title: Mycophenolic acid potently inhibits rotavirus infection with a high barrier to resistance development.
abstract: Rotavirus infection has emerged as an important cause of complications in organ transplantation recipients. Immunosuppressants used to prevent alloreactivity can also interfere with virus infection, but the direct effects of the specific type of immunosuppressants on rotavirus infection are still unclear. Here we profiled the effects of different immunosuppressants on rotavirus using a 2D culture model of Caco2 human intestinal cell line and a 3D model of human primary intestinal organoids inoculated with laboratory and patient-derived rotavirus strains. We found that the responsiveness of rotavirus to Cyclosporine A treatment was moderate and strictly regulated in an opposite direction by its cellular targets cyclophilin A and B. Treatment with mycophenolic acid (MPA) resulted in a 99% inhibition of viral RNA production at the clinically relevant concentration (10 μg/ml) in Caco2 cells. This effect was further confirmed in organoids. Importantly, continuous treatment with MPA for 30 passages did not attenuate its antiviral potency, indicating a high barrier to drug resistance development. Mechanistically, the antiviral effects of MPA act via inhibiting the IMPDH enzyme and resulting in guanosine nucleotide depletion. Thus for transplantation patients at risk for rotavirus infection, the choice of MPA as an immunosuppressive agent appears rational.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Yuebang
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Yijin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Wen
authors.initials: W
authors.lastname: Dang
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Medical Faculty, Kunming University of Science and Technology, Kunming, PR China.
authors.forename: Junhong
authors.initials: J
authors.lastname: Su
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Xinying
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Wenshi
authors.initials: W
authors.lastname: Wang
authors.affiliation: Center for Drug Design, University of Minnesota, Minneapolis, USA.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Felczak
authors.affiliation: Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Luc J W
authors.initials: LJ
authors.lastname: van der Laan
authors.affiliation: Center for Drug Design, University of Minnesota, Minneapolis, USA.
authors.forename: Krzysztof W
authors.initials: KW
authors.lastname: Pankiewicz
authors.affiliation: Department of Viroscience, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Annemiek A
authors.initials: AA
authors.lastname: van der Eijk
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: Bijvelds
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Dave
authors.initials: D
authors.lastname: Sprengers
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Hugo
authors.initials: H
authors.lastname: de Jonge
authors.affiliation: Department of Viroscience, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Marion P G
authors.initials: MP
authors.lastname: Koopmans
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Herold J
authors.initials: HJ
authors.lastname: Metselaar
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Maikel P
authors.initials: MP
authors.lastname: Peppelenbosch
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands. Electronic address: q.pan@erasmusmc.nl.
authors.forename: Qiuwei
authors.initials: Q
authors.lastname: Pan
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D018938:Caco-2 Cells; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D024882:Drug Resistance, Viral; D005938:Glucocorticoids / Q000494:pharmacology; D006151:Guanosine / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000821:virology; D009173:Mycophenolic Acid / Q000494:pharmacology*; D012401:Rotavirus / Q000187:drug effects*; D012400:Rotavirus Infections / Q000188:drug therapy / Q000821:virology; D046509:Tissue Culture Techniques; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D006151:Guanosine; D009173:Mycophenolic Acid
keywords: Immunosuppressants; Intestinal organoids; Mycophenolic acid; Rotavirus