Suppression of Type I Interferon Signaling by Flavivirus NS5

Thurmond, Stephanie; Wang, Boxiao; Song, Jikui; Hai, Rong

doi:10.3390/v10120712

Cited by 43 publications

(37 citation statements)

References 126 publications

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“…This result again points to the potential importance of host-specific differences and/or epistatic interactions in governing the relationship between NS1 mutations and viral fitness. This is perhaps less surprising in the host, as numerous genes including NS2, NS4 and NS5 have well documented roles in interferon modulation and host immunity in general [ 51 – 59 ]. The more phenotypically significant result in mice measured here was with ZIKV-A894G.…”

Section: Discussionmentioning

confidence: 99%

Reversion to ancestral Zika virus NS1 residues increases competence of Aedes albopictus

et al. 2020

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Both mosquito species-specific differences and virus strain -specific differences impact vector competence. Previous results in our laboratory with individual populations of N. American mosquitoes support studies suggesting Aedes aegypti are more competent than Ae . albopictus for American Zika virus (ZIKV) strains and demonstrate that U.S. Ae . albopictus have higher competence for an ancestral Asian ZIKV strain. A982V, an amino acid substitution in the NS1 gene acquired prior to the American outbreak, has been shown to increase competence in Ae . aegypti . We hypothesized that variability in the NS1 could therefore contribute to species-specific differences and developed a reverse genetics system based on a 2016 ZIKV isolate from Honduras (ZIKV-WTic) to evaluate the phenotypic correlates of individual amino acid substitutions. In addition to A982V, we evaluated G894A, which was acquired during circulation in the Americas. Reversion of 982 and 894 to ancestral residues increased infectivity, transmissibility and viral loads in Ae . albopictus but had no effect on competence or replication in Ae . aegypti . In addition, while host cell-specific differences in NS1 secretion were measured, with significantly higher secretion in mammalian cells relative to mosquito cells, strain-specific differences in secretion were not detected, despite previous reports. These results demonstrate that individual mutations in NS1 can influence competence in a species-specific manner independent of differences in NS1 secretion and further indicate that ancestral NS1 residues confer increased competence in Ae . albopictus . Lastly, experimental infections of Ifnar1 -/- mice demonstrated that these NS1 substitutions can influence viral replication in the host and, specifically, that G894A could represent a compensatory change following a fitness loss from A982V with some viral genetic backgrounds. Together these data suggest a possible role for epistatic interactions in ZIKV fitness in invertebrate and vertebrate hosts and demonstrate that strains with increased transmission potential in U.S. Ae . albopictus could emerge.

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Section: Discussionmentioning

confidence: 99%

Reversion to ancestral Zika virus NS1 residues increases competence of Aedes albopictus

et al. 2020

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“…NS5 mutations contribute to replication advantage of JEV genotype I in ducklings activation of IFN-I-stimulated Jak-Stat signaling in primates [48,49]. NS5 of WNV and tickborne encephalitis virus suppresses the maturation and cell surface expression of the IFN-I receptor via interaction with the host protein prolidase, thus preventing IFN-I downstream signaling and the expression of IFN stimulated genes [48].…”

Section: Plos Pathogensmentioning

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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“…The production of type I IFN is triggered by host sensors that detect the presence of virus components such as nucleic acid. Type I IFN then activates a number of interferon-stimulated genes (ISGs) that mediate the antivirus response and establishment of an antiviral state [36,37]. Like its other flavivirus NS5 counterparts, ZIKV NS5 has been well characterized to inhibit the host antiviral response [25,26,39,40] (Table 1).…”

Section: Cell-type-specific Modulation Of the Host Immune Response Bymentioning

confidence: 99%

“…ZIKV is no exception, as its NS2A, NS2B, NS4A and NS4B proteins have been described to antagonize the type I interferon pathway by targeting distinct components of the signaling cascade [35]. The flavivirus NS5 protein is another major player in this process [36,37], as it has been characterized to antagonize type I IFN signaling at multiple points [26,31,38,39]. Like its other flavivirus NS5 counterparts, ZIKV NS5 is able to inhibit the host antiviral response [25,26,39,40], although the significance and contribution of its nuclear localization to this process is not known.…”

Section: Introductionmentioning

confidence: 99%

The Potential Role of the ZIKV NS5 Nuclear Spherical-Shell Structures in Cell Type-Specific Host Immune Modulation during ZIKV Infection

Tan

Chan

et al. 2019

Cells

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The Zika virus (ZIKV) non-structural protein 5 (NS5) plays multiple viral and cellular roles during infection, with its primary role in virus RNA replication taking place in the cytoplasm. However, immunofluorescence assay studies have detected the presence of ZIKV NS5 in unique spherical shell-like structures in the nuclei of infected cells, suggesting potentially important cellular roles of ZIKV NS5 in the nucleus. Hence ZIKV NS5′s subcellular distribution and localization must be tightly regulated during ZIKV infection. Both ZIKV NS5 expression or ZIKV infection antagonizes type I interferon signaling, and induces a pro-inflammatory transcriptional response in a cell type-specific manner, but the mechanisms involved and the role of nuclear ZIKV NS5 in these cellular functions has not been elucidated. Intriguingly, these cells originate from the brain and placenta, which are also organs that exhibit a pro-inflammatory signature and are known sites of pathogenesis during ZIKV infection in animal models and humans. Here, we discuss the regulation of the subcellular localization of the ZIKV NS5 protein, and its putative role in the induction of an inflammatory response and the occurrence of pathology in specific organs during ZIKV infection.

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Suppression of Type I Interferon Signaling by Flavivirus NS5

Cited by 43 publications

References 126 publications

Reversion to ancestral Zika virus NS1 residues increases competence of Aedes albopictus

Reversion to ancestral Zika virus NS1 residues increases competence of Aedes albopictus

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 Potential Role of the ZIKV NS5 Nuclear Spherical-Shell Structures in Cell Type-Specific Host Immune Modulation during ZIKV Infection

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