Meister Toni Luise, Nocke Maximilian K, Heinen Natalie, Burkard Thomas L, Brüggemann Yannick, Westhoven Saskia, Trüeb Bettina, Ebert Nadine, Thomann Lisa, Lubieniecki Krzysztof P, Lubieniecka Joanna M, Döring Kristina, Herrmann Maike, Haid Sibylle, Pietschmann Thomas, Wiegmann Bettina, Tao Ronny, Pfefferle Susanne, Addo Marylyn M, Thiel Volker, Drexler Ingo, Babel Nina, Phuc Nguyen Huu, Brown Richard J P, Todt Daniel, Steinmann Eike, Pfaender Stephanie
Department for Molecular and Medical Virology, Ruhr University Bochum, Bochum 44801, Germany.
Institute for Infection Research and Vaccine Development, Centre for Internal Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg 20251, Germany.
Proc Natl Acad Sci U S A. 2025 Jul 15;122(28):e2500276122. doi: 10.1073/pnas.2500276122. Epub 2025 Jul 9.
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.
霉酚酸（MPA）常用于实体器官移植后的免疫抑制方案。我们证明，MPA治疗可重复性地抑制一系列病毒的复制，包括严重急性呼吸综合征冠状病毒2（SARS-CoV-2）。从机制上讲，我们确定细胞鸟苷三磷酸池耗竭是这种抗病毒作用的关键介质。引人注目的是，这种抑制作用可以被克服，这与SARS-CoV-2基因组中出现的三个突破性突变（S P812R、ORF3 Q185H和E S6L）相关。随后的分析证实，这些突变的组合赋予了加速的复制动力学、更高的病毒滴度和更快出现的细胞病变效应，但并未产生MPA抗性。对感染的整体转录反应的比较突出了在突破性突变出现之前MPA治疗下特定细胞基因程序的失调。总之，这些发现确定了免疫抑制下病毒变异出现的病毒和宿主驱动因素。它们还主张密切监测免疫抑制患者，因为可能会出现具有适应性优势的新型病毒变异。
