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: Yuebang Yin, Yijin Wang, Wen Dang, Lei Xu, Junhong Su, Xinying Zhou, Wenshi Wang, Krzysztof Felczak, Luc J W van der Laan, Krzysztof W Pankiewicz, Annemiek A van der Eijk, Marcel Bijvelds, Dave Sprengers, Hugo de Jonge, Marion P G Koopmans, Herold J Metselaar, Maikel P Peppelenbosch, Qiuwei Pan
• Journal: Antiviral research (Antiviral Res) Vol. 133 Pg. 41-9 (09 2016) ISSN: 1872-9096 [Electronic] Netherlands
• PMID: 27468950 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier B.V. All rights reserved.

Chemical References

• Antiviral Agents
• Glucocorticoids
• Immunosuppressive Agents
• Guanosine
• Mycophenolic Acid

Topics

• Antiviral Agents (pharmacology)
• Caco-2 Cells
• Cell Line
• Dose-Response Relationship, Drug
• Drug Resistance, Viral
• Glucocorticoids (pharmacology)
• Guanosine (metabolism)
• Humans
• Immunosuppressive Agents (pharmacology)
• Intestinal Mucosa (metabolism)
• Intestines (drug effects, virology)
• Mycophenolic Acid (pharmacology)
• Rotavirus (drug effects)
• Rotavirus Infections (drug therapy, virology)
• Tissue Culture Techniques
• Virus Replication (drug effects)