The Essential, Nonredundant Roles of RIG-I and MDA5 in Detecting and Controlling West Nile Virus Infection

Errett, John S.; Suthar, Mehul S.; McMillan, Aimee; Diamond, Michael S.; Gale, Michael

doi:10.1128/jvi.01488-13

Cited by 179 publications

(181 citation statements)

References 53 publications

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“…In mice infected by SeV, MDA5 was shown to be required for sustained expression of type-I and III IFN expression, suggesting a role of MDA5 at late time points of infection [15]. Similarly, in a mouse model of West Nile virus infection, MDA5 was shown to contribute to the innate immune response at late time points of infection likely due to the generation of RIG-I and MDA5-specific PAMPs with differential kinetics over the course of viral replication [34]. These observations are consistent with our results.…”

Section: Discussionmentioning

confidence: 99%

Sustained Activation of Interferon Regulatory Factor 3 during Infection by Paramyxoviruses Requires MDA5

et al. 2014

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Retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) are the main cytosolic sensors of single-stranded RNA viruses, including paramyxoviruses, and are required to initiate a quick and robust innate antiviral response. Despite different ligand-binding properties, the consensus view is that RIG-I and MDA5 trigger common signal(s) to activate interferon regulatory factor 3 (IRF-3) and NF-κB, and downstream antiviral and proinflammatory cytokine expression. Here, we performed a thorough analysis of the temporal involvement of RIG-I and MDA5 in the regulation of IRF-3 during respiratory syncytial virus (RSV) infection. Based on specific RNA interference-mediated knockdown of RIG-I and MDA5 in A549 cells, we confirmed that RIG-I is critical for the initiation of IRF-3 phosphorylation, dimerization and downstream gene expression. On the other hand, our experiments yielded the first evidence that knockdown of MDA5 leads to early ubiquitination and proteasomal degradation of active IRF-3. Conversely, ectopic expression of MDA5 prolonged RIG-I-induced IRF-3 activation. Altogether, we provide novel mechanistic insight into the temporal involvement of RIG-I and MDA5 in the innate antiviral response. While RIG-I is essential for initial IRF-3 activation, engagement of induced MDA5 is essential to prevent early degradation of IRF-3, thereby sustaining IRF-3-dependent antiviral gene expression. MDA5 plays a similar role during Sendai virus infection suggesting that this model is not restricted to RSV amongst paramyxoviruses.

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Section: Discussionmentioning

confidence: 99%

Sustained Activation of Interferon Regulatory Factor 3 during Infection by Paramyxoviruses Requires MDA5

et al. 2014

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“…RIG-I and MDA5 have been demonstrated to recognize WNV and VEEV in vitro. Although their role in shaping VEEV infection in vivo has not been explored [112,113], RIG-I and MDA5 are essential for control of WNV replication in the periphery. Mice lacking mitochondrial antiviral-signaling protein (MAVS), the central adaptor to both RIG-I and MDA5 signaling, exhibited increased viremia and viral load in peripheral tissues [114].…”

Section: Mechanisms Of Peripheral Infection Pathogenesis and Host Dmentioning

confidence: 99%

Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis

2016

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Arboviruses are arthropod-borne viruses that exhibit worldwide distribution, contributing to systemic and neurologic infections in a variety of geographical locations. Arboviruses are transmitted to vertebral hosts during blood feedings by mosquitoes, ticks, biting flies, mites, and nits. While the majority of arboviral infections do not lead to neuroinvasive forms of disease, they are among the most severe infectious risks to the health of the human central nervous system. The neurologic diseases caused by arboviruses include meningitis, encephalitis, myelitis, encephalomyelitis, neuritis, and myositis in which virus-and immune-mediated injury may lead to severe, persisting neurologic deficits or death. Here we will review the major families of emerging arboviruses that cause neurologic infections, their neuropathogenesis and host neuroimmunologic responses, and current strategies for treatment and prevention of neurologic infections they cause.

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“…To elucidate which RLR was responsible for the early innate immune recognition of influenza B virus infection, we used MEFs lacking RIG-I, MDA5, or both proteins (7,33). We infected wt and single-and double-receptor-KO MEFs with influenza B and influenza A viruses at an MOI of 30 and analyzed the expres- followed by infection with influenza B/Shangdong/7/97 (A) and influenza A/Beijing/353/89 (B) viruses at an MOI of 30 on ice for 1 h. Subsequently, virus entry proceeded after warming of the cells to 37°C, and cells were fixed with paraformaldehyde after the indicated incubation times.…”

Section: Rig-i Is Essential For Influenza B Virus-induced Early Irf3mentioning

confidence: 99%

RIG-I Signaling Is Essential for Influenza B Virus-Induced Rapid Interferon Gene Expression

Mäkelä

Österlund

Westenius

et al. 2015

J Virol

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Influenza B virus causes annual epidemics and, along with influenza A virus, accounts for substantial disease and economic burden throughout the world. Influenza B virus infects only humans and some marine mammals and is not responsible for pandemics, possibly due to a very low frequency of reassortment and a lower evolutionary rate than that of influenza A virus. Influenza B virus has been less studied than influenza A virus, and thus, a Influenza A and B viruses are important respiratory pathogens and cause seasonal epidemics with an estimated 250,000 to 500,000 deaths annually. Influenza A and B viruses are structurally similar: they are negative-sense RNA viruses with a singlestranded segmented genome. The genome is structured in eight viral ribonucleoprotein (vRNP) complexes where the singlestranded RNA (ssRNA) is associated with multiple nucleoprotein (NP) molecules and a polymerase complex consisting of the PB1, PB2, and PA proteins (1). The vRNP complexes are packaged in a matrix protein shell surrounded by a host-derived lipid envelope in which the viral glycoproteins hemagglutinin (HA) and neuraminidase (NA) are embedded. Influenza viruses bind to sialic acids on cell surface glycoproteins and enter the cells mainly via clathrin-mediated endocytosis but also by macropinocytosis and clathrin-independent entry pathways (2, 3). Influenza viruses take advantage of the host endocytic pathway; a reduction of pH during the maturation of endosomes induces a conformational change in viral HA molecules and triggers fusion between viral and endosomal membranes. Fusion is followed by the uncoating of the capsid by M1 dissociation due to acidification of the virion via the M2 ion channel protein. This results in the release of vRNPs into the cytosol. The influenza virus genome is then imported into the nucleus for transcription and replication of viral genes. Primary transcription of the viral genome is triggered by the virion-associated polymerase protein complex, which leads to the translation of early viral proteins in the cell cytoplasm. Newly synthesized polymerase, NP, and NS1 proteins are transported into the nucleus, where they initiate and regulate the replication and synthesis of cRNA and viral RNA (vRNA) molecules, followed by secondary rounds of transcription. At later stages of infection, new vRNP complexes are packaged in the nucleus, followed by M1-and nuclear export protein (NEP)-regulated export of vRNPs into the cytoplasm. Here they associate with viral envelope glycoproteins HA and NA on the plasma membrane, leading to budding of the newly formed viral particles (4).

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The Essential, Nonredundant Roles of RIG-I and MDA5 in Detecting and Controlling West Nile Virus Infection

Cited by 179 publications

References 53 publications

Sustained Activation of Interferon Regulatory Factor 3 during Infection by Paramyxoviruses Requires MDA5

Sustained Activation of Interferon Regulatory Factor 3 during Infection by Paramyxoviruses Requires MDA5

Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis

RIG-I Signaling Is Essential for Influenza B Virus-Induced Rapid Interferon Gene Expression

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