A critical link between Toll-like receptor 3 and type II interferon signaling pathways in antiviral innate immunity

Negishi, Hideo; Osawa, Takako; Ogami, Kazuo; Ouyang, Xinshou; Sakaguchi, Shoji; Koshiba, Ryuji; Yanai, Hideyuki; Seko, Yoshinori; Shitara, Hiroshi; Bishop, Keith; Yonekawa, Hiromichi; Tamura, Tomohide; Kaisho, Tsuneyasu; Taya, Choji; Taniguchi, Tadatsugu; Honda, Kenya

doi:10.1073/pnas.0810372105

Cited by 195 publications

(199 citation statements)

References 37 publications

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“…TRIF and RIG-I belong to different antiviral signaling pathways, why TRIF affects RIG-I? In mouse, RIG-I/MDA5 and the TLR3/TRIF signaling axes cooperate for efficient innate antiviral immune responses (Negishi et al, 2008). Antiviral defense within bronchial epithelium requires co-ordinated recognition of rhinovirus infection, initially via TLR3/TRIF and later via inducible RIG-I and MDA5 (Slater et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Identification and functional characterizations of a novel TRIF gene from grass carp (Ctenopharyngodon idella)

Yang

et al. 2013

Developmental & Comparative Immunology

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Section: Discussionmentioning

confidence: 99%

Identification and functional characterizations of a novel TRIF gene from grass carp (Ctenopharyngodon idella)

Yang

et al. 2013

Developmental & Comparative Immunology

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“…Studies using TLR3-deficient mice demonstrated that TLR3 mediates a protective response against positive-strand RNA virus infection, including coxsackie virus group B serotype 3, encephalomyocarditis virus and poliovirus (PV), all of which belong to the Picornaviridae family [13][14][15][16] . TLR3-or TICAM-1-deficient human PV receptor (PVR)-transgenic mice were more susceptible than normal PVR-transgenic mice to intraperitoneal or intravenous inoculation with a low titre of PV 15,16 .…”

mentioning

confidence: 99%

Toll-like receptor 3 recognizes incomplete stem structures in single-stranded viral RNA

et al. 2013

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Endosomal Toll-like receptor 3 (TLR3) serves as a sensor of viral infection and sterile tissue necrosis. Although TLR3 recognizes double-stranded RNA, little is known about structural features of virus-or host-derived RNAs that activate TLR3 in infection/inflammatory states. Here we demonstrate that poliovirus-derived single-stranded RNA segments harbouring stem structures with bulge/internal loops are potent TLR3 agonists. Functional poliovirus-RNAs are resistant to degradation and efficiently induce interferon-a/b and proinflammatory cytokines in human and mouse cells in a TLR3-dependent manner. The N-and C-terminal doublestranded RNA-binding sites of TLR3 are required for poliovirus-RNA-mediated TLR3 activation. Like polyriboinosinic:polyribocytidylic acid, a synthetic double-stranded RNA, these RNAs are internalized into cells via raftlin-mediated endocytosis and colocalized with TLR3. Raftlin-associated RNA uptake machinery and the TLR3 RNA-sensing system appear to recognize an appropriate topology of multiple RNA duplexes in poliovirus-RNAs. Hence, TLR3 is a sensor of extracellular viral/host RNA with stable stem structures derived from infection or inflammation-damaged cells.

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“…A picornavirus CBV activates the TLR3/TICAM-1-IFN-g axis in host-infected cells to induce type II IFN (18). It is possible that CBV promotes TLR3-dependent IFN-g induction in lymphocytes rather than the type I IFN-inducing pathway.…”

Section: Discussionmentioning

confidence: 99%

“…This concept was confirmed by the finding that MDA5 2/2 mice fail to induce type I IFN in response to encephalomyocarditis virus (EMCV) and permit severe EMCV infection (13,17). However, another picornavirus, coxsackie B virus (CBV) serotype 3, is recognized by TLR3 in infected cells and induces IFN-g as an effector for suppressing CBV infection (18). In this study, we analyzed in vivo infection of a popular picornavirus, PV, using PVR transgenic (PVRtg) mice, which show a neurotropic phenotype during PV infection similar to humans (19,20).…”

Section: W Hen Rna Viruses Infect Mammalian Cells Type I Ifnmentioning

confidence: 91%

The TLR3/TICAM-1 Pathway Is Mandatory for Innate Immune Responses to Poliovirus Infection

Oshiumi

Okamoto

Fujii

et al. 2011

The Journal of Immunology

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Cytoplasmic and endosomal RNA sensors recognize RNA virus infection and signals to protect host cells by inducing type I IFN. The cytoplasmic RNA sensors, retinoic acid inducible gene I/melanoma differentiation-associated gene 5, actually play pivotal roles in sensing virus replication. IFN-β promoter stimulator-1 (IPS-1) is their common adaptor for IFN-inducing signaling. Toll/IL-1R homology domain-containing adaptor molecule 1 (TICAM-1), also known as TRIF, is the adaptor for TLR3 that recognizes viral dsRNA in the early endosome in dendritic cells and macrophages. Poliovirus (PV) belongs to the Picornaviridae, and melanoma differentiation-associated gene 5 reportedly detects replication of picornaviruses, leading to the induction of type I IFN. In this study, we present evidence that the TLR3/TICAM-1 pathway governs IFN induction and host protection against PV infection. Using human PVR transgenic (PVRtg) mice, as well as IPS-1−/− and TICAM-1−/− mice, we found that TICAM-1 is essential for antiviral responses that suppress PV infection. TICAM-1−/− mice in the PVRtg background became markedly susceptible to PV, and their survival rates were decreased compared with wild-type or IPS-1−/− mice. Similarly, serum and organ IFN levels were markedly reduced in TICAM-1−/−/PVRtg mice, particularly in the spleen and spinal cord. The sources of type I IFN were CD8α+/CD11c+ splenic dendritic cells and macrophages, where the TICAM-1 pathway was more crucial for PV-derived IFN induction than was the IPS-1 pathway in ex vivo and in vitro analyses. These data indicate that the TLR3/TICAM-1 pathway functions are dominant in host protection and innate immune responses against PV infection.

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A critical link between Toll-like receptor 3 and type II interferon signaling pathways in antiviral innate immunity

Cited by 195 publications

References 37 publications

Identification and functional characterizations of a novel TRIF gene from grass carp (Ctenopharyngodon idella)

Identification and functional characterizations of a novel TRIF gene from grass carp (Ctenopharyngodon idella)

Toll-like receptor 3 recognizes incomplete stem structures in single-stranded viral RNA

The TLR3/TICAM-1 Pathway Is Mandatory for Innate Immune Responses to Poliovirus Infection

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