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.

• Stanelle-Bertram, S.
• Beck, S.
• Mounogou, N. K.
• Schaumburg, B.
• Stoll, F.
• Al Jawazneh, A.
• Schmal, Z.
• Bai, T.
• Zickler, M.
• Beythien, G.
• Becker, K.
• de la Roi, M.
• Heinrich, F.
• Schulz, C.
• Sauter, M.
• Krasemann, S.
• Lange, P.
• Heinemann, A.
• van Riel, D.
• Leijten, L.
• Bauer, L.
• van den Bosch, T. P. P.
• Lopuhaä, B.
• Busche, T.
• Wibberg, D.
• Schaudien, D.
• Goldmann, T.
• Lüttjohann, A.
• Ruschinski, J.
• Jania, H.
• Müller, Z.
• Pinho Dos Reis, V.
• Krupp-Buzimkic, V.
• Wolff, M.
• Fallerini, C.
• Baldassarri, M.
• Furini, S.
• Norwood, K.
• Käufer, C.
• Schützenmeister, N.
• von Köckritz-Blickwede, M.
• Schroeder, M.
• Jarczak, D.
• Nierhaus, A.
• Welte, T.
• Kluge, S.
• McHardy, A. C.
• Sommer, F.
• Kalinowski, J.
• Krauss-Etschmann, S.
• Richter, F.
• von der Thüsen, J.
• Baumgärtner, W.
• Klingel, K.
• Ondruschka, B.
• Renieri, A.
• Gabriel, G.