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

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.

journal_name

Antiviral Res

journal_title

Antiviral research

authors

Yin Y,Chen S,Hakim MS,Wang W,Xu L,Dang W,Qu C,Verhaar AP,Su J,Fuhler GM,Peppelenbosch MP,Pan Q

doi

10.1016/j.antiviral.2018.06.011

subject

Has Abstract

pub_date

2018-08-01 00:00:00

pages

92-101

eissn

0166-3542

issn

1872-9096

pii

S0166-3542(17)30844-6

journal_volume

156

pub_type

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