Cell Stem Cell
Volume 27, Issue 6, 3 December 2020, Pages 876-889.e12
Journal home page for Cell Stem Cell

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

https://doi.org/10.1016/j.stem.2020.11.009Get rights and content
Under an Elsevier user license
open archive

Highlights

  • Drug screens on hESC cardiac cells identify modulators of SARS-CoV-2 receptor ACE2

  • Targets of drugs that reduce ACE2 converge on androgen signaling pathway

  • Androgen signaling inhibition reduces SARS-CoV-2 infection in hESC lung organoids

  • Elevated androgen increases COVID-19 susceptibility and severity in men

Summary

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

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

Cited by (0)

17

These authors contributed equally

18

Lead Contact