6-Thioguanine inhibits rotavirus replication through suppression of Rac1 GDP/GTP cycling

Antiviral Res. 2018 Aug:156:92-101. doi: 10.1016/j.antiviral.2018.06.011. Epub 2018 Jun 18.

Abstract

Rotavirus infection has emerged as an important cause of complications in organ transplantation recipients and might play a role in the pathogenesis of inflammatory bowel disease (IBD). 6-Thioguanine (6-TG) has been widely used as an immunosuppressive drug for organ recipients and treatment of IBD in the clinic. This study aims to investigate the effects and mode-of-action of 6-TG on rotavirus replication. Human intestinal Caco2 cell line, 3D model of human primary intestinal organoids, laboratory rotavirus strain (SA11) and patient-derived rotavirus isolates were used. We have demonstrated that 6-TG significantly inhibits rotavirus replication in these intestinal epithelium models. Importantly, gene knockdown or knockout of Rac1, the cellular target of 6-TG, significantly inhibited rotavirus replication, indicating the supportive role of Rac1 for rotavirus infection. We have further demonstrated that 6-TG can effectively inhibit the active form of Rac1 (GTP-Rac1), which essentially mediates the anti-rotavirus effect of 6-TG. Consistently, ectopic over-expression of GTP-Rac1 facilitates but an inactive Rac1 (N17) or a specific Rac1 inhibitor (NSC23766) inhibits rotavirus replication. In conclusion, we have identified 6-TG as an effective inhibitor of rotavirus replication via the inhibition of Rac1 activation. Thus, for transplantation patients or IBD patients infected with rotavirus or at risk of rotavirus infection, the choice of 6-TG as a treatment appears rational.

Keywords: 6-Thioguanine; Intestinal organoids; Rac1; Rotavirus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / pharmacology*
  • Cells, Cultured
  • Epithelial Cells / virology
  • Guanosine Diphosphate / metabolism*
  • Guanosine Triphosphate / metabolism*
  • Humans
  • Organoids
  • Rotavirus / drug effects*
  • Rotavirus / growth & development
  • Thioguanine / pharmacology*
  • Virus Replication / drug effects*
  • rac1 GTP-Binding Protein / antagonists & inhibitors*

Substances

  • Antiviral Agents
  • RAC1 protein, human
  • Guanosine Diphosphate
  • Guanosine Triphosphate
  • rac1 GTP-Binding Protein
  • Thioguanine