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

2020; Elsevier BV; Volume: 27; Issue: 6 Linguagem: Inglês

10.1016/j.stem.2020.11.009

1934-5909

Ryan M. Samuel, Homa Majd, Mikayla N Richter, Zaniar Ghazizadeh, Seyedeh M. 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‐Hesari, Wei Liu, Raul Andino, Hongyu Zhao, Pradeep Natarajan, David J. Erle, Mélanie Ott, Hani Goodarzi, Faranak Fattahi,

Cardiovascular Disease and Adiposity

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 menSummarySARS-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.Graphical abstract