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Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men

Zaniar Ghazizadeh, Homa Majd, Mikayla Richter, Ryan Samuel, Seyedeh Maryam Zekavat, Hosseinali Asgharian, Sina Farahvashi, Ali Kalantari, Jonathan Ramirez, Hongyu Zhao, Pradeep Natarajan, View ORCID ProfileHani Goodarzi, View ORCID ProfileFaranak Fattahi
doi: https://doi.org/10.1101/2020.05.12.091082
Zaniar Ghazizadeh
1Department of Internal Medicine, Yale School of Medicine, New Haven, CT, 06510
2Yale School of Medicine, New Haven, CT, 06510
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Homa Majd
3Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, 94143
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Mikayla Richter
3Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, 94143
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Ryan Samuel
3Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, 94143
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Seyedeh Maryam Zekavat
4Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142
5Department of computational Biology & Bioinformatics, Yale University, New Haven, CT, 06510
6Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114
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Hosseinali Asgharian
7Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158
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Sina Farahvashi
3Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, 94143
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Ali Kalantari
3Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, 94143
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Jonathan Ramirez
3Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, 94143
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Hongyu Zhao
5Department of computational Biology & Bioinformatics, Yale University, New Haven, CT, 06510
8Department of Biostatistics, Yale School of Public Health, New Haven, CT, 06510
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Pradeep Natarajan
4Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142
6Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114
9Department of Medicine, Harvard Medical School, Boston, MA 02115
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Hani Goodarzi
7Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158
10Department of Urology, University of California, San Francisco, CA 94158
11Bakar Computational Health Sciences Institute, University of California, San Francisco, CA 94158
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  • For correspondence: Faranak.Fattahi@ucsf.edu hani.goodarzi@ucsf.edu
Faranak Fattahi
3Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, 94143
7Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158
12Program in Craniofacial Biology, University of California, San Francisco, CA 94110 USA
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  • ORCID record for Faranak Fattahi
  • For correspondence: Faranak.Fattahi@ucsf.edu hani.goodarzi@ucsf.edu
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Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has led to a global health crisis, and yet our understanding of the disease pathophysiology and potential treatment options remains limited. SARS-CoV-2 infection occurs through binding and internalization of the viral spike protein to angiotensin converting enzyme 2 (ACE2) on the host cell membrane. Lethal complications are caused by damage and failure of vital organs that express high levels of ACE2, including the lungs, the heart and the kidneys. Here, we established a high-throughput drug screening strategy to identify therapeutic candidates that reduce ACE2 levels in human embryonic stem cell (hESC) derived cardiac cells. Drug target analysis of validated hit compounds, including 5 alpha reductase inhibitors, revealed androgen signaling as a key modulator of ACE2 levels. Treatment with the 5 alpha reductase inhibitor dutasteride reduced ACE2 levels and internalization of recombinant spike receptor binding domain (Spike-RBD) in hESC-derived cardiac cells and human alveolar epithelial cells. Finally, clinical data on coronavirus disease 2019 (COVID-19) patients demonstrated that abnormal androgen states are significantly associated with severe disease complications and cardiac injury as measured by blood troponin T levels. These findings provide important insights on the mechanism of increased disease susceptibility in male COVID-19 patients and identify androgen receptor inhibition as a potential therapeutic strategy.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 15, 2020.
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Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men
Zaniar Ghazizadeh, Homa Majd, Mikayla Richter, Ryan Samuel, Seyedeh Maryam Zekavat, Hosseinali Asgharian, Sina Farahvashi, Ali Kalantari, Jonathan Ramirez, Hongyu Zhao, Pradeep Natarajan, Hani Goodarzi, Faranak Fattahi
bioRxiv 2020.05.12.091082; doi: https://doi.org/10.1101/2020.05.12.091082
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Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men
Zaniar Ghazizadeh, Homa Majd, Mikayla Richter, Ryan Samuel, Seyedeh Maryam Zekavat, Hosseinali Asgharian, Sina Farahvashi, Ali Kalantari, Jonathan Ramirez, Hongyu Zhao, Pradeep Natarajan, Hani Goodarzi, Faranak Fattahi
bioRxiv 2020.05.12.091082; doi: https://doi.org/10.1101/2020.05.12.091082

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