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-B, resulting in secretion of the antiviral cytokine, interferon-. Another is induction of apoptosis, killing the host cell before virus disseminates. Mammalian reovirus induces both interferon- 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-B, a known mediator of reovirus-induced apoptosis. Activation of IRF-3 requires functional retinoic acid inducible gene-I and interferon- promoter stimulator-1, but these intracellular sensors are dispensable for activation of NF-B. 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.A primary function of the innate immune system is to detect nascent viral infections and direct subsequent cellular responses. The innate immune system responds to infection by producing a range of soluble cytokines, such as interferon- (IFN-), 5 that create an antiviral state in surrounding tissue. In response to these immune pressures, viruses have evolved multiple strategies for subverting innate immunity, which frequently center on manipulating cell death pathways. The interface between the innate immune response, viral infection, and the cellular apoptotic machinery is therefore a critical nexus of disease pathogenesis.Cells possess a variety of sensors to detect invading pathogens. Toll-like receptors (TLRs) and other pattern recognition receptors, including the nucleotide-binding oligomerization domain proteins and RNA helicases such as retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated protein-5 (Mda-5), recognize viral pathogen-associated molecular patterns (1). TLRs are expressed on the cell surface and recognize extracellular pathogen-associated molecular patterns, whereas RIG-I and Mda-5 detect intracellular viral RNA products (2-4). RIG-I recognizes viral RNAs from the Flaviviridae, Orthomyxoviridae, Paramyxoviridae, and Rhabdoviridae families, whereas Mda-5 is involved in the response to Picornaviridae (4). The ligand for RIG-I has been identified as a 5Ј triphosphate moiety on single-or double-stranded RNA (5, 6); the molecular ligand for Mda-5 is unknown. Following ligand engagement, these intracellular sensors signal through caspase activation and recruitment domains to activate the adaptor, interferon- promoter stimulator-1 (IPS-1/MAVS/ VISA/Cardif) (7-10). IPS-1 activates inhibitor of B kinase (IKK)-␣, IKK-, IKK-⑀, and Tank-binding kinase 1 to phosphorylate transcription factors, including activating transcription factor-2/c-Jun, NF-B, and interferon regulatory factor-3 (IRF-3), which direct transcription of antiviral g...
Viral myocarditis is an important human disease, and reovirus-induced murine myocarditis provides an excellent model system for study. Cardiac myocytes, like neurons in the central nervous system, are not replenished, yet there is no cardiac protective equivalent to the blood-brain barrier. Thus, cardiac myocytes may have evolved a unique antiviral response relative to readily replenished cell types, such as cardiac fibroblasts. Our previous comparisons of these two cell types revealed a conundrum: reovirus T3D induces more beta-interferon (IFN-) mRNA in cardiac myocytes, yet there is a greater induction of IFN-stimulated genes (ISGs) in cardiac fibroblasts. Here, we investigated possible underlying molecular determinants. We found that greater basal expression of IFN- in cardiac myocytes results in greater basal activated nuclear STAT1 and STAT2 and greater basal ISG mRNA expression and provides greater basal antiviral protection relative to cardiac fibroblasts. Conversely, cardiac fibroblasts express greater basal IFN-␣/ receptor 1 (IFNAR1) and greater basal cytoplasmic Jak1, Tyk2, STAT2, and IRF9, leading to a greater increase in reovirus T3D-or IFN-induced nuclear activated STAT1 and STAT2 and greater induction of ISGs for a greater IFN-induced antiviral protection relative to cardiac myocytes. Our results suggest that high basal IFN- expression in cardiac myocytes prearms this vulnerable, nonreplenishable cell type, while high basal expression of IFNAR1 and latent Jak-STAT components in adjacent cardiac fibroblasts renders these cells more responsive to IFN and prevents them from inadvertently serving as a reservoir for viral replication and spread to cardiac myocytes. These studies provide the first indication of an integrated network of cell-type-specific innate immune components for organ protection.
The secreted cytokine alpha/beta interferon (IFN-␣/) binds its receptor to activate the Jak-STAT signal transduction pathway, leading to formation of the heterotrimeric IFN-stimulated gene factor 3 (ISGF3) transcription complex for induction of IFN-stimulated genes (ISGs) and establishment of an antiviral state. Many viruses have evolved countermeasures to inhibit the IFN pathway, thereby subverting the innate antiviral response. Here, we demonstrate that the mildly myocarditic reovirus type 1 Lang (T1L), but not the nonmyocarditic reovirus type 3 Dearing, represses IFN induction of a subset of ISGs and that this repressor function segregates with the T1L M1 gene. Concordantly, the T1L M1 gene product, 2, dramatically inhibits IFN--induced reporter gene expression. Surprisingly, T1L infection does not degrade components of the ISGF3 complex or interfere with STAT1 or STAT2 nuclear translocation as has been observed for other viruses. Instead, infection with T1L or reassortant or recombinant viruses containing the T1L M1 gene results in accumulation of interferon regulatory factor 9 (IRF9) in the nucleus. This effect has not been previously described for any virus and suggests that 2 modulates IRF9 interactions with STATs for both ISGF3 function and nuclear export. The M1 gene is a determinant of virus strain-specific differences in the IFN response, which are linked to virus strain-specific differences in induction of murine myocarditis. We find that virusinduced myocarditis is associated with repression of IFN function, providing new insights into the pathophysiology of this disease. Together, these data provide the first report of an increase in IRF9 nuclear accumulation associated with viral subversion of the IFN response and couple virus strain-specific differences in IFN antagonism to the pathogenesis of viral myocarditis.
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