The Toll-Like Receptor 3-Mediated Antiviral Response Is Important for Protection against Poliovirus Infection in Poliovirus Receptor Transgenic Mice

Abe, Yuko; Fujii, Ken; Nagata, Noriyo; Takeuchi, Osamu; Akira, Shizuo; Oshiumi, Hiroyuki; Matsumoto, Misako; Seya, Tsukasa; Koike, Sachiko

doi:10.1128/jvi.05245-11

Cited by 85 publications

(80 citation statements)

References 56 publications

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“…Several lines of evidence demonstrate that TLR3 plays a role in the antiviral response against enterovirus infections (31)(32)(33)(34)(35)(36)(37). Rhinovirus infection is recognized initially by TLR3 (38).…”

Section: Discussionmentioning

confidence: 99%

Enterovirus 68 3C Protease Cleaves TRIF To Attenuate Antiviral Responses Mediated by Toll-Like Receptor 3

Zou

Lei

et al. 2014

J Virol

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Human enterovirus 68 (EV68) is a member of the EV-D species, which belongs to the EV genus of the Picornaviridae family.Over the past several years, there have been increasingly documented outbreaks of respiratory disease associated with EV68. As a globally emerging pathogen, EV68 infects both adults and children. However, the molecular basis of EV68 pathogenesis is unknown. Here we report that EV68 inhibits Toll-like receptor 3 IFN-␤) (TLR3)-mediated innate immune responses by targeting the TIR domain-containing adaptor inducing beta interferon (TRIF). In infected HeLa cells, EV68 inhibits poly(I·C)-induced interferon regulatory factor 3 (IRF3) activation and beta interferon ( IMPORTANCE EV68 is a globally emerging pathogen, but the molecular basis of EV68 pathogenesis is unclear. Here we report that EV68 inhibits TLR3-mediated innate immune responses by targeting TRIF. Further investigations revealed that TRIF is cleaved by 3Cpro . These results suggest that control of TRIF by 3C pro may be a mechanism by which EV68 impairs type I IFN production in response to TLR3 activation.

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Section: Discussionmentioning

confidence: 99%

Enterovirus 68 3C Protease Cleaves TRIF To Attenuate Antiviral Responses Mediated by Toll-Like Receptor 3

Zou

Lei

et al. 2014

J Virol

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“…In the case of PV infection, TLR3-mediated type I IFN production is important for viral clearance in vivo 15,16 . In vitro PV infection of splenic DCs promotes type I IFN production in a TLR3-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

“…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 . TLR3-dependent type I IFN production by splenic CD11c þ DCs and macrophages was essential for the protection of PVR-transgenic mice against PV infection.…”

mentioning

confidence: 99%

“…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 .…”

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confidence: 99%

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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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“…Several studies using MDA5 Ϫ/Ϫ mice demonstrated that MDA5 signaling is critical for type I IFN induction after virus infection (68,69). MDA5-deficient mice have an increased susceptibility to lethal infection induced by poliovirus (68,69).…”

Section: C Pro Inhibits Mda5-mediated Cellular Defensementioning

confidence: 99%

Disruption of MDA5-Mediated Innate Immune Responses by the 3C Proteins of Coxsackievirus A16, Coxsackievirus A6, and Enterovirus D68

Rui

Wang

et al. 2017

J Virol

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Coxsackievirus A16 (CV-A16), CV-A6, and enterovirus D68 (EV-D68) belong to the Picornaviridae family and are major causes of hand, foot, and mouth disease (HFMD) and pediatric respiratory disease worldwide. The biological characteristics of these viruses, especially their interplay with the host innate immune system, have not been well investigated. In this study, we discovered that the 3C pro proteins from CV-A16, CV-A6, and EV-D68 bind melanoma differentiation-associated gene 5 (MDA5) and inhibit its interaction with MAVS. Consequently, MDA5-triggered type I interferon (IFN) signaling in the retinoic acid-inducible gene I-like receptor (RLR) pathway was blocked by the CV-A16, CV-A6, and EV-D68 3C pro proteins. Furthermore, the CV-A16, CV-A6, and EV-D68 3C pro proteins all cleave transforming growth factor ␤-activated kinase 1 (TAK1), resulting in the inhibition of NF-B activation, a host response also critical for Toll-like receptor (TLR)-mediated signaling. Thus, our data demonstrate that circulating HFMD-associated CV-A16 and CV-A6, as well as severe respiratory disease-associated EV-D68, have developed novel mechanisms to subvert host innate immune responses by targeting key factors in the RLR and TLR pathways. Blocking the ability of 3C pro proteins from diverse enteroviruses and coxsackieviruses to interfere with type I IFN induction should restore IFN antiviral function, offering a potential novel antiviral strategy.IMPORTANCE CV-A16, CV-A6, and EV-D68 are emerging pathogens associated with hand, foot, and mouth disease and pediatric respiratory disease worldwide. The pathogenic mechanisms of these viruses are largely unknown. Here we demonstrate that the CV-A16, CV-A6, and EV-D68 3C pro proteins block MDA5-triggered type I IFN induction. The 3C pro proteins of these viruses bind MDA5 and inhibit its interaction with MAVS. In addition, the CV-A16, CV-A6, and EV-D68 3C pro proteins cleave TAK1 to inhibit the NF-B response. Thus, our data demonstrate that circulating HFMDassociated CV-A16 and CV-A6, as well as severe respiratory disease-associated EV-D68, have developed a mechanism to subvert host innate immune responses by simultaneously targeting key factors in the RLR and TLR pathways. These findings indicate the potential merit of targeting the CV-A16, CV-A6, and EV-D68 3C pro proteins as an antiviral strategy.KEYWORDS MDA5, TAK1, MAVS, 3C protease, CV-A16, CV-A6, EV-D68, HFMD, innate immune response

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The Toll-Like Receptor 3-Mediated Antiviral Response Is Important for Protection against Poliovirus Infection in Poliovirus Receptor Transgenic Mice

Cited by 85 publications

References 56 publications

Enterovirus 68 3C Protease Cleaves TRIF To Attenuate Antiviral Responses Mediated by Toll-Like Receptor 3

Enterovirus 68 3C Protease Cleaves TRIF To Attenuate Antiviral Responses Mediated by Toll-Like Receptor 3

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

Disruption of MDA5-Mediated Innate Immune Responses by the 3C Proteins of Coxsackievirus A16, Coxsackievirus A6, and Enterovirus D68

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