Abstract
To evaluate the anti-HSV-1 mechanisms of murine IFN-beta in ocular infection, mice were transduced with an adenoviral vector expressing murine IFN-beta (Ad:IFN-beta). Ocular transduction with Ad:IFN-beta resulted in enhanced survival following infection with HSV-1. The protective effect was associated with a reduction in 1) viral titer, 2) viral gene expression, 3) IFN-gamma levels, and 4) the percentage of CD8(+) T lymphocyte and NK cell infiltration in infected tissue. Expression of IFN-beta resulted in an elevation of the IFN-induced antiviral gene 2',5'-oligoadenylate synthetase (OAS1a) but not dsRNA-dependent protein kinase R (PKR) in the cornea and trigeminal ganglion (TG). Mice deficient in the downstream effector molecule of the OAS pathway, RNase L, were no more sensitive to ocular HSV-1 compared with wild-type controls in the TG based on measurements of viral titer. However, the efficacy of Ad:IFN-beta was transiently lost in the eyes of RNase L mice. By comparison, PKR-deficient mice were more susceptible to ocular HSV-1 infection, and the antiviral efficacy following transduction with Ad:IFN-beta was significantly diminished in the eye and TG. These results suggest that PKR is central in controlling ocular HSV-1 infection in the absence of exogenous IFN, whereas the OAS pathway appears to respond to exogenous IFN, contributing to the establishment of an antiviral environment in a tissue-restricted manner.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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2',5'-Oligoadenylate Synthetase / physiology*
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Adenoviridae / genetics*
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Adenoviridae / immunology*
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Adjuvants, Immunologic / administration & dosage
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Adjuvants, Immunologic / genetics
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Adjuvants, Immunologic / physiology
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Administration, Topical
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Animals
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Antiviral Agents / administration & dosage*
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Antiviral Agents / pharmacology
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / pathology
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Cell Migration Inhibition
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Cells, Cultured
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Female
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Genetic Vectors
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Green Fluorescent Proteins
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Herpesvirus 1, Human / immunology
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Interferon-beta / administration & dosage
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Interferon-beta / biosynthesis*
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Interferon-beta / genetics*
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Interferon-gamma / antagonists & inhibitors
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Interferon-gamma / biosynthesis
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Keratitis, Herpetic / enzymology
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Keratitis, Herpetic / immunology
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Keratitis, Herpetic / mortality
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Keratitis, Herpetic / therapy
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Killer Cells, Natural / immunology
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Killer Cells, Natural / pathology
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Luminescent Proteins / administration & dosage
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Luminescent Proteins / biosynthesis
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Luminescent Proteins / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Inbred ICR
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Mice, Knockout
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Survival Analysis
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Trigeminal Ganglion / enzymology
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Trigeminal Ganglion / immunology
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Trigeminal Ganglion / pathology
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Virus Replication / genetics
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Virus Replication / immunology
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eIF-2 Kinase / deficiency
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eIF-2 Kinase / genetics
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eIF-2 Kinase / physiology*
Substances
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Adjuvants, Immunologic
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Antiviral Agents
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Luminescent Proteins
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Green Fluorescent Proteins
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Interferon-beta
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Interferon-gamma
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eIF-2 Kinase
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2',5'-Oligoadenylate Synthetase