Mx Is Not Responsible for the Antiviral Activity of Interferon-α against Japanese Encephalitis Virus

Zhou, Jing; Wang, Shiqi; Wei, Jianchao; Zhang, Xiaomin; Gao, Zhi-Can; Liu, Ke; Ma, Zhiyong; Pu-yan, Chen; Zhou, Bin

doi:10.3390/v9010005

Cited by 15 publications

(9 citation statements)

References 53 publications

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“…BFA has also been reported to have antiviral activities against some viruses including poliovirus [ 14 ] and Rotavirus [ 15 ]. Recently, Zhou et al demonstrated the inhibitory effect of BFA on Japanese encephalitis virus (JEV) in BHK-21 cells [ 16 ]. To our knowledge, this is the first report to demonstrate antiviral activity of BFA on DENV.…”

Section: Resultsmentioning

confidence: 99%

Identification of novel antiviral of fungus-derived brefeldin A against dengue viruses

et al. 2017

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Microbial natural products possess a wide range of biological and biochemical potential. Among them, fungal secondary metabolites are one of the most important sources for discovering new drugs or lead compounds. In the present study, we explored substances produced by the strain Penicillium sp. FKI-7127 for its antiviral activity. We identified brefeldin A as a novel antiviral agent against dengue viruses. The inhibitory effect of brefeldin A was confirmed by virus titer and immunofluorescence assay. Brefeldin A inhibited dengue viruses regardless of serotypes and other related viruses including Zika virus and Japanese encephalitis virus. Time-of-addition study showed that brefeldin A exerts its antiviral effect at an early stage of the dengue virus (DENV) life cycle. These studies demonstrate that (i) brefeldin A could be used as a lead compound for drug development of anti-DENV and other related viruses and (ii) fungal metabolites are a potential and valuable source for dengue virus drug discovery.

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Section: Resultsmentioning

confidence: 99%

Identification of novel antiviral of fungus-derived brefeldin A against dengue viruses

et al. 2017

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“…Semliki Forest virus and type C footand-mouth disease virus enter BHK-21 cells by clathrin-dependent endocytosis (16,17). Persistent JEV infection has been demonstrated in BHK-21 cells, and numerous studies on JEV have been conducted in BHK-21 cells (18)(19)(20)(21); however, the precise entry mechanism for JEV internalization into BHK-21 cells remains unclear.…”

mentioning

confidence: 99%

Rab5 and Rab11 Are Required for Clathrin-Dependent Endocytosis of Japanese Encephalitis Virus in BHK-21 Cells

Liu

Zhang

et al. 2017

J Virol

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During infection Japanese encephalitis virus (JEV) generally enters host cells via receptor-mediated clathrin-dependent endocytosis. The trafficking of JEV within endosomes is controlled by Rab GTPases, but which Rab proteins are involved in JEV entry into BHK-21 cells is unknown. In this study, entry and postinternalization of JEV were analyzed using biochemical inhibitors, RNA interference, and dominant negative (DN) mutants. Our data demonstrate that JEV entry into BHK-21 cells depends on clathrin, dynamin, and cholesterol but not on caveolae or macropinocytosis. The effect on JEV infection of dominant negative (DN) mutants of four Rab proteins that regulate endosomal trafficking was examined. Expression of DN Rab5 and DN Rab11, but not DN Rab7 and DN Rab9, significantly inhibited JEV replication. These results were further tested by silencing Rab5 or Rab11 expression before viral infection. Confocal microscopy showed that virus particles colocalized with Rab5 or Rab11 within 15 min after virus entry, suggesting that after internalization JEV moves to early and recycling endosomes before the release of the viral genome. Our findings demonstrate the roles of Rab5 and Rab11 on JEV infection of BHK-21 cells through the endocytic pathway, providing new insights into the life cycle of flaviviruses. Although Japanese encephalitis virus (JEV) utilizes different endocytic pathways depending on the cell type being infected, the detailed mechanism of its entry into BHK-21 cells is unknown. Understanding the process of JEV endocytosis and postinternalization will advance our knowledge of JEV infection and pathogenesis as well as provide potential novel drug targets for antiviral intervention. With this objective, we used systematic approaches to dissect this process. The results show that entry of JEV into BHK-21 cells requires a low-pH environment and that the process occurs through dynamin-, actin-, and cholesterol-dependent clathrin-mediated endocytosis that requires Rab5 and Rab11. Our work provides a detailed picture of the entry of JEV into BHK-21 cells and the cellular events that follow.

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“…Furthermore, recent studies have shown that poMx1 inhibits the replication of foot-and-mouth disease virus (FMDV) and bovine viral diarrhea virus (BVDV) (27,28). However, our research has shown that neither poMx1 nor poMx2 is responsible for the antiviral activity of IFN-␣ against Japanese encephalitis virus (JEV) (29). Our work has shown that wild-type (WT) poMx1 inhibits CSFV replication although the molecular mechanism of the inhibition remains to be elucidated.…”

mentioning

confidence: 76%

“…Plasmid construction and cell transfection. pcDNA3.0-poMx1-HA, pcDNA3.0-poMx2-HA, pEGFP-poMx1, and pEGFP-poMx2 have been described previously (26,29). The human MxA gene (UniProt ID P20591) and mouse Mx1 gene (UniProt ID P09922), which were kindly provided by Song Gao (Sun Yat-sen University Cancer Center, Guangzhou, China), were cloned into pcDNA3.0 fused to an HA tag or pEGFP-C1, creating pcDNA3.0-huMxA-HA, pcDNA3.0-mmMx1-HA, pEGFP-huMxA, or pEGFP-mmMx1.…”

Section: Methodsmentioning

confidence: 99%

Porcine Mx1 Protein Inhibits Classical Swine Fever Virus Replication by Targeting Nonstructural Protein NS5B

Zhou

Chen

Zhang³

et al. 2018

J Virol

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Mx proteins are interferon (IFN)-induced GTPases that have broad antiviral activity against a wide range of RNA and DNA viruses; they belong to the dynamin superfamily of large GTPases. In this study, we confirmed the anti-classical swine fever virus (CSFV) activity of porcine Mx1 and showed that porcine Mx2 (poMx2), human MxA (huMxA), and mouse Mx1 (mmMx1) also have anti-CSFV activity Small interfering RNA (siRNA) experiments revealed that depletion of endogenous poMx1 or poMx2 enhanced CSFV replication, suggesting that porcine Mx proteins are responsible for the antiviral activity of interferon alpha (IFN-α) against CSFV infection. Confocal microscopy, immunoprecipitation, glutathione -transferase (GST) pulldown, and bimolecular fluorescence complementation (BiFC) demonstrated that poMx1 associated with NS5B, the RNA-dependent RNA polymerase (RdRp) of CSFV. We used mutations in the poMx1 protein to elucidate the mechanism of their anti-CSFV activity and found that mutants that disrupted the association with NS5B lost all anti-CSV activity. Moreover, an RdRp activity assay further revealed that poMx1 undermined the RdRp activities of NS5B. Together, these results indicate that porcine Mx proteins exert their antiviral activity against CSFV by interacting with NS5B. Our previous studies have shown that porcine Mx1 (poMx1) inhibits classical swine fever virus (CSFV) replication and, but the molecular mechanism of action remains largely unknown. In this study, we dissect the molecular mechanism of porcine Mx1 and Mx2 against CSFV Our results show that poMx1 associates with NS5B, the RNA-dependent RNA polymerase of CSFV, resulting in the reduction of CSFV replication. Moreover, the mutants of poMx1 further elucidate the mechanism of their anti-CSFV activities.

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Mx Is Not Responsible for the Antiviral Activity of Interferon-α against Japanese Encephalitis Virus

Cited by 15 publications

References 53 publications

Identification of novel antiviral of fungus-derived brefeldin A against dengue viruses

Identification of novel antiviral of fungus-derived brefeldin A against dengue viruses

Rab5 and Rab11 Are Required for Clathrin-Dependent Endocytosis of Japanese Encephalitis Virus in BHK-21 Cells

Porcine Mx1 Protein Inhibits Classical Swine Fever Virus Replication by Targeting Nonstructural Protein NS5B

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