Yijin Wang1, Xinying Zhou1, Yannick Debing2, Kan Chen3, Luc J W Van Der Laan4, Johan Neyts2, Harry L A Janssen5, Herold J Metselaar1, Maikel P Peppelenbosch1, Qiuwei Pan6. 1. Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, Netherlands. 2. Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium. 3. Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, Netherlands; Bio-X Center, College of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, China. 4. Department of Surgery, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, Netherlands. 5. Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, Netherlands; Division of Gastroenterology, University Health Network, Toronto, Canada. 6. Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, Netherlands. Electronic address: q.pan@erasmusmc.nl.
Abstract
BACKGROUND & AIMS: Many recipients of organ transplants develop chronic hepatitis, due to infection with the hepatitis E virus (HEV). Although chronic HEV infection is generally associated with immunosuppressive therapies, little is known about how different immunosuppressants affect HEV infection. METHODS: A subgenomic HEV replication model, in which expression of a luciferase reporter gene is measured, and a full-length infection model were used. We studied the effects of different immunosuppressants, including steroids, calcineurin inhibitors (tacrolimus [FK506] and cyclosporin A), and mycophenolic acid (MPA, an inhibitor of inosine monophosphate dehydrogenase) on HEV replication in human hepatoma cell line Huh7. Expression of cyclophilins A and B (the targets of cyclosporin A) were knocked down using small hairpin RNAs. RESULTS: Steroids had no significant effect on HEV replication. Cyclosporin A promoted replication of HEV in the subgenomic and infectious models. Knockdown of cyclophilin A and B increased levels of HEV genomic RNA by 4.0- ± 0.6-fold and 7.2- ± 1.9-fold, respectively (n = 6; P < .05). A high dose of FK506 promoted infection of liver cells with HEV. In contrast, MPA inhibited HEV replication. Incubation of cells with guanosine blocked the antiviral activity of MPA, indicating that the antiviral effects of this drug involve nucleotide depletion. The combination of MPA and ribavirin had a greater ability to inhibit HEV replication than MPA or ribavirin alone. CONCLUSIONS: Cyclophilins A and B inhibit replication of HEV; this might explain the ability of cyclosporin A to promote HEV infection. On the other hand, the immunosuppressant MPA inhibits HEV replication. These findings should be considered when physicians select immunosuppressive therapies for recipients of organ transplants who are infected with HEV.
BACKGROUND & AIMS: Many recipients of organ transplants develop chronic hepatitis, due to infection with the hepatitis E virus (HEV). Although chronic HEV infection is generally associated with immunosuppressive therapies, little is known about how different immunosuppressants affect HEV infection. METHODS: A subgenomic HEV replication model, in which expression of a luciferase reporter gene is measured, and a full-length infection model were used. We studied the effects of different immunosuppressants, including steroids, calcineurin inhibitors (tacrolimus [FK506] and cyclosporin A), and mycophenolic acid (MPA, an inhibitor of inosine monophosphate dehydrogenase) on HEV replication in humanhepatoma cell line Huh7. Expression of cyclophilins A and B (the targets of cyclosporin A) were knocked down using small hairpin RNAs. RESULTS:Steroids had no significant effect on HEV replication. Cyclosporin A promoted replication of HEV in the subgenomic and infectious models. Knockdown of cyclophilin A and B increased levels of HEV genomic RNA by 4.0- ± 0.6-fold and 7.2- ± 1.9-fold, respectively (n = 6; P < .05). A high dose of FK506 promoted infection of liver cells with HEV. In contrast, MPA inhibited HEV replication. Incubation of cells with guanosine blocked the antiviral activity of MPA, indicating that the antiviral effects of this drug involve nucleotide depletion. The combination of MPA and ribavirin had a greater ability to inhibit HEV replication than MPA or ribavirin alone. CONCLUSIONS: Cyclophilins A and B inhibit replication of HEV; this might explain the ability of cyclosporin A to promote HEV infection. On the other hand, the immunosuppressant MPA inhibits HEV replication. These findings should be considered when physicians select immunosuppressive therapies for recipients of organ transplants who are infected with HEV.
Authors: Natalie E Netzler; Daniel Enosi Tuipulotu; Subhash G Vasudevan; Jason M Mackenzie; Peter A White Journal: Antimicrob Agents Chemother Date: 2019-05-24 Impact factor: 5.191
Authors: Yijin Wang; Wenshi Wang; Lei Xu; Xinying Zhou; Ehsan Shokrollahi; Krzysztof Felczak; Luc J W van der Laan; Krzysztof W Pankiewicz; Dave Sprengers; Nicolaas J H Raat; Herold J Metselaar; Maikel P Peppelenbosch; Qiuwei Pan Journal: Antimicrob Agents Chemother Date: 2016-04-22 Impact factor: 5.191
Authors: Xianfang Wu; Viet Loan Dao Thi; Peng Liu; Constantin N Takacs; Kuanhui Xiang; Linda Andrus; Jérôme Gouttenoire; Darius Moradpour; Charles M Rice Journal: Gastroenterology Date: 2017-12-24 Impact factor: 22.682