Provision of Continuous Maturation Signaling to Dendritic Cells by RIG-I–Stimulating Cytosolic RNA Synthesis of Sendai Virus

Okano, Shinji; Yonemitsu, Yoshikazu; Shirabe, Ken; Kakeji, Yoshihiro; Maehara, Yoshihiko; Harada, Mamoru; Yoshikai, Yasunobu; Hasegawa, Mamoru; Sueishi, Katsuo

doi:10.4049/jimmunol.0901641

Cited by 16 publications

(10 citation statements)

References 79 publications

(130 reference statements)

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“…SeV infection was used as an initial stimulus because it induces IFN-␣/␤ by activating RIG-I, although some reports suggest that it may also activate MDA5 (33). SeV also provides a strong RIG-I-dependent DC maturation stimulus (34). As expected, SeV infection stimulated phosphorylation of IRF-3 and a strong IFN-␣/␤ response from the empty vector-transduced MDDC control.…”

Section: Discussionmentioning

confidence: 68%

Molecular Basis for Ebolavirus VP35 Suppression of Human Dendritic Cell Maturation

Yen

Mulder

Martinez

et al. 2014

J Virol

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Zaire ebolavirus (EBOV) VP35 is a double-stranded RNA (dsRNA)-binding protein that inhibits RIG-I signaling and alpha/beta interferon (IFN-␣/␤) responses by both dsRNA-binding-dependent and -independent mechanisms. VP35 also suppresses dendritic cell (DC) maturation. Here, we define the pathways and mechanisms through which VP35 impairs DC maturation. Wildtype VP35 (VP35-WT) and two well-characterized VP35 mutants ( IMPORTANCEThe VP35 protein, which is an inhibitor of RIG-I signaling and alpha/beta interferon (IFN-␣/␤) responses, has been implicated as an EBOV-encoded factor that contributes to suppression of dendritic cell (DC) function. We used wild-type VP35 and previously characterized VP35 mutants to clarify VP35-DC interactions. Our data demonstrate that VP35 is a general inhibitor of RIG-I-like receptor (RLR) signaling that blocks not only RIG-I-but also MDA5-mediated induction of IFN-␣/␤ responses. Furthermore, in DCs, VP35 also impairs the RLR-mediated induction of proinflammatory cytokine production, upregulation of costimulatory markers, and activation of T cells. These inhibitory activities require VP35 dsRNA-binding activity, an activity previously correlated to VP35 RIG-I inhibitory function. In contrast, while VP35 can inhibit IFN-␣/␤ production induced by TLR3 or TLR4 agonists, this occurs in a dsRNA-independent fashion, and VP35 does not inhibit TLR-mediated expression of proinflammatory cytokines. These data suggest strategies to overcome VP35 inhibition of DC function.

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Section: Discussionmentioning

confidence: 68%

Molecular Basis for Ebolavirus VP35 Suppression of Human Dendritic Cell Maturation

Yen

Mulder

Martinez

et al. 2014

J Virol

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“…Transduction of DCs with replication-defective lentiviruses reproducibly achieves efficiencies of Ͼ90% and induces little to no IFN-␣/␤ response or other evidence of DC activation (31,35,36). After 72 h, the MDDCs were infected with SeV, known to activate DCs in a RIG-I-dependent manner (37). The expression of eVP35 or mVP35 was verified by Western blotting (Fig.…”

Section: Resultsmentioning

confidence: 99%

Effects of Filovirus Interferon Antagonists on Responses of Human Monocyte-Derived Dendritic Cells to RNA Virus Infection

Yen

Basler

2016

J Virol

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Dendritic cells (DCs) are major targets of filovirus infection in vivo. Previous studies have shown that the filoviruses Ebola virus (EBOV) and Marburg virus (MARV) suppress DC maturation in vitro.Both viruses also encode innate immune evasion functions. The EBOV VP35 (eVP35) and the MARV VP35 (mVP35) proteins each can block RIG-I-like receptor signaling and alpha/ beta interferon (IFN-␣/␤) production. The EBOV VP24 (eVP24) and MARV VP40 (mVP40) proteins each inhibit the production of IFN-stimulated genes (ISGs) by blocking Jak-STAT signaling; however, this occurs by different mechanisms, with eVP24 blocking nuclear import of tyrosine-phosphorylated STAT1 and mVP40 blocking Jak1 function. MARV VP24 (mVP24) has been demonstrated to modulate host cell antioxidant responses. Previous studies demonstrated that eVP35 is sufficient to strongly impair primary human monocyte-derived DC (MDDC) responses upon stimulation induced through the RIG-I-like receptor pathways. We demonstrate that mVP35, like eVP35, suppresses not only IFN-␣/␤ production but also proinflammatory responses after stimulation of MDDCs with RIG-I activators. In contrast, eVP24 and mVP40, despite suppressing ISG production upon RIG-I activation, failed to block upregulation of maturation markers or T cell activation. mVP24, although able to stimulate expression of antioxidant response genes, had no measurable impact of DC function. These data are consistent with a model where filoviral VP35 proteins are the major suppressors of DC maturation during filovirus infection, whereas the filoviral VP24 proteins and mVP40 are insufficient to prevent DC maturation. Zaire ebolavirus (EBOV) and Marburg marburgvirus (MARV) belong to the Filovirus family of emerging, zoonotic negativesense RNA viruses. Both EBOV and MARV cause severe, frequently fatal disease in humans (1). The West African Ebola epidemic, which was first recognized in early 2014, is the largest filovirus outbreak on record with over 28,000 cases worldwide and a reported case fatality rate of approximately 40% (2). The severity of EBOV and MARV infections reflects, at least in part, robust systemic virus replication that is not effectively restrained by host immune responses (3).Both EBOV and MARV encode multiple proteins that impair innate antiviral immune responses and likely contribute to excessive virus replication (3, 4). Both viruses encode VP35, a doublestranded RNA (dsRNA)-binding protein that carries out multiple functions critical for virus propagation. One such function is the inhibition of signaling by RIG-I and MDA5 through (RLR) signaling, which otherwise triggers alpha/beta interferon (IFN-␣/␤) gene expression (5-13). For both EBOV VP35 (eVP35) and MARV VP35 (mVP35), point mutations that disrupt VP35 dsR-NA-binding activity also greatly impair RLR inhibition activity (5,9,14,15). In vitro studies suggest that dsRNA-binding allows eVP35 to sequester RIG-I stimulatory dsRNAs (8, 9). eVP35 also interacts with the cellular protein PACT, which binds to and facilitates activatio...

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“…Indeed, studies have found that in murine systems, the dependency of DC on RIG-I for inducing antiviral responses varies by the different DC subtypes, with conventional DCs relying on RLR activation and plasmocytoid DCs possibly operating independently of RLRs [15,39]. In contrast, an in vitro study using human monocyte-derived DCs found that overexpression of a dominant negative RIG-I construct completely abrogated the induction of cytokines induced by a recombinant Sendai virus vector and only partially inhibited expression of DC maturation markers CD86 and HLA-DR [40]. Recent work has shown that RLRs are differentially expressed in specific DC subsets, wherein CD4+ and CD4−/CD8− DCs, the RLRs may function to program antigen presentation and cytokine production [41].…”

Section: Targeted Therapeutic Applications For Rlr Agonistsmentioning

confidence: 99%

RIG-I Like Receptors in Antiviral Immunity and Therapeutic Applications

Ireton

Gale

2011

Viruses

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The RNA helicase family of RIG-I-like receptors (RLRs) is a key component of host defense mechanisms responsible for detecting viruses and triggering innate immune signaling cascades to control viral replication and dissemination. As cytoplasm-based sensors, RLRs recognize foreign RNA in the cell and activate a cascade of antiviral responses including the induction of type I interferons, inflammasome activation, and expression of proinflammatory cytokines and chemokines. This review provides a brief overview of RLR function, ligand interactions, and downstream signaling events with an expanded discussion on the therapeutic potential of targeting RLRs for immune stimulation and treatment of virus infection.

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Provision of Continuous Maturation Signaling to Dendritic Cells by RIG-I–Stimulating Cytosolic RNA Synthesis of Sendai Virus

Abstract: Material Supplementary 1.DC1http://www.jimmunol.org/content/suppl/2010/12/27/jimmunol.090164

Cited by 16 publications

References 79 publications

Molecular Basis for Ebolavirus VP35 Suppression of Human Dendritic Cell Maturation

Molecular Basis for Ebolavirus VP35 Suppression of Human Dendritic Cell Maturation

Effects of Filovirus Interferon Antagonists on Responses of Human Monocyte-Derived Dendritic Cells to RNA Virus Infection

RIG-I Like Receptors in Antiviral Immunity and Therapeutic Applications

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