Dataset Information

2'-Fluoro-2'-deoxycytidine inhibits murine norovirus replication and synergizes MPA, ribavirin and T705.

ABSTRACT: Noroviruses are the main causative agents of acute viral gastroenteritis worldwide. However, no vaccine or specific antiviral treatment is available, imposing a heavy global health burden. The nucleoside analogue 2'-fluoro-2'-deoxycytidine (2'-FdC) has been reported to have broad antiviral activity. Here, we report that 2'-FdC significantly inhibits murine norovirus replication in macrophages. This effect was partially reversed by exogenous supplementation of cytidine triphosphate. The combination of 2'-FdC with mycophenolic acid, ribavirin or favipiravir (T705) exerts synergistic antiviral effects. These results indicate that 2'-FdC is a potential candidate for antiviral drug development against norovirus infection.

SUBMITTER: Yu P

PROVIDER: S-EPMC7414258 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Publications

2'-Fluoro-2'-deoxycytidine inhibits murine norovirus replication and synergizes MPA, ribavirin and T705.

Yu Peifa P Wang Yining Y Li Yunlong Y Li Yang Y Miao Zhijiang Z Peppelenbosch Maikel P MP Pan Qiuwei Q

Archives of virology 20200808 11

Noroviruses are the main causative agents of acute viral gastroenteritis worldwide. However, no vaccine or specific antiviral treatment is available, imposing a heavy global health burden. The nucleoside analogue 2'-fluoro-2'-deoxycytidine (2'-FdC) has been reported to have broad antiviral activity. Here, we report that 2'-FdC significantly inhibits murine norovirus replication in macrophages. This effect was partially reversed by exogenous supplementation of cytidine triphosphate. The combinati ...[more]

PMID: 32770483

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Project description:UnlabelledMany viruses replicate most efficiently in specific phases of the cell cycle, establishing or exploiting favorable conditions for viral replication, although little is known about the relationship between caliciviruses and the cell cycle. Microarray and Western blot analysis of murine norovirus 1 (MNV-1)-infected cells showed changes in cyclin transcript and protein levels indicative of a G1 phase arrest. Cell cycle analysis confirmed that MNV-1 infection caused a prolonging of the G1 phase and an accumulation of cells in the G0/G1 phase. The accumulation in G0/G1 phase was caused by a reduction in cell cycle progression through the G1/S restriction point, with MNV-1-infected cells released from a G1 arrest showing reduced cell cycle progression compared to mock-infected cells. MNV-1 replication was compared in populations of cells synchronized into specific cell cycle phases and in asynchronously growing cells. Cells actively progressing through the G1 phase had a 2-fold or higher increase in virus progeny and capsid protein expression over cells in other phases of the cell cycle or in unsynchronized populations. These findings suggest that MNV-1 infection leads to prolonging of the G1 phase and a reduction in S phase entry in host cells, establishing favorable conditions for viral protein production and viral replication. There is limited information on the interactions between noroviruses and the cell cycle, and this observation of increased replication in the G1 phase may be representative of other members of the Caliciviridae.ImportanceNoroviruses have proven recalcitrant to growth in cell culture, limiting our understanding of the interaction between these viruses and the infected cell. In this study, we used the cell-culturable MNV-1 to show that infection of murine macrophages affects the G1/S cell cycle phase transition, leading to an arrest in cell cycle progression and an accumulation of cells in the G0/G1 phase. Furthermore, we show that MNV replication is enhanced in the G1 phase compared to other stages of the cell cycle. Manipulating the cell cycle or adapting to cell cycle responses of the host cell is a mechanism to enhance virus replication. To the best of our knowledge, this is the first report of a norovirus interacting with the host cell cycle and exploiting the favorable conditions of the G0/G1 phase for RNA virus replication.

Dataset Information

2'-Fluoro-2'-deoxycytidine inhibits murine norovirus replication and synergizes MPA, ribavirin and T705.

Publications

2'-Fluoro-2'-deoxycytidine inhibits murine norovirus replication and synergizes MPA, ribavirin and T705.

Similar Datasets

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