Androgen Signaling Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men.
Ryan M Samuel, Homa Majd, Mikayla N Richter, Zaniar Ghazizadeh, Seyedeh Maryam Zekavat, Albertas Navickas, Jonathan T Ramirez, Hosseinali Asgharian, Camille R Simoneau, Luke R Bonser, Kyung Duk Koh, Miguel Garcia-Knight, Michel Tassetto, Sara Sunshine, Sina Farahvashi, Ali Kalantari, Wei Liu, Raul Andino, Hongyu Zhao, Pradeep Natarajan, David J Erle, Melanie Ott, Hani Goodarzi, Faranak Fattahi
Author Information
Ryan M Samuel: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143, USA.
Homa Majd: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143, USA.
Mikayla N Richter: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143, USA.
Zaniar Ghazizadeh: Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA; Yale School of Medicine, New Haven, CT 06510, USA.
Seyedeh Maryam Zekavat: Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Program of Computational Biology & Bioinformatics, Yale University, New Haven, CT 06510, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA.
Albertas Navickas: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA.
Jonathan T Ramirez: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143, USA.
Hosseinali Asgharian: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA.
Camille R Simoneau: Gladstone Institutes, San Francisco, CA 94158, USA.
Luke R Bonser: Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
Kyung Duk Koh: Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
Miguel Garcia-Knight: Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
Michel Tassetto: Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
Sara Sunshine: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA.
Sina Farahvashi: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143, USA.
Ali Kalantari: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143, USA.
Wei Liu: Program of Computational Biology & Bioinformatics, Yale University, New Haven, CT 06510, USA.
Raul Andino: Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
Hongyu Zhao: Program of Computational Biology & Bioinformatics, Yale University, New Haven, CT 06510, USA; Department of Biostatistics, Yale School of Public Health, New Haven, CT 06510, USA.
Pradeep Natarajan: Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
David J Erle: Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
Melanie Ott: Gladstone Institutes, San Francisco, CA 94158, USA; Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
Hani Goodarzi: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA; Department of Urology, University of California, San Francisco, CA 94158, USA; Bakar Computational Health Sciences Institute, University of California, San Francisco, CA 94158, USA. Electronic address: hani.goodarzi@ucsf.edu.
Faranak Fattahi: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA; Program in Craniofacial Biology, University of California, San Francisco, CA 94110, USA. Electronic address: faranak.fattahi@ucsf.edu.
SARS-CoV-2 infection has led to a global health crisis, and yet our understanding of the disease and potential treatment options remains limited. The infection occurs through binding of the virus with angiotensin converting enzyme 2 (ACE2) on the cell membrane. Here, we established a screening strategy to identify drugs that reduce ACE2 levels in human embryonic stem cell (hESC)-derived cardiac cells and lung organoids. Target analysis of hit compounds revealed androgen signaling as a key modulator of ACE2 levels. Treatment with antiandrogenic drugs reduced ACE2 expression and protected hESC-derived lung organoids against SARS-CoV-2 infection. Finally, clinical data on COVID-19 patients demonstrated that prostate diseases, which are linked to elevated androgen, are significant risk factors and that genetic variants that increase androgen levels are associated with higher disease severity. These findings offer insights on the mechanism of disproportionate disease susceptibility in men and identify antiandrogenic drugs as candidate therapeutics for COVID-19.
