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

Autor:	Stanelle-Bertram S; Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany., Beck S; Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany., Mounogou NK; Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany., Schaumburg B; Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany., Stoll F; Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany., Al Jawazneh A; Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany., Schmal Z; Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany., Bai T; Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany., Zickler M; Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany., Beythien G; Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany., Becker K; Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany., de la Roi M; Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany., Heinrich F; Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Schulz C; Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Hannover, Germany., Sauter M; Institute for Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany., Krasemann S; Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Core Facility Experimental Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Lange P; Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Heinemann A; Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., van Riel D; Department of Viroscience, Erasmus Medical Center, Rotterdam, the Netherlands., Leijten L; Department of Viroscience, Erasmus Medical Center, Rotterdam, the Netherlands., Bauer L; Department of Viroscience, Erasmus Medical Center, Rotterdam, the Netherlands., van den Bosch TPP; Department of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands., Lopuhaä B; Department of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands., Busche T; Medical School East Westphalia-Lippe & Center for Biotechnology (CeBiTec), Bielefeld University, Bielefeld, Germany., Wibberg D; Microbial Genomics and Biotechnology, Center for Biotechnology (CeBiTec), Bielefeld University, Bielefeld, Germany., Schaudien D; Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany., Goldmann T; Pathology of the University Medical Center Schleswig-Holstein, Campus Lübeck and the Research Center Borstel, Research Center Borstel, Leibniz Center for Medicine and Biosciences, German Center for Lung Research (DZL), Borstel, Germany., Lüttjohann A; Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany., Ruschinski J; Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany., Jania H; Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany., Müller Z; Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany., Pinho Dos Reis V; Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany., Krupp-Buzimkic V; Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany; Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Hannover, Germany., Wolff M; Early Life Origins of Chronic Lung Disease, Research Center Borstel, Leibniz Lung Center, Member of the German Center for Lung Research (DZL), Borstel, Germany., Fallerini C; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy; Medical Genetics, University of Siena, Siena, Italy., Baldassarri M; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy; Medical Genetics, University of Siena, Siena, Italy., Furini S; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy., Norwood K; Department for Computational Biology of Infection Research, Helmholtz Center for Infection Research, Braunschweig, Germany; Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universität Braunschweig, Braunschweig, Germany., Käufer C; Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany., Schützenmeister N; Department of Pharmaceutical Sciences, University of Vienna, Vienna, Austria., von Köckritz-Blickwede M; Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Hannover, Germany; Department of Biochemistry, University of Veterinary Medicine Hannover, Hannover, Germany., Schroeder M; Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Jarczak D; Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Nierhaus A; Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Welte T; Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease, Member of the German Center for Lung Research, Hannover, Germany., Kluge S; Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., McHardy AC; German Center for Infection Research (DZIF), Braunschweig, Germany; Department for Computational Biology of Infection Research, Helmholtz Center for Infection Research, Braunschweig, Germany; Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universität Braunschweig, Braunschweig, Germany; Cluster of Excellence RESIST (EXC 2355), Hannover Medical School, Hannover, Germany., Sommer F; Division Men's Health, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Kalinowski J; Microbial Genomics and Biotechnology, Center for Biotechnology (CeBiTec), Bielefeld University, Bielefeld, Germany., Krauss-Etschmann S; Early Life Origins of Chronic Lung Disease, Research Center Borstel, Leibniz Lung Center, Member of the German Center for Lung Research (DZL), Borstel, Germany; Institute for Experimental Medicine, Christian-Albrechts-Universität zu Kiel, Kiel, Germany., Richter F; Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany., von der Thüsen J; Department of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands., Baumgärtner W; Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany., Klingel K; Institute for Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany., Ondruschka B; Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Renieri A; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy; Medical Genetics, University of Siena, Siena, Italy; Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Siena, Italy., Gabriel G; Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany; Institute of Virology, University of Veterinary Medicine Hannover, Hannover, Germany; German Center for Infection Research (DZIF), Braunschweig, Germany. Electronic address: guelsah.gabriel@leibniz-liv.de.
Jazyk:	angličtina
Zdroj:	Cell reports. Medicine [Cell Rep Med] 2023 Sep 19; Vol. 4 (9), pp. 101152. Date of Electronic Publication: 2023 Aug 12.
DOI:	10.1016/j.xcrm.2023.101152
Abstrakt:	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. Competing Interests: Declaration of interests Method for predicting the course of a viral disease. Inventors: G.G. and S.S.-B. Filing date: 04.30.2021. Pending patent applications: Europe (EP21722231.4), USA (US17995728), Japan (JP2022-566073), China (CN202180031796.5). (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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