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., et al. (2023). CYP19A1 mediates severe SARS-CoV-2 disease outcome in males. CELL REPORTS MEDICINE, 4(9), 1-25 [10.1016/j.xcrm.2023.101152].

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

Furini, Simone;
2023

Abstract

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.
2023
Stanelle-Bertram, S., Beck, S., Mounogou, N.K., Schaumburg, B., Stoll, F., Al Jawazneh, A., et al. (2023). CYP19A1 mediates severe SARS-CoV-2 disease outcome in males. CELL REPORTS MEDICINE, 4(9), 1-25 [10.1016/j.xcrm.2023.101152].
Stanelle-Bertram, Stephanie; Beck, Sebastian; Mounogou, Nancy Kouassi; Schaumburg, Berfin; Stoll, Fabian; Al Jawazneh, Amirah; Schmal, Zoé; Bai, Tian;...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/952704
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