Antagonism of type I interferon by flaviviruses

Miorin, Lisa; Maestre, Ana; Fernández-Sesma, Ana; García‐Sastre, Adolfo

doi:10.1016/j.bbrc.2017.05.146

Cited by 59 publications

(54 citation statements)

References 132 publications

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“…Flavivirus subversion of the type I interferon (IFN) pathway is well described (11,12) and includes reports of degradation of STAT2 and subsequent reduction of IFN signaling during ZIKV infection of human cells (13)(14)(15)(16). The relationship between ZIKV and the oligoadenylate synthetase-RNase L (OAS-RNase L) pathway has yet to be investigated, although there are reports of other flaviviruses sensitive to this pathway (17,18).…”

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confidence: 99%

Zika Virus Production Is Resistant to RNase L Antiviral Activity

Whelan

Silverman

et al. 2019

J Virol

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There is currently no knowledge of how the emerging human pathogen Zika virus (ZIKV) interacts with the antiviral endoribonuclease L (RNase L) pathway during infection. Since activation of RNase L during infection typically limits virus production dramatically, we used CRISPR-Cas9 gene editing technology to knockout (KO) targeted host genes involved in the RNase L pathway to evaluate the effects of RNase L on ZIKV infection in human A549 cells. RNase L was activated in response to ZIKV infection, which degraded ZIKV genomic RNA. Surprisingly, despite viral genome reduction, RNase L activity did not reduce ZIKV infectious titers. In contrast, both the flavivirus dengue virus and the alphavirus Sindbis virus replicated to significantly higher titers in RNase L KO cells compared to wild-type (WT) cells. Using MAVS/RNase L double KO cells, we demonstrated that the absence of increased ZIKV production in RNase L KO cells was not due to compensation by enhanced type I interferon transcripts to thus inhibit virus production. Finally, when synthetic doublestranded RNA was detected by OAS3 to induce RNase L antiviral activity prior to ZIKV infection, we observed reduced ZIKV replication factory formation, as well as a 42-fold reduction in virus yield in WT but not RNase L KO cells. This study proposes that ZIKV evades RNase L antiviral activity by generating a viral genome reservoir protected from RNase L cleavage during early infection, allowing for sufficient virus production before RNase L activation is detectable.

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confidence: 99%

Zika Virus Production Is Resistant to RNase L Antiviral Activity

Whelan

Silverman

et al. 2019

J Virol

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“…Tick-borne encephalitis virus (TBEV) is an arthropodborne flavivirus that causes a febrile disease in humans that sometimes progresses to encephalitis, with mortality rates as high as 20-30% (52). The nonstructural protein (NS) 5, the most conserved flaviviral protein, is a methyltransferase and an RNA-dependent RNA polymerase involved in viral genome replication (53,54) and has an important role in immune evasion because of its potent inhibition of type I IFN (55)(56)(57). TBEV NS5 has 2 PDZbms: a canonical CT type I (SSII) and an internal PDZbm (EMYYS) within the methyltransferase domain (58).…”

Section: Tick-borne Encephalitis Virusmentioning

confidence: 99%

Viral targeting of PDZ polarity proteins in the immune system as a potential evasion mechanism

Gutiérrez‐González¹,

Santos‐Mendoza

2019

FASEB j.

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PDZ proteins are highly conserved through evolution; the principal function of this large family of proteins is to assemble protein complexes that are involved in many cellular processes, such as cell‐cell junctions, cell polarity, recycling, or trafficking. Many PDZ proteins that have been identified as targets of viral pathogens by promoting viral replication and spread are also involved in epithelial cell polarity. Here, we briefly review the PDZ polarity proteins in cells of the immune system to subsequently focus on our hypothesis that the viral PDZ‐dependent targeting of PDZ polarity proteins in these cells may alter the cellular fitness of the host to favor that of the virus; we further hypothesize that this modification of the cellular fitness landscape occurs as a common and widespread mechanism for immune evasion by viruses and possibly other pathogens.—Gutiérrez‐González, L. H., Santos‐Mendoza, T. Viral targeting of PDZ polarity proteins in the immune system as a potential evasion mechanism. FASEB J. 33, 10607–10617 (2019). http://www.fasebj.org

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“…The compact flavivirus genome encodes seven non-structural proteins that are responsible for viral replication and immune evasion. Six of these proteins are not secreted implying that intracellular pathways are central targets for evasion (Chen et al, 2017;Grant et al, 2016;Laurent-Rolle et al, 2014;Miorin et al, 2017;Ngono and Shresta, 2018). For instance, DV nonstructural protein 5 (NS5), which is the viral RNA-dependent-RNA-polymerase (RdRp) and a methyltransferase, mediates STAT2 degradation by facilitating its interaction with UBR4, leading to its ubiquitination and subsequent proteasomal targeting (Morrison et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

ISG15/USP18/STAT2 is a molecular hub regulating autocrine IFN I-mediated control of Dengue and Zika virus replication

Espada

Rocha

Santos

et al. 2019

Preprint

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The establishment of a virus infection is the result of the pathogen's ability to replicate in a hostile environment generated by the host's immune system.Here, we found that ISG15 restricts Dengue and Zika viruses' replication through the stabilization of its binding partner USP18. ISG15 expression was necessary to control DV replication driven by both autocrine and paracrine type one interferon (IFN-I) signaling. Moreover, USP18 competes with NS5mediated STAT2 degradation, a major mechanism for establishment of flavivirus infection. Strikingly, reconstitution of USP18 in ISG15-deficient cells was sufficient to restore the cells' immune response and restrict virus growth, suggesting that the IFNAR regulatory function of ISG15 is also antiviral. Our results suggest that NS5 has a narrow window of opportunity to degrade STAT2, therefore suppressing host's IFN-I mediated response and promoting virus replication, adding another layer of complexity in the virus/host interaction interface.

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Antagonism of type I interferon by flaviviruses

Cited by 59 publications

References 132 publications

Zika Virus Production Is Resistant to RNase L Antiviral Activity

Zika Virus Production Is Resistant to RNase L Antiviral Activity

Viral targeting of PDZ polarity proteins in the immune system as a potential evasion mechanism

ISG15/USP18/STAT2 is a molecular hub regulating autocrine IFN I-mediated control of Dengue and Zika virus replication

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