Mycophenolic acid treatment drives the emergence of novel SARS-CoV-2 variants

• 成果类型: Article
• 署名作者: Meister, Toni Luise; Nocke, Maximilian K.; Heinen, Natalie; Burkard, Thomas L.; Brueggemann, Yannick; Westhoven, Saskia; Trueb, Bettina; Ebert, Nadine; Thomann, Lisa; Lubieniecki, Krzysztof P.; Lubieniecka, Joanna M.; Doering, Kristina; Herrmann, Maike; Haid, Sibylle; Pietschmann, Thomas; Wiegmann, Bettina; Tao, Ronny; Pfefferle, Susanne; Addo, Marylyn M.; Thiel, Volker; Drexler, Ingo; Babel, Nina; Nguyen, Huu Phuc; Brown, Richard J. P.; Todt, Daniel; Steinmann, Elike; Pfaender, Stephanie
• 署名单位: Ruhr University Bochum; University of Hamburg; University Medical Center Hamburg-Eppendorf; Leibniz Association; Bernhard Nocht Institut fur Tropenmedizin; German Center for Infection Research; Ruhr University Bochum; University of Bern; Ruhr University Bochum; Paul Ehrlich Institute; Helmholtz Association; Helmholtz-Center for Infection Research; Hannover Medical School; Hannover Medical School; Hannover Medical School; Heinrich Heine University Dusseldorf; University of Hamburg; University Medical Center Hamburg-Eppendorf; Leibniz Association; Bernhard Nocht Institut fur Tropenmedizin; University of Bern; Ruhr University Bochum; St. Marien Hospital; Ruhr University Bochum; St. Marien Hospital; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Free University of Berlin; Humboldt University of Berlin; German Center for Infection Research; University of Lubeck
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12438
• DOI: 10.1073/pnas.2500276122
• 发表日期: 2025-07-15
• 关键词: hepatitis-c virus; in-vitro; inhibits replication; ribavirin; infection; region; cell; pharmacokinetics; cyclosporine; CORONAVIRUS

摘要

Mycophenolic acid (MPA) is commonly used in immunosuppressive regimens following solid organ transplantation. We demonstrate that MPA treatment reproducibly inhibits the replication of a range of viruses, including severe respiratory syndrome coronavirus 2 (SARS-CoV-2). Mechanistically, we identified cellular guanosine triphosphate pool depletion as a key mediator of this antiviral effect. Strikingly, this inhibition can be overcome which was correlated with the emergence of three breakthrough mutations in the SARS-CoV-2 genome (S P812R, ORF3 Q185H, and E S6L). Subsequent analyses confirmed that the combination of these mutations conferred accelerated replication kinetics, higher viral titers, and more rapid onset of cytopathic effects, but not MPA resistance. Comparison of global transcriptional responses to infection highlighted dysregulation of specific cellular gene programs under MPA treatment prior to breakthrough mutation emergence. Together, these findings identify viral and host drivers of variant emergence under immunosuppression. They also advocate for close monitoring of immunosuppressed patients, where emergence of novel viral variants with a fitness advantage may arise.