Mycophenolic acid treatment drives the emergence of novel SARS-CoV-2 variants
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (27)
Toni Luise Meister
Department for Molecular and Medical Virology, Ruhr University Bochum
Maximilian K. Nocke
Department for Molecular and Medical Virology, Ruhr University Bochum
Natalie Heinen
Department for Molecular and Medical Virology, Ruhr University Bochum
Thomas L. Burkard
Department for Molecular and Medical Virology, Ruhr University Bochum
Yannick Brüggemann
Department for Molecular and Medical Virology, Ruhr University Bochum
Saskia Westhoven
Department for Molecular and Medical Virology, Ruhr University Bochum
Bettina Trüeb
Institute of Virology and Immunology, Bern and Mittelhäusern
Nadine Ebert
Institute of Virology and Immunology, Bern and Mittelhäusern
Lisa Thomann
Institute of Virology and Immunology, Bern and Mittelhäusern
Krzysztof P. Lubieniecki
Department of Human Genetics, Ruhr University Bochum
Joanna M. Lubieniecka
Department of Human Genetics, Ruhr University Bochum
Kristina Döring
Maike Herrmann
Section VET5 - Veterinary Medicine Research, Paul Ehrlich Institute
Sibylle Haid
TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between Helmholtz-Centre for Infection Research and Hannover Medical School
Thomas Pietschmann
TWINCORE, Centre for Experimental and Clinical Infection Research, A Joint Venture between Helmholtz-Centre for Infection Research and Hannover Medical School
Bettina Wiegmann
Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School
Ronny Tao
Institute of Virology, Medical Faculty, Heinrich-Heine-University
Susanne Pfefferle
Institute of Medical Microbiology, Virology and Hygiene, Centre for Diagnostics, University Medical Centre Hamburg-Eppendorf
Marylyn M. Addo
Institute for Infection Research and Vaccine Development, Centre for Internal Medicine, University Medical Centre Hamburg-Eppendorf
Volker Thiel
Institute of Virology and Immunology, Bern and Mittelhäusern
Ingo Drexler
Institute of Virology, Medical Faculty, Heinrich-Heine-University
Nina Babel
Medical Department I, Centre for Translational Medicine and Immune Diagnostics Laboratory, Marien Hospital Herne, University Hospital of the Ruhr-University Bochum
Huu Phuc Nguyen
Department of Human Genetics, Ruhr University Bochum
Richard J. P. Brown
Department for Molecular and Medical Virology, Ruhr University Bochum
Daniel Todt
Department for Molecular and Medical Virology, Ruhr University Bochum
Eike Steinmann
Department for Molecular and Medical Virology, Ruhr University Bochum
Stephanie Pfaender
Department for Molecular and Medical Virology, Ruhr University Bochum