combat COVID-19 |
title_full |
Targeting androgen regulation of TMPRSS2 and ACE2 as a therapeutic strategy to combat COVID-19 |
title_fullStr |
Targeting androgen regulation of TMPRSS2 and ACE2 as a therapeutic strategy to combat COVID-19 |
title_full_unstemmed |
Targeting androgen regulation of TMPRSS2 and ACE2 as a therapeutic strategy to combat COVID-19 |
title_sort |
targeting androgen regulation of tmprss2 and ace2 as a therapeutic strategy to combat covid-19 |
publisher |
Elsevier |
series |
iScience |
issn |
2589-0042 |
publishDate |
2021-03-01 |
description |
Summary: Epidemiological data showing increased severity and mortality of COVID-19 in men suggests a potential role for androgen in SARS-CoV-2 infection. Here, we present evidence for the transcriptional regulation of SARS-CoV-2 host cell receptor ACE2 and TMPRSS2 by androgen in mouse and human cells. Additionally, we demonstrate the endogenous interaction between TMPRSS2 and ACE2 in human cells and validate ACE2 as a TMPRSS2 substrate. Furthermore, camostat—a TMPRSS2 inhibitor—blocked the cleavage of pseudotype SARS-CoV-2 surface Spike without disrupting TMPRSS2-ACE2 interaction, thus providing evidence for the first time of a direct role of TMPRSS2 in priming the SARS-CoV-2 Spike, required for viral fusion to the host cell. Importantly, androgen-deprivation, anti-androgens, or camostat attenuated the SARS-CoV-2 S-mediated cellular entry. Together, our data provide a strong rationale for clinical evaluations of TMPRSS2 inhibitors and androgen-deprivation therapy/androgen receptor antagonists alone or in combination with antiviral drugs as early as clinically possible to prevent COVID-19 progression. |
topic |
Biological Sciences Molecular Biology Virology |
url |
http://www.sciencedirect.com/science/article/pii/S2589004221002224 |
work_keys_str_mv |
AT qudeng targetingandrogenregulationoftmprss2andace2asatherapeuticstrategytocombatcovid19 AT reyazurrasool targetingandrogenregulationoftmprss2andace2asatherapeuticstrategytocombatcovid19 AT ronniemrussell targetingandrogenregulationoftmprss2andace2asatherapeuticstrategytocombatcovid19 AT ramakrishnannatesan targetingandrogenregulationoftmprss2andace2asatherapeuticstrategytocombatcovid19 AT irfanaasangani targetingandrogenregulationoftmprss2andace2asatherapeuticstrategytocombatcovid19 |
_version_ |
1724207559068352512 |