Japanese Encephalitis Virus NS1′ Protein Antagonizes Interferon Beta Production

Zhou, Dengyuan; Fan, Jia; Li, Qiuyan; Zhang, Luping; Chen, Zheng; Zhao, Zikai; Cui, Min; Song, Yinglin; Chen, Huanchun; Cao, Shengbo; Ye, Jing

doi:10.1007/s12250-018-0067-5

Cited by 27 publications

(26 citation statements)

References 31 publications

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“…In this context, it was highly surprising that no obvious type I IFN response was observed in any of the studied brain tissues upon JEV infection. This is most probably due to the capacity of JEV to actively suppress IFN expression as was reported before [34][35][36]. In our experiment, the OAS gene expression could have been activated by a type I IFN-independent mechanism as has been reported for WNV infection [37].…”

Section: Discussionsupporting

confidence: 75%

Efficient control of Japanese encephalitis virus in the central nervous system of infected pigs occurs in the absence of a pronounced inflammatory immune response

Redant

Favoreel

Dallmeier

et al. 2020

J Neuroinflammation

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Background Japanese encephalitis virus (JEV) is the leading cause of viral encephalitis in Asia. JEV infection of mice and humans can lead to an uncontrolled inflammatory response in the central nervous system (CNS), resulting in a detrimental outcome. Pigs act as important amplification and reservoir hosts, and JEV infection of pigs is mostly subclinical. Information on virus spread in the CNS and immune responses controlling JEV infection in the CNS of pigs, however remains scarce. Methods Nine-week-old pigs were inoculated intranasal or intradermal with a relevant dose of 105 TCID50 of JEV genotype 3 Nakayama strain. Clinical signs were assessed daily, and viral spread was followed by RT-qPCR. mRNA expression profiles were determined to study immune responses in the CNS. Results Besides a delay of 2 days to reach the peak viremia upon intranasal compared to intradermal inoculation, the overall virus spread via both inoculation routes was highly similar. JEV appearance in lymphoid and visceral organs was in line with a blood-borne JEV dissemination. JEV showed a particular tropism to the CNS but without the induction of neurological signs. JEV entry in the CNS probably occurred via different hematogenous and neuronal pathways, but replication in the brain was mostly efficiently suppressed and associated with a type I IFN-independent activation of OAS1 expression. In the olfactory bulb and thalamus, where JEV replication was not completely controlled by this mechanism, a short but strong induction of chemokine gene expression was detected. An increased IFNy expression was simultaneously observed, probably originating from infiltrating T cells, correlating with a fast suppression of JEV replication. The chemokine response was however not associated with the induction of a strong inflammatory response, nor was an induction of the NLRP3 inflammasome observed. Conclusions These findings indicate that an adequate antiviral response and an attenuated inflammatory response contribute to a favorable outcome of JEV infection in pigs and help to explain the limited neurological disease compared to other hosts. We show that the NLRP3 inflammasome, a key mediator of neurologic disease in mice, is not upregulated in pigs, further supporting its important role in JEV infections.

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Section: Discussionsupporting

confidence: 75%

Efficient control of Japanese encephalitis virus in the central nervous system of infected pigs occurs in the absence of a pronounced inflammatory immune response

Redant

Favoreel

Dallmeier

et al. 2020

J Neuroinflammation

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“…The amino acid variations were distributed in three structural proteins (C, PrM, and E) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) ( Table 1 ). Notably, some non-structural proteins with relatively high numbers of amino acid variations, such as NS1, NS3, and NS5, have been demonstrated to be involved in antagonizing the IFN-I mediated antiviral response in flavivirus[ 33 – 36 ].…”

Section: Resultsmentioning

confidence: 99%

NS5-V372A and NS5-H386Y variations are responsible for differences in interferon α/β induction and co-contribute to the replication advantage of Japanese encephalitis virus genotype I over genotype III in ducklings

Huang

et al. 2020

PLoS Pathog

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Japanese encephalitis virus (JEV) genotype I (GI) replicates more efficiently than genotype III (GIII) in birds, and this difference is considered to be one of the reasons for the JEV genotype shift. In this study, we utilized duck embryo fibroblasts and domestic ducklings as in vitro and in vivo models of a JEV amplifying avian host to identify the viral determinants of the differing replication efficiency between the GI and GIII strains in birds. GI strains induced significantly lower levels of interferon (IFN)-α and β production than GIII strains, an effect orrelated with the enhanced replication efficiency of GI strains over GIII strains. By using a series of chimeric viruses with exchange of viral structural and non-structural (NS) proteins, we identified NS5 as the viral determinant of the differences in IFN-α and β induction and replication efficiency between the GI and III strains. NS5 inhibited IFN-α and β production induced by poly(I:C) stimulation and harbored 11 amino acid variations, of which the NS5-V372A and NS5-H386Y variations were identified to co-contribute to the differences in IFNα and β induction and replication efficiency between the strains. The NS5-V372A and NS5-H386Y variations resulted in alterations in the number of hydrogen bonds formed with neighboring residues, which were associated with the different ability of the GI and GIII strains to inhibit IFN-α and β production. Our findings indicated that the NS5-V372A and NS5-H386Y variations enabled GI strains to inhibit IFN-α and β production more efficiently than GIII strains for antagonism of the IFN-I mediated antiviral response, thereby leading to the replication and host adaption advantages of GI strains over GIII strains in birds. These findings provide new insight into the molecular basis of the JEV genotype shift.

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“…In our previous study, JEV NS19 was demonstrated to inhibit IFN-I production, which contributes to viral virulence (16). However, the exact mechanism remains unclear.…”

mentioning

confidence: 94%

“…Some evidences demonstrated that NS19 has a similar cellular distribution with NS1, and it is able to substitute for NS1 in replication of WNV (11). In addition, increasing reports suggest that NS19 is closely related to virulence (12)(13)(14)(15)(16). Abolishing NS19 in JEV and WNV resulted in the attenuation of viral neuroinvasiveness in mice (12,13).…”

mentioning

confidence: 99%

The Japanese Encephalitis Virus NS1′ Protein Inhibits Type I IFN Production by Targeting MAVS

Zhou

Fan

et al. 2020

The Journal of Immunology

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Japanese encephalitis virus (JEV) is a mosquito-borne Flavivirus that causes severe neurologic disease in humans. NS19 is a NS1-related protein only reported in the Japanese encephalitis serogroup members of Flavivirus. It is produced through programmed 21 ribosomal frameshift in NS2A. Our previous study demonstrated that JEV NS19 could antagonize type I IFN (IFN-I) production, but the mechanism is still unclear. In the current study, we found that JEV NS19 inhibits the expression of MAVS, and knockdown of MAVS hampers inhibition of IFN-b induction by NS19, suggesting that JEV NS19 inhibits IFN-I production by targeting MAVS. This finding is further supported by the result of the in vivo assay that showed the similar mortality caused by NS19-deficient virus and its wild type virus in MAVS-deficient mice. Based on our previous sequencing results of noncoding RNA in JEV-infected cells, microRNA-22 (miR-22) was identified to be a key regulator for MAVS expression during JEV infection. Furthermore, we demonstrated that JEV NS19 could induce the expression of miR-22 by increasing the binding of transcriptional factors, CREB and c-Rel, to the promoter elements of miR-22. Taken together, our results reveal a novel mechanism by which JEV NS19 antagonizes host MAVS by regulating miR-22, thereby inhibiting the IFN-I production and facilitating viral replication.

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Japanese Encephalitis Virus NS1′ Protein Antagonizes Interferon Beta Production

Cited by 27 publications

References 31 publications

Efficient control of Japanese encephalitis virus in the central nervous system of infected pigs occurs in the absence of a pronounced inflammatory immune response

Efficient control of Japanese encephalitis virus in the central nervous system of infected pigs occurs in the absence of a pronounced inflammatory immune response

NS5-V372A and NS5-H386Y variations are responsible for differences in interferon α/β induction and co-contribute to the replication advantage of Japanese encephalitis virus genotype I over genotype III in ducklings

The Japanese Encephalitis Virus NS1′ Protein Inhibits Type I IFN Production by Targeting MAVS

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