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

GEN-COVID Multicenter Study Group, Stephanie Stanelle-Bertram, Sebastian Beck, Nancy Kouassi Mounogou, Berfin Schaumburg, Fabian Stoll, Amirah Al Jawazneh, Zoé Schmal, Tian Bai, Martin Zickler, Georg Beythien, Kathrin Becker, Madeleine de la Roi, Fabian Heinrich, Claudia Schulz, Martina Sauter, Susanne Krasemann, Philine Lange, Axel Heinemann, Debby van RielLonneke Leijten, Lisa Bauer, Thierry P.P. van den Bosch, Boaz Lopuhaä, Tobias Busche, Daniel Wibberg, Dirk Schaudien, Torsten Goldmann, Anna Lüttjohann, Jenny Ruschinski, Hanna Jania, Zacharias Müller, Vinicius Pinho dos Reis, Vanessa Krupp-Buzimkic, Martin Wolff, Chiara Fallerini, Margherita Baldassarri, Simone Furini, Katrina Norwood, Christopher Käufer, Nina Schützenmeister, Maren von Köckritz-Blickwede, Maria Schroeder, Dominik Jarczak, Axel Nierhaus, Tobias Welte, Stefan Kluge, Alice C. McHardy, Frank Sommer, Jörn Kalinowski, Jan von der Thüsen

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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.

Original languageEnglish
Article number101152
JournalCell Reports Medicine
Volume4
Issue number9
Early online date11 Aug 2023
DOIs
Publication statusPublished - 19 Sept 2023

Bibliographical note

Acknowledgments:
This study is dedicated to the memory of my academic mentor Hans Dieter Klenk (∗06.25.1938, †06.01.2021), a pioneer in influenza research on interspecies transmission. He will be dearly missed. This study was supported by various grants obtained from the Federal Ministry of Health, Germany (BMG; ZMV I 1-2520COR501 to G.G.), the Federal Ministry of Education and Research, Germany (BMBF; project no. 03COV06B to G.G.; no. 01KI1723G to W.B.; no. 01KX2121 to F.H. P.L. A.H. and B.O.), the Ministry for Science and Culture of Lower Saxony (14-76103-184-CORONA-15/20 to W.B. and M.v.K.-B.), the Ministry of Science, Research and the Arts Baden-Württemberg and the Deutsche Herzstiftung (to K.K.), and ZonMw, the Netherlands (project no. 10430 01 201 0016 to J.T.). We thank all staff of the Core Facility Small Animal Models of the Leibniz Institute of Virology, particularly Ursula Müller and Oliver Strauch for their excellent support with the golden hamster model. We thank the NGS team of the Omics CF NGS and CeBiTec as well as the technical staff of the CeBiTec Technology Platform Genomics, particularly Eva Schulte-Bernd, Yvonne Kutter, and Katharina Hanuschka for technical assistance. We thank Kristin Hartmann and Martin Müller from the Leibniz Institute of Virology in Hamburg for technical assistance. This study is part of the Italian GEN-COVID Multicenter Study (https://sites.google.com/dbm.unisi.it/gen-covid) aimed at identifying the COVID-19 host genetic bases. Specimens were provided by the COVID-19 Biobank of Siena, part of the Genetic Biobank of Siena, member of Telethon Network of Genetic Biobanks, BBMRI-IT, EuroBioBank, and RD-Connect. CINECA consortium and Network for Italian Genomes (http://www.nig.cineca.it) provided computational resources and support. We thank private donors for the support provided to A.R. (Department of Medical Biotechnologies, University of Siena, D.L n.18 of March 17, 2020) and the GEN-COVID Multicenter Study Group (https://www.covid19hg.org/). We also thank the following projects: MIUR-Dipartimenti di Eccellenza 2018–2020; Bando Ricerca COVID-19 Toscana; Intesa San Paolo-2020 charity; Italian Ministry of University and Research - Bando FISR 2020 - HACKTHECOV; Instituto Buddista Italiano Soka Gakkai - PAT-COVID; and EU project H2020-SC1-FA-DTS-2018-2020 - INTERVENE). G.G. designed the study and wrote the manuscript. S.S.B. S.B. N.K.M. and B.S. performed all animal experiments, analyzed the data, and revised the manuscript. F. Stoll, A.A.J. T. Bai, M.Z. A.L. J.R. H.J. Z.M. K.B. V.P.d.R. M.v.K.-B. C.S. and V.K.-B. assisted with the animal experiments and performed molecular analysis. N.K.M. S.S.B. B.S. S.B. Z.S. M.W. and S.K.-E. performed and/or interpreted data obtained from lung function experiments. A.A.J. isolated and treated lung macrophages from golden hamsters. G.B. K.B. M.d.l.R. D.S. T.G. and W.B. performed histopathological and immunohistochemical analysis of the animal organs. C.K. and F.R. performed letrozole HPLC measurement in plasma and lung tissue of letrozole-treated golden hamsters. T. Busche, D.W. and J.K. performed RNA-sequencing and transcriptomic data analysis. M.S. D.J. A.N. and S. Kluge provided clinical samples from COVID-19 patients for SARS-CoV-2 virus isolation. K.K. M. Schroeder. F.H. S. Krasemann, P.L. A.H. B.O. L.L. L.B. T.P.P.v.d.B. B.L. D.v.R. J.v.d.T. K.K. and M. Sauter sampled and analyzed the lungs of fatal COVID-19 cases. K.N. and A.C.M. supported the analysis of transcriptomic data. N.S. performed structural analysis. F. Sommer supported the design of letrozole treatment studies. T.W. supported the evaluation of the human cohort data. GEN-COVID Multicenter Study, M.B. and A.R. provided and curated clinical data. C.F. S.F. and A.R. performed WES data analysis and statistical data analysis. All authors approved the manuscript. 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). We support inclusive, diverse, and equitable conduct of research.

Funding Information:
This study was supported by various grants obtained from the Federal Ministry of Health , Germany ( BMG; ZMV I 1-2520COR501 to G.G.), the Federal Ministry of Education and Research , Germany (BMBF; project no. 03COV06B to G.G.; no. 01KI1723G to W.B.; no. 01KX2121 to F.H., P.L., A.H., and B.O.), the Ministry for Science and Culture of Lower Saxony ( 14-76103-184-CORONA-15/20 to W.B. and M.v.K.-B.), the Ministry of Science, Research and the Arts Baden-Württemberg and the Deutsche Herzstiftung (to K.K.), and ZonMw , the Netherlands (project no. 10430 01 201 0016 to J.T.). We thank all staff of the Core Facility Small Animal Models of the Leibniz Institute of Virology, particularly Ursula Müller and Oliver Strauch for their excellent support with the golden hamster model. We thank the NGS team of the Omics CF NGS and CeBiTec as well as the technical staff of the CeBiTec Technology Platform Genomics, particularly Eva Schulte-Bernd, Yvonne Kutter, and Katharina Hanuschka for technical assistance. We thank Kristin Hartmann and Martin Müller from the Leibniz Institute of Virology in Hamburg for technical assistance. This study is part of the Italian GEN-COVID Multicenter Study ( https://sites.google.com/dbm.unisi.it/gen-covid ) aimed at identifying the COVID-19 host genetic bases. Specimens were provided by the COVID-19 Biobank of Siena , part of the Genetic Biobank of Siena , member of Telethon Network of Genetic Biobanks, BBMRI-IT, EuroBioBank, and RD-Connect. CINECA consortium and Network for Italian Genomes ( http://www.nig.cineca.it ) provided computational resources and support. We thank private donors for the support provided to A.R. (Department of Medical Biotechnologies, University of Siena, D.L n.18 of March 17, 2020) and the GEN-COVID Multicenter Study Group ( https://www.covid19hg.org/ ). We also thank the following projects: MIUR-Dipartimenti di Eccellenza 2018–2020 ; Bando Ricerca COVID-19 Toscana ; Intesa San Paolo-2020 charity ; Italian Ministry of University and Research - Bando FISR 2020 - HACKTHECOV ; Instituto Buddista Italiano Soka Gakkai - PAT-COVID ; and EU project H2020-SC1-FA-DTS-2018-2020 - INTERVENE).

Publisher Copyright:
© 2023 The Author(s)

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