Abstract
During viral infection, cells initiate antiviral responses to contain replication and inhibit virus spread. One protective mechanism involves activation of transcription factors interferon regulatory factor-3 (IRF-3) and NF-kappaB, resulting in secretion of the antiviral cytokine, interferon-beta. Another is induction of apoptosis, killing the host cell before virus disseminates. Mammalian reovirus induces both interferon-beta and apoptosis, raising the possibility that both pathways are initiated by a common cellular sensor. We show here that reovirus activates IRF-3 with kinetics that parallel the activation of NF-kappaB, a known mediator of reovirus-induced apoptosis. Activation of IRF-3 requires functional retinoic acid inducible gene-I and interferon-beta promoter stimulator-1, but these intracellular sensors are dispensable for activation of NF-kappaB. Interferon-beta promoter stimulator-1 and IRF-3 are required for efficient apoptosis following reovirus infection, suggesting a common mechanism of antiviral cytokine induction and activation of the cell death response.
Highlights
A primary function of the innate immune system is to detect nascent viral infections and direct subsequent cellular responses
To determine whether interferon regulatory factor-3 (IRF-3) is activated following reovirus infection, we assayed for the presence of IRF-3 in nuclear extracts by immunoblotting (Fig. 1A) and for IRF-3 dimers by native PAGE (Fig. 1B) during a time course of reovirus type 3 Dearing (T3D) infection
To determine whether IRF-7 is activated by reovirus, we examined IRF-7 levels in nuclear extracts by immunoblotting over the same time course of reovirus T3D infection
Summary
A primary function of the innate immune system is to detect nascent viral infections and direct subsequent cellular responses. Interferon- promoter stimulator-1 and IRF-3 are required for efficient apoptosis following reovirus infection, suggesting a common mechanism of antiviral cytokine induction and activation of the cell death response. The results demonstrate that reovirus activates IRF-3 via a mechanism dependent on virion disassembly in endosomes, viral genomic dsRNA, RIG-I, and IPS-1.
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