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

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 i...

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Autores principales: Yin, Yuebang, Chen, Sunrui, Hakim, Mohamad S., Wang, Wenshi, Xu, Lei, Dang, Wen, Qu, Changbo, Verhaar, Auke P., Su, Junhong, Fuhler, Gwenny M., Peppelenbosch, Maikel P., Pan, Qiuwei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Authors. Published by Elsevier B.V. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113846/
https://www.ncbi.nlm.nih.gov/pubmed/29920300
http://dx.doi.org/10.1016/j.antiviral.2018.06.011
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author Yin, Yuebang
Chen, Sunrui
Hakim, Mohamad S.
Wang, Wenshi
Xu, Lei
Dang, Wen
Qu, Changbo
Verhaar, Auke P.
Su, Junhong
Fuhler, Gwenny M.
Peppelenbosch, Maikel P.
Pan, Qiuwei
author_facet Yin, Yuebang
Chen, Sunrui
Hakim, Mohamad S.
Wang, Wenshi
Xu, Lei
Dang, Wen
Qu, Changbo
Verhaar, Auke P.
Su, Junhong
Fuhler, Gwenny M.
Peppelenbosch, Maikel P.
Pan, Qiuwei
author_sort Yin, Yuebang
collection PubMed
description 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.
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spelling pubmed-71138462020-04-02 6-Thioguanine inhibits rotavirus replication through suppression of Rac1 GDP/GTP cycling Yin, Yuebang Chen, Sunrui Hakim, Mohamad S. Wang, Wenshi Xu, Lei Dang, Wen Qu, Changbo Verhaar, Auke P. Su, Junhong Fuhler, Gwenny M. Peppelenbosch, Maikel P. Pan, Qiuwei Antiviral Res Article 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. The Authors. Published by Elsevier B.V. 2018-08 2018-06-18 /pmc/articles/PMC7113846/ /pubmed/29920300 http://dx.doi.org/10.1016/j.antiviral.2018.06.011 Text en © 2018 The Authors Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.
spellingShingle Article
Yin, Yuebang
Chen, Sunrui
Hakim, Mohamad S.
Wang, Wenshi
Xu, Lei
Dang, Wen
Qu, Changbo
Verhaar, Auke P.
Su, Junhong
Fuhler, Gwenny M.
Peppelenbosch, Maikel P.
Pan, Qiuwei
6-Thioguanine inhibits rotavirus replication through suppression of Rac1 GDP/GTP cycling
title 6-Thioguanine inhibits rotavirus replication through suppression of Rac1 GDP/GTP cycling
title_full 6-Thioguanine inhibits rotavirus replication through suppression of Rac1 GDP/GTP cycling
title_fullStr 6-Thioguanine inhibits rotavirus replication through suppression of Rac1 GDP/GTP cycling
title_full_unstemmed 6-Thioguanine inhibits rotavirus replication through suppression of Rac1 GDP/GTP cycling
title_short 6-Thioguanine inhibits rotavirus replication through suppression of Rac1 GDP/GTP cycling
title_sort 6-thioguanine inhibits rotavirus replication through suppression of rac1 gdp/gtp cycling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113846/
https://www.ncbi.nlm.nih.gov/pubmed/29920300
http://dx.doi.org/10.1016/j.antiviral.2018.06.011
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