Rotavirus and Reovirus Modulation of the Interferon Response

Sherry, Barbara

doi:10.1089/jir.2009.0072

Cited by 78 publications

(67 citation statements)

References 82 publications

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“…The efficiency of cell-to-cell spread for a lytic virus depends not only on the ability of the cell to invoke an antiviral response, but also on the capacity of the virus to counteract it (28,29). For cancer treatment, viruses possessing strong evasion strategies would not be ideal as they likely also infect normal healthy cells.…”

Section: Discussionmentioning

confidence: 99%

Oncogenic Ras Promotes Reovirus Spread by Suppressing IFN-β Production through Negative Regulation of RIG-I Signaling

et al. 2010

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Reovirus is the first naturally occurring human virus reported to exploit activated Ras signaling in the host cell for infection, and is currently undergoing clinical trials as a cancer therapeutic. Recent evidence suggests that Ras transformation promotes three reoviral replication steps during the first round of infection: uncoating of the incoming virion, generation of progeny viruses with enhanced infectivity, and virus release through enhanced apoptosis. Whether oncogenic Ras also enhances reovirus spread in subsequent rounds of infection through other mechanisms has not been examined. Here, we show that compared with nontransformed cells, Ras-transformed cells are severely compromised not only in their response to IFN-β, but also in the induction of IFN-β mRNA following reovirus infection. Defects in both IFN-β production and response allow for efficient virus spread in Ras-transformed cells. We show that the MEK/ERK pathway downstream of Ras is responsible for inhibiting IFN-β expression by blocking signaling from the retinoic acid-inducible gene I (RIG-I) which recognizes viral RNAs. Overexpression of wild-type RIG-I restores INF-β expression in reovirus-infected Rastransformed cells. In vitro-synthesized viral mRNAs also invoke robust RIG-I-mediated IFN-β production in transfected nontransformed cells, but not in Ras-transformed cells. Collectively, our data suggest that oncogenic Ras promotes virus spread by suppressing viral RNA-induced IFN-β production through negative regulation of RIG-I signaling. Cancer Res; 70(12); 4912-21. ©2010 AACR.

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Section: Discussionmentioning

confidence: 99%

Oncogenic Ras Promotes Reovirus Spread by Suppressing IFN-β Production through Negative Regulation of RIG-I Signaling

et al. 2010

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“…SA11-4F, in contrast with SA11-5S, rapidly degrades the transcriptional factor IRF3 in IECs (43). Whereas RRV NSP1 variably modulated IRF3 in fibroblasts and dendritic cells in a cell type-specific manner (44,45), in preliminary studies, we found RRV signaling through IRF3 was largely intact in RRV-infected HT-29 and HCA-7 cells. Virus was grown in MA-104 cells infected at low multiplicity, and incubated for 72 h in presence of trypsin (0.44 mg/ml), after which cells were lysed by freezing and thawing to achieve virus release.…”

Section: Rotavirus Infectionmentioning

confidence: 65%

RIG-I/MDA5/MAVS Are Required To Signal a Protective IFN Response in Rotavirus-Infected Intestinal Epithelium

Broquet

Hirata

McAllister

et al. 2011

The Journal of Immunology

200

175

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Rotavirus is a dsRNA virus that infects epithelial cells that line the surface of the small intestine. It causes severe diarrheal illness in children and ∼500,000 deaths per year worldwide. We studied the mechanisms by which intestinal epithelial cells (IECs) sense rotavirus infection and signal IFN-β production, and investigated the importance of IFN-β production by IECs for controlling rotavirus production by intestinal epithelium and virus excretion in the feces. In contrast with most RNA viruses, which interact with either retinoic acid-inducible gene I (RIG-I) or melanoma differentiation-associated gene 5 (MDA5) inside cells, rotavirus was sensed by both RIG-I and MDA5, alone and in combination. Rotavirus did not signal IFN-β through either of the dsRNA sensors TLR3 or dsRNA-activated protein kinase (PKR). Silencing RIG-I or MDA5, or their common adaptor protein mitochondrial antiviral signaling protein (MAVS), significantly decreased IFN-β production and increased rotavirus titers in infected IECs. Overexpression of laboratory of genetics and physiology 2, a RIG-I–like receptor that interacts with viral RNA but lacks the caspase activation and recruitment domains required for signaling through MAVS, significantly decreased IFN-β production and increased rotavirus titers in infected IECs. Rotavirus-infected mice lacking MAVS, but not those lacking TLR3, TRIF, or PKR, produced significantly less IFN-β and increased amounts of virus in the intestinal epithelium, and shed increased quantities of virus in the feces. We conclude that RIG-I or MDA5 signaling through MAVS is required for the activation of IFN-β production by rotavirus-infected IECs and has a functionally important role in determining the magnitude of rotavirus replication in the intestinal epithelium.

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“…The genomic dsRNA of GCRV is speculated to be recognized by host sensors for induction of IFN in UVinactivated GCRV-infected CABs (42). In mammals, RIG-I and MDA5 recognize reovirus genome-derived dsRNA that trigger the IFN response, although reovirus dsRNA is rarely seen to be exposed during natural infection (29). Given that there is leaked dsRNA during GCRV replication and that the exposed dsRNA is responsible for induction of IFN and activation of fish PKR, it is hard to understand how PKZ is activated in GCRV-infected cells.…”

Section: Discussionmentioning

confidence: 99%

Cooperative Roles of Fish Protein Kinase Containing Z-DNA Binding Domains and Double-Stranded RNA-Dependent Protein Kinase in Interferon-Mediated Antiviral Response

Liu

Zhang

Liu

et al. 2011

J Virol

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The double-stranded RNA (dsRNA)-dependent protein kinase (PKR) inhibits protein synthesis by phosphorylating eukaryotic translation initiation factor 2␣ (eIF2␣). In fish species, in addition to PKR, there exists a PKR-like protein kinase containing Z-DNA binding domains (PKZ). However, the antiviral role of fish PKZ and the functional relationship between fish PKZ and PKR remain unknown. Here we confirmed the coexpression of fish PKZ and PKR proteins in Carassius auratus blastula embryonic (CAB) cells and identified them as two typical interferon (IFN)-inducible eIF2␣ kinases, both of which displayed an ability to inhibit virus replication. Strikingly, fish IFN or all kinds of IFN stimuli activated PKZ and PKR to phosphorylated eIF2␣. Overexpression of both fish kinases together conferred much more significant inhibition of virus replication than overexpression of either protein, whereas morpholino knockdown of both made fish cells more vulnerable to virus infection than knockdown of either. The antiviral ability of fish PKZ was weaker than fish PKR, which correlated with its lower ability to phosphorylate eIF2␣ than PKR. Moreover, the independent association of fish PKZ or PKR reveals that each of them formed homodimers and that fish PKZ phosphorylated eIF2␣ independently on fish PKR and vice versa. These results suggest that fish PKZ and PKR play a nonredundant but cooperative role in IFN antiviral response.

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Rotavirus and Reovirus Modulation of the Interferon Response

Cited by 78 publications

References 82 publications

Oncogenic Ras Promotes Reovirus Spread by Suppressing IFN-β Production through Negative Regulation of RIG-I Signaling

Oncogenic Ras Promotes Reovirus Spread by Suppressing IFN-β Production through Negative Regulation of RIG-I Signaling

RIG-I/MDA5/MAVS Are Required To Signal a Protective IFN Response in Rotavirus-Infected Intestinal Epithelium

Cooperative Roles of Fish Protein Kinase Containing Z-DNA Binding Domains and Double-Stranded RNA-Dependent Protein Kinase in Interferon-Mediated Antiviral Response

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