PT  - JOURNAL ARTICLE
AU  - Zaniar Ghazizadeh
AU  - Homa Majd
AU  - Mikayla Richter
AU  - Ryan Samuel
AU  - Seyedeh Maryam Zekavat
AU  - Hosseinali Asgharian
AU  - Sina Farahvashi
AU  - Ali Kalantari
AU  - Jonathan Ramirez
AU  - Hongyu Zhao
AU  - Pradeep Natarajan
AU  - Hani Goodarzi
AU  - Faranak Fattahi
TI  - Androgen Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men
AID  - 10.1101/2020.05.12.091082
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.05.12.091082
4099  - http://biorxiv.org/content/early/2020/05/15/2020.05.12.091082.short
4100  - http://biorxiv.org/content/early/2020/05/15/2020.05.12.091082.full
AB  - 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 StatementThe authors have declared no competing interest.