Critical Role for the Oligoadenylate Synthetase/RNase L Pathway in Response to IFN-β during Acute Ocular Herpes Simplex Virus Type 1 Infection

Austin, Bobbie Ann; James, Cassandra M.; Silverman, Robert H.; Carr, Daniel J.J.

doi:10.4049/jimmunol.175.2.1100

Cited by 53 publications

(53 citation statements)

References 46 publications

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“…Yet, in the absence of CD118, the antiviral efficacy of the Ad:IFN-␥ was not lost. It was anticipated the effectiveness of Ad:IFN-␥ would not require antiviral pathways including OAS and PKR pathways implicated in the inhibition of HSV-1 (16,17,39,42,43). In contrast to previous observations in vitro (15), effectiveness of IFN-␥ transgene was lost in vivo in the absence of intact OAS or PKR signaling.…”

Section: Discussioncontrasting

confidence: 54%

Oligoadenylate Synthetase/Protein Kinase R Pathways and αβ TCR+ T Cells Are Required for Adenovirus Vector: IFN-γ Inhibition of Herpes Simplex Virus-1 in Cornea

Austin

Halford

Williams

et al. 2007

The Journal of Immunology

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An adenoviral (Ad) vector containing the murine IFN-γ transgene (Ad:IFN-γ) was evaluated for its capacity to inhibit HSV-1. To measure effectiveness, viral titers were analyzed in cornea and trigeminal ganglia (TG) during acute ocular HSV-1 infection. Ad:IFN-γ potently suppressed HSV-1 replication in a dose-dependent fashion, requiring IFN-γ receptor. Moreover, Ad:IFN-γ was effective when delivered −72 and −24 h before infection as well as 24 h postinfection. Associated with antiviral opposition, TG from Ad:IFN-γ-transduced mice harbored fewer T cells. Also related to T cell involvement, Ad:IFN-γ was effective but attenuated in TG from αβ TCR-deficient mice. In corneas, αβ TCR+ T cells were obligatory for protection against viral multiplication. Type I IFN involvement amid antiviral efficacy of Ad:IFN-γ was further investigated because types I and II IFN pathways have synergistic anti-HSV-1 activity. Ad:IFN-γ inhibited viral reproduction in corneas and TG from αβ IFNR-deficient (CD118−/−) mice, although viral titers were 2- to 3-fold higher in cornea and TG compared with wild-type mice. The absence of IFN-stimulated antiviral proteins, 2′-5′ oligoadenylate synthetase/RNase L, and dsRNA-dependent protein kinase R completely eliminated the antiviral effectiveness of Ad:IFN-γ. Collectively, the results demonstrate the following: 1) nonexistence of type I IFN receptor does not abolish defense of Ad:IFN-γ against HSV-1; 2) antiviral pathways oligoadenylate synthetase-RNase L and protein kinase R are mandatory; and 3) αβ TCR+ T cells are compulsory for Ad:IFN-γ effectiveness against HSV-1 in cornea but not in TG.

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Section: Discussioncontrasting

confidence: 54%

Oligoadenylate Synthetase/Protein Kinase R Pathways and αβ TCR+ T Cells Are Required for Adenovirus Vector: IFN-γ Inhibition of Herpes Simplex Virus-1 in Cornea

Austin

Halford

Williams

et al. 2007

The Journal of Immunology

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“…In addition, it has been shown that RNase L is activated in West Nile virus-infected cells and plays a role in the cellular antiviral response to flaviviruses [64]. The RNase L pathway has also been implicated in the response to IFN-beta during acute ocular herpes simplex virus type 1 infection (HSV-1) of mouse trigeminal-ganglia (TG) cells [65]. a) Mechanism of action-A localized model of activation of RNase L could lead to preferential degradation of viral vs. cellular RNA.…”

Section: Iii) Biological Activities Of Rnase L 1) Antiviral Activitymentioning

confidence: 99%

Diverse functions of RNase L and implications in pathology

Bisbal

Silverman

2007

Biochimie

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The endoribonuclease L (RNase L) is the effector of the 2-5A system, a major enzymatic pathway involved in the molecular mechanism of interferons (IFN). RNase L is a very unusual nuclease with a complex mechanism of regulation. It is a latent enzyme, expressed in nearly every mammalian cell type. Its activation requires its binding to a small oligonucleotide, 2-5A. 2-5A is a series of unique 5′-triphosphorylated oligoadenylates with 2′-5′ phosphodiester bonds. By regulating viral and cellular RNA expression, RNase L plays an important role in the antiviral and antiproliferative activities of IFN and contributes to innate immunity and cell metabolism. The 2-5A/RNase L pathway is implicated in mediating apoptosis in response to viral infections and to several types of external stimuli. Several recent studies have suggested that RNase L could have a role in cancer biology and evidence of a tumor suppressor function of RNase L has emerged from studies on the genetics of hereditary prostate cancer. KeywordsInterferon; RNase L; RNA expression; apoptosis; prostate; virus; cancer I) IntroductionThe endoribonuclease L (RNase L) is the effector of the 2-5A system, a major enzymatic pathway regulated by interferons (IFN) [1] (Figure 1). The 2-5A system is one of the two antiviral pathways induced by IFN and activated by double stranded RNA (dsRNA), the other is mediated by the dsRNA dependent protein kinase (PKR) [2]. RNase L is a very unusual nuclease. It is a latent enzyme, expressed in nearly every mammalian cell type. Its activation requires its binding to a small oligonucleotide, 2-5A ( Figure 1). 2-5A itself is very unusual, consisting of a series of 5′-triphosphorylated oligoadenylates with 2′-5′ phosphodiester bonds in contrast to the 3′-5′ linkages found in RNA and DNA. The initial and essential observation was made by Ian Kerr's group in 1974 reporting an IFN-induced increase in the sensitivity of protein synthesis to inhibition by dsRNA [3]. Peter Lengyel's group observed increased nuclease activity in extracts of interferon treated cells incubated with dsRNA [4,5]. The identification by Ian Kerr's group of the activators of this nuclease, 2-5A [6] and of the enzyme responsible for their synthesis, the 2-5A-synthetase [7][8][9], led to the discovery of the 2-5A pathway. Clemens and Williams directly demonstrated a nuclease, now recognized as RNase Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (Figure 2). The N-terminal domain could be considered as the regulatory domain of RNase L. It is composed of eight complete and one partial ankyrin motifs (R1-R9). Two wal...

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“…Evidence of this includes studies in the Friend retrovirus (FV) model, which showed that treatment with distinct IFN-␣ subtypes induced specific downstream responses that effectively controlled FV infections, whereas other subtypes induced responses that were ineffective (7,8). Furthermore, murine herpesvirus or influenza virus infections were controlled by different subtypes than those inhibiting FV (9)(10)(11)(12)(13). Recent in vitro work demonstrated not only differential relative expression of IFN-␣ subtypes in human plasmacytoid dendritic cells (pDCs) after human immunodeficiency virus type 1 (HIV-1) exposure, but also variable HIV-1 antiviral potencies of IFN-␣ subtypes in gut lamina propria mononuclear cell (LPMC) cultures (14).…”

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confidence: 99%