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

Female Humans Male Aromatase / genetics Letrozole SARS-CoV-2 COVID-19 / genetics Estradiol Testosterone
COVID-19 CYP19A1 estradiol letrozole lung health male sex testosterone

Journal

Cell reports. Medicine
ISSN: 2666-3791
Titre abrégé: Cell Rep Med
Pays: United States
ID NLM: 101766894

Informations de publication

Date de publication:
19 09 2023
Historique:
received: 12 07 2022
revised: 10 05 2023
accepted: 18 07 2023
medline: 22 9 2023
pubmed: 13 8 2023
entrez: 12 8 2023
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.xcrm.2023.101152 PMID: 37572667 PMC: PMC10518605
pubmed: 37572667
pii: S2666-3791(23)00305-1
doi: 10.1016/j.xcrm.2023.101152
pmc: PMC10518605
pii:
doi:

Substances chimiques

Aromatase EC 1.14.14.1
Letrozole 7LKK855W8I
Estradiol 4TI98Z838E
Testosterone 3XMK78S47O
CYP19A1 protein, human EC 1.14.14.1

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

101152

Informations de copyright

Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

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).

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Auteurs

Stephanie Stanelle-Bertram (S)

Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany.

Sebastian Beck (S)

Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany.

Nancy Kouassi Mounogou (NK)

Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany.

Berfin Schaumburg (B)

Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany.

Fabian Stoll (F)

Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany.

Amirah Al Jawazneh (A)

Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany.

Zoé Schmal (Z)

Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany.

Tian Bai (T)

Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany.

Martin Zickler (M)

Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany.

Georg Beythien (G)

Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany.

Kathrin Becker (K)

Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany.

Madeleine de la Roi (M)

Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany.

Fabian Heinrich (F)

Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Claudia Schulz (C)

Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, Hannover, Germany.

Martina Sauter (M)

Institute for Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany.

Susanne Krasemann (S)

Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Core Facility Experimental Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Philine Lange (P)

Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Axel Heinemann (A)

Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Debby van Riel (D)

Department of Viroscience, Erasmus Medical Center, Rotterdam, the Netherlands.

Lonneke Leijten (L)

Department of Viroscience, Erasmus Medical Center, Rotterdam, the Netherlands.

Lisa Bauer (L)

Department of Viroscience, Erasmus Medical Center, Rotterdam, the Netherlands.

Thierry P P van den Bosch (TPP)

Department of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands.

Boaz Lopuhaä (B)

Department of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands.

Tobias Busche (T)

Medical School East Westphalia-Lippe & Center for Biotechnology (CeBiTec), Bielefeld University, Bielefeld, Germany.

Daniel Wibberg (D)

Microbial Genomics and Biotechnology, Center for Biotechnology (CeBiTec), Bielefeld University, Bielefeld, Germany.

Dirk Schaudien (D)

Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany.

Torsten 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.

Anna Lüttjohann (A)

Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany.

Jenny Ruschinski (J)

Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany.

Hanna Jania (H)

Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany.

Zacharias Müller (Z)

Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany.

Vinicius Pinho Dos Reis (V)

Department for Viral Zoonoses - One Health, Leibniz Institute of Virology, Hamburg, Germany.

Vanessa 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.

Martin 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.

Chiara Fallerini (C)

Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy; Medical Genetics, University of Siena, Siena, Italy.

Margherita Baldassarri (M)

Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy; Medical Genetics, University of Siena, Siena, Italy.

Simone Furini (S)

Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy.

Katrina 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.

Christopher Käufer (C)

Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany.

Nina Schützenmeister (N)

Department of Pharmaceutical Sciences, University of Vienna, Vienna, Austria.

Maren 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.

Maria Schroeder (M)

Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Dominik Jarczak (D)

Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Axel Nierhaus (A)

Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Tobias 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.

Stefan Kluge (S)

Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Alice C 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.

Frank Sommer (F)

Division Men's Health, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Jörn Kalinowski (J)

Microbial Genomics and Biotechnology, Center for Biotechnology (CeBiTec), Bielefeld University, Bielefeld, Germany.

Susanne 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.

Franziska Richter (F)

Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany.

Jan von der Thüsen (J)

Department of Pathology, Erasmus University Medical Center, Rotterdam, the Netherlands.

Wolfgang Baumgärtner (W)

Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany.

Karin Klingel (K)

Institute for Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany.

Benjamin Ondruschka (B)

Institute of Legal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Alessandra 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.

Gülsah 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.

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Classifications MeSH

Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › CYP19A1 mediates severe SARS-CoV-2 disease...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Hémoprotéines › Cytochromes › Cytochrome P-450 enzyme system › Steroid hydroxylases › Aromatase › CYP19A1 mediates severe SARS-CoV-2 disease...
Recherchemedicale.com › Composés hétérocycliques › Composés hétéromonocycliques › Azoles › Triazoles › Létrozole › CYP19A1 mediates severe SARS-CoV-2 disease...
Recherchemedicale.com › Virus › Virus à ARN › Virus à ARN à brin positif › Nidovirales › Coronaviridae › Coronavirus › Betacoronavirus › Virus du SRAS › SARS-CoV-2 › CYP19A1 mediates severe SARS-CoV-2 disease...
Recherchemedicale.com › Maladies de l'appareil respiratoire › Infections de l'appareil respiratoire › Pneumopathie infectieuse › Pneumopathie virale › COVID-19 › CYP19A1 mediates severe SARS-CoV-2 disease...
Recherchemedicale.com › Hormones gonadiques › Hormones sexuelles stéroïdiennes › Congénères de l'oestradiol › Oestradiol › CYP19A1 mediates severe SARS-CoV-2 disease...
Recherchemedicale.com › Hormones gonadiques › Hormones sexuelles stéroïdiennes › Congénères de la testostérone › Testostérone › CYP19A1 mediates severe SARS-CoV-2 disease...