Both RIG-I and MDA5 detect alphavirus replication in concentration-dependent mode

Akhrymuk, Ivan; Frolov, Ilya; Frolova, Elena I.

doi:10.1016/j.virol.2015.09.023

Cited by 59 publications

(54 citation statements)

References 55 publications

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“…As shown in Fig. 6, all viruses exhibited significantly higher titers in both cell types lacking MAVS, an observation consistent with an inhibitory impact of the IFN-inducing activity of the MAVS-dependent PRRs RIG-I and MDA5 on innate detection of viral RNA during alphavirus infection (34,36,37). Consistent with this, cells lacking IFNAR also displayed significantly higher replication of CHIKV, VEEV, RRV, and ONNV, suggesting that type I IFN signaling contributes substantially to the innate control of these viruses.…”

Section: Resultssupporting

confidence: 81%

“…Infection of host cells is associated with a rapid and strong induction of innate signaling pathways, including those leading to activation of IRF3 (34,35). This occurs through detection of virus-associated dsRNA by cytoplasmic PRRs, such as RIG-I and MDA5, which signal to IRF3 via MAVS (34,(36)(37)(38), as well as through protein kinase R (PKR), which inhibits the cellular translational machinery through phosphorylation-based inactivation of eukaryotic initiation factor 2␣ (34,39). Despite this, alphaviruses are extremely susceptible to the effects of type I IFNs and replicate poorly in cells in which an IFN-induced state has been elicited (reviewed in references 40 and 41).…”

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confidence: 99%

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Emerging Alphaviruses Are Sensitive to Cellular States Induced by a Novel Small-Molecule Agonist of the STING Pathway

Gall

Pryke

Abraham

et al. 2018

J Virol

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The type I interferon (IFN) system represents an essential innate immune response that renders cells resistant to virus growth via the molecular actions of IFN-induced effector proteins. IFN-mediated cellular states inhibit growth of numerous and diverse virus types, including those of known pathogenicity as well as potentially emerging agents. As such, targeted pharmacologic activation of the IFN response may represent a novel therapeutic strategy to prevent infection or spread of clinically impactful viruses. In light of this, we employed a high-throughput screen to identify small molecules capable of permeating the cell and of activating IFN-dependent signaling processes. Here we report the identification and characterization of -(methylcarbamoyl)-2-{[5-(4-methylphenyl)-1,3,4-oxadiazol-2-yl]sulfanyl}-2-phenylacetamide (referred to as C11), a novel compound capable of inducing IFN secretion from human cells. Using reverse genetics-based loss-of-function assays, we show that C11 activates the type I IFN response in a manner that requires the adaptor protein STING but not the alternative adaptors MAVS and TRIF. Importantly, treatment of cells with C11 generated a cellular state that potently blocked replication of multiple emerging alphavirus types, including chikungunya, Ross River, Venezuelan equine encephalitis, Mayaro, and O'nyong-nyong viruses. The antiviral effects of C11 were subsequently abrogated in cells lacking STING or the type I IFN receptor, indicating that they are mediated, at least predominantly, by way of STING-mediated IFN secretion and subsequent autocrine/paracrine signaling. This work also allowed characterization of differential antiviral roles of innate immune signaling adaptors and IFN-mediated responses and identified MAVS as being crucial to cellular resistance to alphavirus infection. Due to the increase in emerging arthropod-borne viruses, such as chikungunya virus, that lack FDA-approved therapeutics and vaccines, it is important to better understand the signaling pathways that lead to clearance of virus. Here we show that C11 treatment makes human cells refractory to replication of a number of these viruses, which supports its value in increasing our understanding of the immune response and viral pathogenesis required to establish host infection. We also show that C11 depends on signaling through STING to produce antiviral type I interferon, which further supports its potential as a therapeutic drug or research tool.

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Section: Resultssupporting

confidence: 81%

mentioning

confidence: 99%

Emerging Alphaviruses Are Sensitive to Cellular States Induced by a Novel Small-Molecule Agonist of the STING Pathway

Gall

Pryke

Abraham

et al. 2018

J Virol

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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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“…In humans and other vertebrates, the interferon (IFN) response has evolved as the primary innate immune response to viral infection (18). During alphavirus infection, intracellular viral RNA is detected by cytoplasmic RIG-I-like receptors, resulting in the expression of type I IFNs (IFN-␣/␤) (19)(20)(21). Secreted type I IFNs then bind the transmembrane IFN-␣/␤ receptors (IFNAR) on the plasma membranes in an autocrine and paracrine manner.…”

mentioning

confidence: 99%

The Methyltransferase-Like Domain of Chikungunya Virus nsP2 Inhibits the Interferon Response by Promoting the Nuclear Export of STAT1

Göertz

McNally

Robertson

et al. 2018

J Virol

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Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that has evolved effective mechanisms to counteract the type I interferon (IFN) response. Upon recognition of the virus, cells secrete IFNs, which signal through transmembrane receptors (IFNAR) to phosphorylate STAT proteins (pSTAT). pSTAT dimers are transported into the nucleus by importin-α5 and activate the transcription of IFN-stimulated genes (ISGs), increasing cellular resistance to infection. Subsequently, STAT proteins are shuttled back into the cytoplasm by the exportin CRM1. CHIKV nonstructural protein 2 (nsP2) reduces ISG expression by inhibiting general host cell transcription and by specifically reducing the levels of nuclear pSTAT1 via an unknown mechanism. To systematically examine where nsP2 acts within the JAK/STAT signaling cascade, we used two well-characterized mutants of nsP2, P718S and KR649AA. Both mutations abrogate nsP2's ability to shut off host transcription, but only the KR649AA mutant localizes exclusively to the cytoplasm and no longer specifically inhibits JAK/STAT signaling. These mutant nsP2 proteins did not differentially affect IFNAR expression levels or STAT1 phosphorylation in response to IFNs. Coimmunoprecipitation experiments showed that in the presence of nsP2, STAT1 still effectively bound importin-α5. Chemically blocking CRM1-mediated nuclear export in the presence of nsP2 additionally showed that nuclear translocation of STAT1 is not affected by nsP2. nsP2 putatively has five domains. Redirecting the nsP2 KR649AA mutant or just nsP2's C-terminal methyltransferase-like domain into the nucleus strongly reduced nuclear pSTAT in response to IFN stimulation. This demonstrates that the C-terminal domain of nuclear nsP2 specifically inhibits the IFN response by promoting the nuclear export of STAT1. Chikungunya virus is an emerging pathogen associated with large outbreaks on the African, Asian, European, and both American continents. In most patients, infection results in high fever, rash, and incapacitating (chronic) arthralgia. CHIKV effectively inhibits the first line of defense, the innate immune response. As a result, stimulation of the innate immune response with interferons (IFNs) is ineffective as a treatment for CHIKV disease. The IFN response requires an intact downstream signaling cascade called the JAK/STAT signaling pathway, which is effectively inhibited by CHIKV nonstructural protein 2 (nsP2) via an unknown mechanism. The research described here specifies where in the JAK/STAT signaling cascade the IFN response is inhibited and which protein domain of nsP2 is responsible for IFN inhibition. The results illuminate new aspects of antiviral defense and CHIKV counterdefense strategies and will direct the search for novel antiviral compounds.

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Both RIG-I and MDA5 detect alphavirus replication in concentration-dependent mode

Cited by 59 publications

References 55 publications

Emerging Alphaviruses Are Sensitive to Cellular States Induced by a Novel Small-Molecule Agonist of the STING Pathway

Emerging Alphaviruses Are Sensitive to Cellular States Induced by a Novel Small-Molecule Agonist of the STING Pathway

Encephalitic Arboviruses: Emergence, Clinical Presentation, and Neuropathogenesis

The Methyltransferase-Like Domain of Chikungunya Virus nsP2 Inhibits the Interferon Response by Promoting the Nuclear Export of STAT1

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