Inhibition of type I and type III interferons by a secreted glycoprotein from Yaba-like disease virus

391

410

Type III IFNs (IFN-λ/IL-28/29) are cytokines with type I IFN-like antiviral activities, which remain poorly characterized. We herein show that most cell types expressed both types I and III IFNs after TLR stimulation or virus infection, whereas the ability of cells to respond to IFN-λ was restricted to a narrow subset of cells, including plasmacytoid dendritic cells and epithelial cells. To examine the role of type III IFN in antiviral defense, we generated IL-28Rα-deficient mice. These mice were indistinguishable from wild-type mice with respect to clearance of a panel of different viruses, whereas mice lacking the type I IFN receptor (IFNAR−/−) were significantly impaired. However, the strong antiviral activity evoked by treatment of mice with TLR3 or TLR9 agonists was significantly reduced in both IL-28RA−/− and IFNAR−/− mice. The type I IFN receptor system has been shown to mediate positive feedback on IFN-αβ expression, and we found that the type I IFN receptor system also mediates positive feedback on IFN-λ expression, whereas IL-28Rα signaling does not provide feedback on either type I or type III IFN expression in vivo. Finally, using bone-marrow chimeric mice we showed that TLR-activated antiviral defense requires expression of IL-28Rα only on nonhemopoietic cells. In this compartment, epithelial cells responded to IFN-λ and directly restricted virus replication. Our data suggest type III IFN to target a specific subset of cells and to contribute to the antiviral response evoked by TLRs.

Section: Discussionmentioning

confidence: 82%

An Important Role for Type III Interferon (IFN-λ/IL-28) in TLR-Induced Antiviral Activity

Ank

Iversen

Bartholdy

et al. 2008

391

410

“…The NS3/4A protease of HCV blocks IFN-λ production (45). A secreted glycoprotein from Yaba-like disease virus blocks IFN-λ signals (46). Vaccinia Virus inhibits IFN-λR-mediated signals and gene expression and blocks the IFN-λR antiviral response through a PKR-dependent pathway (47); moreover, a recombinant-vaccinia virus that over-expresses IFN-λ shows reduced levels of replication in vivo, indicating that poxviruses are susceptible to this interferon and have evolved mechanisms to limit its activity (22).…”

Section: Introductionmentioning

confidence: 99%

IFN-λ Exerts Opposing Effects on T Cell Responses Depending on the Chronicity of the Virus Infection

Misumi

Whitmire

2014

IFN-lambda (IFN-λ) induces an antiviral state in many cell types and may contribute to the overall inflammatory environment following infection. Either of these effects may influence adaptive immune responses, but the role of type-3 interferons in the development of primary and memory T cell responses to infection has not been evaluated. Herein, we examined T cell responses to acute or persistent lymphocytic choriomeningitis virus (LCMV) infection in IFN-λR1-deficient mice. Following acute infection, we find that IFN-λR1-deficient mice produced normal levels of interferon, robust NK cell responses, but greater than normal CD4+ and CD8+ T cell responses compared to WT Balb/c mice. There were more T cells that were IL-7Rhi and, correspondingly, the IFN-λR-deficient mice showed a 2–3-fold increase in memory T cell number. The inhibitory effect of IFN-λR expression was independent of direct cytokine signaling into T cells. In contrast to acute infection, the IFN-λR-deficient mice generated markedly diminished T cell responses and had greater weight loss compared to WT mice when confronted with a highly disseminating variant of LCMV. These data indicate that IFN-λR limits T cell responses and memory following transient infection but augments T cell responses during persisting infection. Thus, the immune regulatory functions for IFN-λR are complex and vary with the overall inflammatory environment.

“…6). The role of the more recently discovered type III IFNs is less clear, but they are crucial for preventing influenza infection via the nasal route (7) and some viral proteins also target this subgroup (8).…”

mentioning

confidence: 99%

The Two Groups of Zebrafish Virus-Induced Interferons Signal via Distinct Receptors with Specific and Shared Chains

Aggad

Mazel

Boudinot

et al. 2009

232

246

Because the availability of fish genomic data, the number of reported sequences for fish type II helical cytokines is rapidly growing, featuring different IFNs including virus-induced IFNs (IFNφ) and IFN-γ, and IL-10 with its related cytokines (IL-20, IL-22, and IL-26). Many candidate receptors exist for these cytokines and various authors have postulated which receptor chain would be involved in which functional receptor in fish. To date, only the receptor for zebrafish IFNφ1 has been identified functionally. Three genes encoding virus-induced IFNφs have been reported in zebrafish. In addition to these genes clustered on chromosome 3, we have identified a fourth IFNφ gene on chromosome 12. All these genes possess the intron-exon organization of mammalian λ IFNs. In the zebrafish larva, all induce the expression of reporter antiviral genes; protection in a viral challenge assay was observed for IFNφ1 and IFNφ2. Using a combination of gain- and loss-of-function experiments, we also show that all zebrafish IFNφs do not bind to the same receptor. Two subgroups of fish virus-induced IFNs have been defined based on conserved cysteines, and we find that this subdivision correlates with receptor usage. Both receptor complexes include a common short chain receptor (CRFB5) and a specific long chain receptor (CRFB1 or CRFB2).