CYP19A1 mediates severe SARS-CoV-2 disease outcome in males.

Male sex represents one of the major risk factors for severe COVID-19 outcome. However, underlying mechanisms that mediate sex-dependent disease outcome are as yet unknown. Here, we identify the CYP19A1 gene encoding for the testosterone-to-estradiol metabolizing enzyme CYP19A1 (also known as aromatase) as a host factor that contributes to worsened disease outcome in SARS-CoV-2-infected males. We analyzed exome sequencing data obtained from a human COVID-19 cohort (n = 2,866) using a machine-learning approach and identify a CYP19A1-activity-increasing mutation to be associated with the development of severe disease in men but not women. We further analyzed human autopsy-derived lungs (n = 86) and detect increased pulmonary CYP19A1 expression at the time point of death in men compared with women. In the golden hamster model, we show that SARS-CoV-2 infection causes increased CYP19A1 expression in the lung that is associated with dysregulated plasma sex hormone levels and reduced long-term pulmonary function in males but not females. Treatment of SARS-CoV-2-infected hamsters with a clinically approved CYP19A1 inhibitor (letrozole) improves impaired lung function and supports recovery of imbalanced sex hormones specifically in males. Our study identifies CYP19A1 as a contributor to sex-specific SARS-CoV-2 disease outcome in males. Furthermore, inhibition of CYP19A1 by the clinically approved drug letrozole may furnish a new therapeutic strategy for individualized patient management and treatment. Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Stephanie Stanelle-Bertram, Sebastian Beck, Nancy Kouassi Mounogou, Berfin Schaumburg, Fabian Stoll, Amirah Al Jawazneh, Zoé Schmal, Tian Bai, Martin Zickler, Georg Beythien, Kathrin Becker, Madeleine de la Roi, Fabian Heinrich, Claudia Schulz, Martina Sauter, Susanne Krasemann, Philine Lange, Axel Heinemann, Debby van Riel, Lonneke Leijten, Lisa Bauer, Thierry P P van den Bosch, Boaz Lopuhaä, Tobias Busche, Daniel Wibberg, Dirk Schaudien, Torsten Goldmann, Anna Lüttjohann, Jenny Ruschinski, Hanna Jania, Zacharias Müller, Vinicius Pinho Dos Reis, Vanessa Krupp-Buzimkic, Martin Wolff, Chiara Fallerini, Margherita Baldassarri, Simone Furini, Katrina Norwood, Christopher Käufer, Nina Schützenmeister, Maren von Köckritz-Blickwede, Maria Schroeder, Dominik Jarczak, Axel Nierhaus, Tobias Welte, Stefan Kluge, Alice C McHardy, Frank Sommer, Jörn Kalinowski, Susanne Krauss-Etschmann, Franziska Richter, Jan von der Thüsen, Wolfgang Baumgärtner, Karin Klingel, Benjamin Ondruschka, GEN-COVID Multicenter Study Group, Alessandra Renieri, Gülsah Gabriel. CYP19A1 mediates severe SARS-CoV-2 disease outcome in males. Cell reports. Medicine. 2023 Sep 19;4(9):101152

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PMID: 37572667

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