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Critical role of RIG-I and MDA5 in early and late stages of Tulane virus infection.

ABSTRACT: Human noroviruses are a major cause of acute gastroenteritis worldwide, but the lack of a robust cell culture system or small animal model have hampered a better understanding of innate immunity against these viruses. Tulane virus (TV) is the prototype virus of a tentative new genus, Recovirus, in the family Caliciviridae. Its epidemiology and biological properties most closely resemble human norovirus. The host innate immune response to RNA virus infection primarily involves pathogen-sensing toll-like receptors (TLRs) TLR3 and TLR7 and retinoic acid-inducible gene I-like receptor RIG-I and melanoma differentiation associated gene 5 (MDA5). In this study, by using siRNA knockdown, we report that TV infection in LLC-MK2 cells results in an early [3?h post infection (h p.i.), P<0.05] RIG-I-dependent and type I interferon-mediated antiviral response, whereas an MDA5-mediated antiviral effect was observed at later (12?h p.i.; P<0.05) stages of TV replication. Induction of RIG-I and MDA5 was critical for inhibition of TV replication. Furthermore, pre-activation of the RIG-I/MDA5 pathway prevented TV replication (>900-fold decrease; P<0.05), suggesting that RIG-I and MDA5 ligands could be used to develop novel preventive and therapeutic measures against norovirus.

SUBMITTER: Chhabra P

PROVIDER: S-EPMC5916764 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Critical role of RIG-I and MDA5 in early and late stages of Tulane virus infection.

Chhabra Preeti P Ranjan Priya P Cromeans Theresa T Sambhara Suryaprakash S Vinjé Jan J

The Journal of general virology 20170522 5

Human noroviruses are a major cause of acute gastroenteritis worldwide, but the lack of a robust cell culture system or small animal model have hampered a better understanding of innate immunity against these viruses. Tulane virus (TV) is the prototype virus of a tentative new genus, Recovirus, in the family Caliciviridae. Its epidemiology and biological properties most closely resemble human norovirus. The host innate immune response to RNA virus infection primarily involves pathogen-sensing to ...[more]

PMID: 28530548

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Project description:West Nile virus (WNV) is a mosquito-borne flavivirus that causes epidemics of encephalitis and viscerotropic disease worldwide. This virus has spread rapidly and has posed a significant public health threat since the outbreak in New York City in 1999. The interferon (IFN)-mediated antiviral response represents an important component of virus-host interactions and plays an essential role in regulating viral replication. Previous studies have suggested that multifunctional nonstructural proteins encoded by flaviviruses antagonize the host IFN response via various means in order to establish efficient viral replication. In this study, we demonstrated that the nonstructural protein 1 (NS1) of WNV antagonizes IFN-? production, most likely through suppression of retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) activation. In a dual-luciferase reporter assay, WNV NS1 significantly inhibited the activation of the IFN-? promoter after Sendai virus infection or poly(I·C) treatment. NS1 also suppressed the activation of the IFN-? promoter when it was stimulated by interferon regulatory factor 3 (IRF3)/5D or its upstream molecules in the RLR signaling pathway. Furthermore, NS1 blocked the phosphorylation and nuclear translocation of IRF3 upon stimulation by various inducers. Mechanistically, WNV NS1 targets RIG-I and melanoma differentiation-associated gene 5 (MDA5) by interacting with them and subsequently causing their degradation by the proteasome. Furthermore, WNV NS1 inhibits the K63-linked polyubiquitination of RIG-I, thereby inhibiting the activation of downstream sensors in the RLR signaling pathway. Taken together, our results reveal a novel mechanism by which WNV NS1 interferes with the host antiviral response.IMPORTANCE WNV Nile virus (WNV) has received increased attention since its introduction to the United States. However, the pathogenesis of this virus is poorly understood. This study demonstrated that the nonstructural protein 1 (NS1) of WNV antagonizes the induction of interferon beta (IFN-?) by interacting with and degrading retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5), which are crucial viral sensors in the host innate immune system. Further experiments suggested that NS1-mediated inhibition of the RIG-I-like receptor (RLR) signaling pathway involves inhibition of RIG-I K63-linked polyubiquitination and that the proteasome plays a role in RIG-I degradation. This study provides new insights into the regulation of WNV NS1 in the RLR signaling pathway and reveals a novel mechanism by which WNV evades the host innate immune response. The novel findings may guide us to discover new therapeutic targets and develop effective vaccines for WNV infections.

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Critical role of RIG-I and MDA5 in early and late stages of Tulane virus infection.

Publications

Critical role of RIG-I and MDA5 in early and late stages of Tulane virus infection.

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