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

doi:10.1016/j.stem.2020.11.009

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

Cell Stem Cell. 2020 Dec 3;27(6):876-889.e12. doi: 10.1016/j.stem.2020.11.009. Epub 2020 Nov 17.

Authors

Ryan M Samuel¹, Homa Majd¹, Mikayla N Richter¹, Zaniar Ghazizadeh², Seyedeh Maryam Zekavat³, Albertas Navickas⁴, Jonathan T Ramirez¹, Hosseinali Asgharian⁴, Camille R Simoneau⁵, Luke R Bonser⁶, Kyung Duk Koh⁶, Miguel Garcia-Knight⁷, Michel Tassetto⁷, Sara Sunshine⁴, Sina Farahvashi¹, Ali Kalantari¹, Wei Liu⁸, Raul Andino⁷, Hongyu Zhao⁹, Pradeep Natarajan¹⁰, David J Erle⁶, Melanie Ott¹¹, Hani Goodarzi¹², Faranak Fattahi¹³

Affiliations

¹ Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA 94143, USA.
² Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA; Yale School of Medicine, New Haven, CT 06510, USA.
³ 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.
⁴ Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA.
⁵ Gladstone Institutes, San Francisco, CA 94158, USA.
⁶ Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
⁷ Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
⁸ Program of Computational Biology & Bioinformatics, Yale University, New Haven, CT 06510, USA.
⁹ 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.
¹⁰ 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.
¹¹ Gladstone Institutes, San Francisco, CA 94158, USA; Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
¹² 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.
¹³ 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.

Abstract

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.

Keywords: 5-alpha reductase inhibitors; ACE2 regulation; COVID-19 risk factors; COVID-19 sex bias; SARS-CoV-2 infection model; deep learning; drug re-purposing; hPSC-based disease modeling; high content screening; virtual drug screen.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Androgen Antagonists
Androgens / metabolism*
Androgens / therapeutic use
Angiotensin-Converting Enzyme 2 / metabolism*
Angiotensin-Converting Enzyme Inhibitors / therapeutic use
Animals
Antiviral Agents / therapeutic use
COVID-19 / complications
COVID-19 / metabolism*
COVID-19 Drug Treatment
Cells, Cultured
Chlorocebus aethiops
Drug Evaluation, Preclinical
Female
Humans
Male
Myocytes, Cardiac / drug effects
Myocytes, Cardiac / metabolism
Organoids / drug effects
Organoids / virology
Patient Acuity*
Receptors, Coronavirus / metabolism*
Risk Factors
Sex Factors
Signal Transduction*
Vero Cells

Substances

Androgen Antagonists
Androgens
Angiotensin-Converting Enzyme Inhibitors
Antiviral Agents
Receptors, Coronavirus
ACE2 protein, human
Angiotensin-Converting Enzyme 2

Abstract

Publication types

MeSH terms

Substances

Grants and funding