Mycophenolic Acid Treatment May Be Useful to Treat Rotavirus Infection in Transplant Patients

Based on 2D and 3D in vitro models, treatment with mycophenolic acid (MPA), an inhibitor of the type II isoform of inosine monophosphate dehydrogenase (IMPDH), confers very high levels of drug resistant rotavirus viral replication suppression and may therefore be a useful immunosuppressive agent for preventing rotavirus infection in transplantation patients, according to the results of a study published recently in Antiviral Research¹.

Following organ transplantation, immunosuppressant drugs are administered as a matter of routine in order to prevent graft rejection. Unfortunately, immunosuppression in general increases susceptibility to infection with rotavirus, a leading cause of gastroenteritis. At present, only the calcineurin inhibitor cyclosporine A has been shown to inhibit rotavirus replication in experimental models.² The direct effects of other types of immunosuppressants on rotavirus infection have not been elucidated to date.

First author Yuebang Yin, Msc, a PhD student in the Department of Gastroenterology and Hepatology at the Erasmus MC-University Medical Center in Rotterdam, and his colleagues addressed this unexplored topic. The stated objectives of the study were, "... to comprehensively profile the effects and mode-of-action of different types of immunosuppressants on rotavirus including corticosteroids (prednisolone [Pred] and dexamethasone [Dex]), calcineurin inhibitors (CsA and tacrolimus [FK506]) and selective antiproliferative agents (e.g., MPA)." Furthermore, Yin et al explained that, "In vitro cell culture systems that do not contain immune cells are the ideal models for studying such direct effects of immunosuppressants on viral replication."

To accomplish their stated goals, Yin et al used a 2D culture model of the Caco2 human intestinal cell line. Because these, "... convenient and valid model systems do not capture the dynamics and architectures of the intestinal epithelium," additional experiments were also conducted using a 3D model of human primary intestinal organoids inoculated with laboratory and patient-derived rotavirus strains. These 3D cultures are regarded as capable of reproducing the in vivo tissue architecture of the intestinal epithelium,³ and had been developed previously by this research group for modeling rotavirus infection.⁴ According to the authors, the intended use of these 3D primary organoid cultures in this study was to validate findings obtained from the 2D system.

Through the use of a large battery of experiments employing a variety of methodologies, Yin et al made several important discoveries regarding the mechanisms of rotavirus immunosuppression. For example, they demonstrated that glucocorticosteroids and FK506 did not affect rotavirus replication. Additionally, study results revealed that the cellular targets of CsA, CypA and CypB, inhibited and promoted rotavirus replication, respectively, and collectively determined responsiveness to CsA. MPA was also found to be a potent inhibitor of rotavirus replication in both SA11 and patient-derived rotavirus strains in cell line and organoid models through depletion of the cellular guanosine nucleotide pool. Lastly, MPA was shown to have a high barrier to the development of drug resistance.

In discussing the results generated from the experiments conducted in their study, Yin et al said that, "... by profiling different immunosuppressants, we have found that the responsiveness of rotavirus to CsA treatment is largely determined by the relative expression levels of its cellular targets, CypA and CypB. Importantly, we have identified MPA as a potent inhibitor of rotavirus infection with a high barrier to resistance development. It acts via the inhibition of the IMPDH enzymes to deplete cellular nucleotide to restrict rotavirus infection."

Regarding the broader implications of the study’s results, Yin et al stated, "... understanding the distinct effects and their mode-of-actions of different immunosuppressants on rotavirus infection bears important implications for transplant clinicians to design optimal protocols of immunosuppression for infected organ recipients." Furthermore, the authors noted that, "Understanding such direct effects on rotavirus by different immunosuppressive agents is certainly relevant to the management of infected transplantation patients, as well as to the development of potential new antivirals."

William Perlman, PhD, CMPP is a former research scientist currently working as a medical/scientific content development specialist. He earned his BA in Psychology from Johns Hopkins University, his PhD in Neuroscience at UCLA, and completed three years of postdoctoral fellowship in the Neuropathology Section of the Clinical Brain Disorders Branch of the National Institute of Mental Health.

References

1. Yin Y, Wang Y, Dang W, et al. Mycophenolic acid potently inhibits rotavirus infection with a high barrier to resistance development. Antiviral Res. 2016;133:41—49.
2. Shen Z, Tian Z, He H, Zhang J, Li J, Wu Y. Antiviral effects of cyclosporin a in neonatal mice with rotavirus-induced diarrhea. J. Pediatr. Gastroenterol. Nutr. 2015;60:11—17.
3. Sato T, Clevers H. Growing self-organizing mini-guts from a single intestinal stem cell: mechanism and applications. Science. 2013;340:1190—1194.
4. Yin Y, Bijvelds M, Dang W, et al. Modeling rotavirus infection and antiviral therapy using primary intestinal organoids. Antivir. Res. 2015;123;120—131.