Dataset Information

Cell Cycle Arrest in G2/M Phase Enhances Replication of Interferon-Sensitive Cytoplasmic RNA Viruses via Inhibition of Antiviral Gene Expression.

ABSTRACT: Vesicular stomatitis virus (VSV) (a rhabdovirus) and its variant VSV-?M51 are widely used model systems to study mechanisms of virus-host interactions. Here, we investigated how the cell cycle affects replication of these viruses using an array of cell lines with different levels of impairment of antiviral signaling and a panel of chemical compounds arresting the cell cycle at different phases. We observed that all compounds inducing cell cycle arrest in G2/M phase strongly enhanced the replication of VSV-?M51 in cells with functional antiviral signaling. G2/M arrest strongly inhibited type I and type III interferon (IFN) production as well as expression of IFN-stimulated genes in response to exogenously added IFN. Moreover, G2/M arrest enhanced the replication of Sendai virus (a paramyxovirus), which is also highly sensitive to the type I IFN response but did not stimulate the replication of a wild-type VSV that is more effective at evading antiviral responses. In contrast, the positive effect of G2/M arrest on virus replication was not observed in cells defective in IFN signaling. Altogether, our data show that replication of IFN-sensitive cytoplasmic viruses can be strongly stimulated during G2/M phase as a result of inhibition of antiviral gene expression, likely due to mitotic inhibition of transcription, a global repression of cellular transcription during G2/M phase. The G2/M phase thus could represent an "Achilles' heel" of the infected cell, a phase when the cell is inadequately protected. This model could explain at least one of the reasons why many viruses have been shown to induce G2/M arrest.IMPORTANCE Vesicular stomatitis virus (VSV) (a rhabdovirus) and its variant VSV-?M51 are widely used model systems to study mechanisms of virus-host interactions. Here, we investigated how the cell cycle affects replication of VSV and VSV-?M51. We show that G2/M cell cycle arrest strongly enhances the replication of VSV-?M51 (but not of wild-type VSV) and Sendai virus (a paramyxovirus) via inhibition of antiviral gene expression, likely due to mitotic inhibition of transcription, a global repression of cellular transcription during G2/M phase. Our data suggest that the G2/M phase could represent an "Achilles' heel" of the infected cell, a phase when the cell is inadequately protected. This model could explain at least one of the reasons why many viruses have been shown to induce G2/M arrest, and it has important implications for oncolytic virotherapy, suggesting that frequent cell cycle progression in cancer cells could make them more permissive to viruses.

SUBMITTER: Bressy C

PROVIDER: S-EPMC6364032 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Cell Cycle Arrest in G<sub>2</sub>/M Phase Enhances Replication of Interferon-Sensitive Cytoplasmic RNA Viruses via Inhibition of Antiviral Gene Expression.

Bressy Christian C Droby Gaith N GN Maldonado Bryant D BD Steuerwald Nury N Grdzelishvili Valery Z VZ

Journal of virology 20190205 4

Vesicular stomatitis virus (VSV) (a rhabdovirus) and its variant VSV-ΔM51 are widely used model systems to study mechanisms of virus-host interactions. Here, we investigated how the cell cycle affects replication of these viruses using an array of cell lines with different levels of impairment of antiviral signaling and a panel of chemical compounds arresting the cell cycle at different phases. We observed that all compounds inducing cell cycle arrest in G<sub>2</sub>/M phase strongly enhanced t ...[more]

PMID: 30487274

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Project description:Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly identified phlebovirus associated with severe hemorrhagic fever in humans. While many viruses subvert the host cell cycle to promote viral growth, it is unknown whether this is a strategy employed by SFTSV. In this study, we investigated how SFTSV manipulates the cell cycle and the effect of the host cell cycle on SFTSV replication. Our results suggest that cells arrest at the G2/M transition following infection with SFTSV. The accumulation of cells at the G2/M transition did not affect virus adsorption and entry but did facilitate viral replication. In addition, we found that SFTSV NSs, a nonstructural protein that forms viroplasm-like structures in the cytoplasm of infected cells and promotes virulence by modulating the interferon response, induces a large number of cells to arrest at the G2/M transition by interacting with CDK1. The interaction between NSs and CDK1, which is inclusion body dependent, inhibits formation and nuclear import of the cyclin B1-CDK1 complex, thereby leading to cell cycle arrest. Expression of a CDK1 loss-of-function mutant reversed the inhibitive effect of NSs on the cell cycle, suggesting that this protein is a potential antiviral target. Our study provides new insight into the role of a specific viral protein in SFTSV replication, indicating that NSs induces G2/M arrest of SFTSV-infected cells, which promotes viral replication.IMPORTANCE Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne pathogen that causes severe hemorrhagic fever. Although SFTSV poses a serious threat to public health and was recently isolated, its pathogenesis remains unclear. In particular, the relationship between SFTSV infection and the host cell cycle has not been described. Here, we show for the first time that both asynchronized and synchronized SFTSV-susceptible cells arrest at the G2/M checkpoint following SFTSV infection and that the accumulation of cells at this checkpoint facilitates viral replication. We also identify a key mechanism underlying SFTSV-induced G2/M arrest, in which SFTSV NSs interacts with CDK1 to inhibit formation and nuclear import of the cyclin B1-CDK1 complex, thus preventing it from regulating cell cycle progression. Our study highlights the key role that NSs plays in SFTSV-induced G2/M arrest.

Dataset Information

Cell Cycle Arrest in G2/M Phase Enhances Replication of Interferon-Sensitive Cytoplasmic RNA Viruses via Inhibition of Antiviral Gene Expression.

Publications

Cell Cycle Arrest in G<sub>2</sub>/M Phase Enhances Replication of Interferon-Sensitive Cytoplasmic RNA Viruses via Inhibition of Antiviral Gene Expression.

Similar Datasets

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