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

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.

SUBMITTER: Stanelle-Bertram S

PROVIDER: S-EPMC10518605 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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

Stanelle-Bertram Stephanie S Beck Sebastian S Mounogou Nancy Kouassi NK Schaumburg Berfin B Stoll Fabian F Al Jawazneh Amirah A Schmal Zoé Z Bai Tian T Zickler Martin M Beythien Georg G Becker Kathrin K de la Roi Madeleine M Heinrich Fabian F Schulz Claudia C Sauter Martina M Krasemann Susanne S Lange Philine P Heinemann Axel A van Riel Debby D Leijten Lonneke L Bauer Lisa L van den Bosch Thierry P P TPP Lopuhaä Boaz B Busche Tobias T Wibberg Daniel D Schaudien Dirk D Goldmann Torsten T Lüttjohann Anna A Ruschinski Jenny J Jania Hanna H Müller Zacharias Z Pinho Dos Reis Vinicius V Krupp-Buzimkic Vanessa V Wolff Martin M Fallerini Chiara C Baldassarri Margherita M Furini Simone S Norwood Katrina K Käufer Christopher C Schützenmeister Nina N von Köckritz-Blickwede Maren M Schroeder Maria M Jarczak Dominik D Nierhaus Axel A Welte Tobias T Kluge Stefan S McHardy Alice C AC Sommer Frank F Kalinowski Jörn J Krauss-Etschmann Susanne S Richter Franziska F von der Thüsen Jan J Baumgärtner Wolfgang W Klingel Karin K Ondruschka Benjamin B Renieri Alessandra A Gabriel Gülsah G

Cell reports. Medicine 20230812 9

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-lea ...[more]

PMID: 37572667

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Project description:IntroductionThe coronavirus disease 2019 (COVID-19) pandemic is a global public health emergency causing a disparate burden of death and disability around the world. The viral genetic variants associated with outcome severity are still being discovered.MethodsWe downloaded 155 958 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes from GISAID. Of these genomes, 3637 samples included useable metadata on patient outcomes. Using this subset, we evaluated whether SARS-CoV-2 viral genomic variants improved prediction of reported severity beyond age and region. First, we established whether including genomic variants as model features meaningfully increased the predictive power of our model. Next, we evaluated specific variants in order to determine the magnitude of association with severity and the frequency of these variants among SARS-CoV-2 genomes.ResultsLogistic regression models that included viral genomic variants outperformed other models (area under the curve = 0.91 as compared with 0.68 for age and gender alone; P < 0.001). We found 84 variants with odds ratios greater than 2 for outcome severity (17 and 67 for higher and lower severity, respectively). The median frequency of associated variants was 0.15% (interquartile range 0.09-0.45%). Altogether 85% of genomes had at least one variant associated with patient outcome.ConclusionNumerous SARS-CoV-2 variants have 2-fold or greater association with odds of mild or severe outcome and collectively, these variants are common. In addition to comprehensive mitigation efforts, public health measures should be prioritized to control the more severe manifestations of COVID-19 and the transmission chains linked to these severe cases.Lay summary: This study explores which, if any, SARS-CoV-2 viral genomic variants are associated with mild or severe COVID-19 patient outcomes. Our results suggest that there are common genomic variants in SARS-CoV-2 that are more often associated with negative patient outcomes, which may impact downstream public health measures.

Dataset Information

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

Publications

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

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