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

TY - JOUR

T1 - CYP19A1 mediates severe SARS-CoV-2 disease outcome in males

AU - Stanelle-Bertram, Stephanie

AU - Beck, Sebastian

AU - Mounogou, Nancy Kouassi

AU - Schaumburg, Berfin

AU - Stoll, Fabian

AU - Al Jawazneh, Amirah

AU - Schmal, Zoé

AU - Bai, Tian

AU - Zickler, Martin

AU - Beythien, Georg

AU - Becker, Kathrin

AU - de la Roi, Madeleine

AU - Heinrich, Fabian

AU - Schulz, Claudia

AU - Sauter, Martina

AU - Krasemann, Susanne

AU - Lange, Philine

AU - Heinemann, Axel

AU - van Riel, Debby

AU - Leijten, Lonneke

AU - Bauer, Lisa

AU - van den Bosch, Thierry P P

AU - Lopuhaä, Boaz

AU - Busche, Tobias

AU - Wibberg, Daniel

AU - Schaudien, Dirk

AU - Goldmann, Torsten

AU - Lüttjohann, Anna

AU - Ruschinski, Jenny

AU - Jania, Hanna

AU - Müller, Zacharias

AU - Pinho Dos Reis, Vinicius

AU - Krupp-Buzimkic, Vanessa

AU - Wolff, Martin

AU - Fallerini, Chiara

AU - Baldassarri, Margherita

AU - Furini, Simone

AU - Norwood, Katrina

AU - Käufer, Christopher

AU - Schützenmeister, Nina

AU - von Köckritz-Blickwede, Maren

AU - Schroeder, Maria

AU - Jarczak, Dominik

AU - Nierhaus, Axel

AU - Welte, Tobias

AU - Kluge, Stefan

AU - McHardy, Alice C

AU - Sommer, Frank

AU - Kalinowski, Jörn

AU - Krauss-Etschmann, Susanne

AU - Richter, Franziska

AU - von der Thüsen, Jan

AU - Baumgärtner, Wolfgang

AU - Klingel, Karin

AU - Ondruschka, Benjamin

AU - Renieri, Alessandra

AU - Gabriel, Gülsah

AU - GEN-COVID Multicenter Study Group

PY - 2023/9/19

Y1 - 2023/9/19

N2 - 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.

AB - 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.

U2 - 10.1016/j.xcrm.2023.101152

DO - 10.1016/j.xcrm.2023.101152

M3 - SCORING: Journal article

C2 - 37572667

VL - 4

SP - 101152

JO - CELL REP MED

JF - CELL REP MED

SN - 2666-3791

IS - 9

ER -