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

Zou, Xiang; Li, Linlin; Lei, Xiaobo; Zhou, Hongli; Zhou, Zhuo; He, Bin; Wang, Jianwei

doi:10.1128/jvi.03138-13

Cited by 66 publications

(65 citation statements)

References 40 publications

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“…S4). Reduced protein expression levels of TRIF and/or IPS1 have previously been linked to a block in type I IFN expression in enterovirusinfected cells (Lei et al, 2011;Mukherjee et al, 2011;Xiang et al, 2014). Our results support the notion that coxsackieviruses disrupt TLR and MDA5/RIG-I signalling by targeting the adaptor molecules TRIF and IPS1, respectively.…”

Section: Discussionsupporting

confidence: 80%

Coxsackievirus counters the host innate immune response by blocking type III interferon expression

Lind

Svedin

Domsgen

et al. 2016

Journal of General Virology

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Type I IFNs play an important role in the immune response to enterovirus infections. Their importance is underscored by observations showing that many enteroviruses including coxsackie B viruses (CVBs) have developed strategies to block type I IFN production. Recent studies have highlighted a role for the type III IFNs (also called IFNls) in reducing permissiveness to infections with enteric viruses including coxsackievirus. However, whether or not CVBs have measures to evade the effects of type III IFNs remains unknown. By combining virus infection studies and different modes of administrating the dsRNA mimic poly I : C, we discovered that CVBs target both Toll-like receptor 3-and MDA5/RIG-I-mediated type III IFN expression. Consistent with this, the cellular protein expression levels of the signal transduction proteins TRIF and IPS1 were reduced and no hyperphosphorylation of interferon regulatory factor 3 was observed following infection with the virus. Notably, decreased expression of full-length TRIF and IPS1 and the appearance of cleavage products was observed upon both CVB3 infection and in cellular protein extracts incubated with recombinant 2A pro , indicating an important role for the viral protease in subverting the cellular immune system. Collectively, our study reveals that CVBs block the expression of type III IFNs, and that this is achieved by a similar mechanism as the virus uses to block type I IFN production. We also demonstrate that the virus blocks several intracellular viral recognition pathways of importance for both type I and III IFN production. The simultaneous targeting of numerous arms of the host immune response may be required for successful viral replication and dissemination.

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Section: Discussionsupporting

confidence: 80%

Coxsackievirus counters the host innate immune response by blocking type III interferon expression

Lind

Svedin

Domsgen

et al. 2016

Journal of General Virology

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“…Human monocytic THP1 (TIB-202; ATCC) cells were cultured in RPMI 1640 media supplemented with 10% FBS. EV-D68 infection was carried out as described previously (35). Peripheral blood mononuclear cells (PBMCs) isolated from healthy donors were cultured in RPMI 1640 media supplemented with 10% FBS, penicillin (100 U/ml), streptomycin (100 U/ml), glutamine (2 mM), HEPES (5 mM), and sodium pyruvate (0.5 mM).…”

Section: Methodsmentioning

confidence: 99%

“…Plasmids pEGFPC1, pEGFP-3C and pEGFP-3C variants, pCMV6-Flag-Myc-IRF7, pGL3-IFN-␤-Luc, IFN-␣4 -Luc, and pRL-SV40 have been described elsewhere (35,40). The IRF7 mutants were constructed by using Pfu DNA polymerase (Stratagene, La Jolla, CA).…”

Section: Methodsmentioning

confidence: 99%

“…Once activated, IRF7 cooperates with IRF3 to mediate antiviral responses. Recently, we reported that 3C pro of EV-D68 perturbs the Toll-like receptor 3 (TLR3) pathway that controls cytokine expression (35). Nonetheless, whether EV-D68 targets other immune factors is unknown.…”

mentioning

confidence: 99%

“…In addition, EV-D68 is able to infect leukocyte cells (34). As such, active replication of EV-D68 is thought to trigger cytokine responses (35).…”

mentioning

confidence: 99%

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3C Protease of Enterovirus D68 Inhibits Cellular Defense Mediated by Interferon Regulatory Factor 7

Zou

Liu

Lei

et al. 2016

J Virol

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Human enterovirus 68 (EV-D68) is a member of the EV-D species, which belongs to the EV genus of the Picornaviridae family.Over the past several years, clusters of EV-D68 infections have occurred worldwide. A recent outbreak in the United States is the largest one associated with severe respiratory illness and neurological complication. Although clinical symptoms are recognized, the virus remains poorly understood. Here we report that EV-D68 inhibits innate antiviral immunity by downregulation of interferon regulatory factor 7 (IRF7), an immune factor with a pivotal role in viral pathogenesis. This process depends on 3C pro , an EV-D68-encoded protease, to mediate IRF7 cleavage. When expressed in host cells, 3C pro targets Q167 and Q189 within the constitutive activation domain, resulting in cleavage of IRF7. Accordingly, wild-type IRF7 is fully active. However, IRF7 cleavage abrogated its capacity to activate type I interferon expression and limit replication of EV-D68. Notably, IRF7 cleavage strictly requires the protease activity of 3C pro . Together, these results suggest that a dynamic interplay between 3C pro and IRF7 may determine the outcome of EV-D68 infection. IMPORTANCE EV-D68 is a globally emerging pathogen, but the molecular basis of EV-D68 pathogenesis is unclear. Here we report that EV-D68 inhibits innate immune responses by targeting an immune factor, IRF7. This involves the 3C protease encoded by EV-D68, which mediates the cleavage of IRF7. These observations suggest that the 3C pro -IRF7 interaction may represent an interface that dictates EV-D68 infection.E nterovirus D68 (EV-D68) was first isolated from children with lower respiratory tract infections in California, USA, in 1962 and belongs to the species Enterovirus D within the Enterovirus genus, Picornaviridae (1). A global upsurge of EV-D68 infections in patients with respiratory tract infections (RTIs) has been observed in recent years (2-21). In 2014, a large outbreak of EV-D68 infections occurred in the United States, which raised public health concern owing to severe respiratory illness and neurological complications (22)(23)(24)(25)(26)(27)(28)(29)(30).Although linked to clinical disease, EV-D68 remains poorly characterized. EV-D68 is structurally similar to other enteroviruses (31). The virus possesses a genome approximately 7.4 kb in size, with the capacity to encode a large precursor that is processed into structural proteins (VP1, VP2, VP3, and VP4) and nonstructural proteins (2A, 2B, 2C, 3A, 3B, 3C, and 3D) (17). Viral infection initiates with sialic acids of the epithelial cells (32). In this process, the virus preferentially binds to ␣2,6-linked sialic acids rather than to ␣2,3-linked sialic acids (33). In addition, EV-D68 is able to infect leukocyte cells (34). As such, active replication of EV-D68 is thought to trigger cytokine responses (35).It is well established that the pattern-recognition receptors (PRRs) initiate innate antiviral immunity through activation of interferon regulatory factor 3 (IRF3), interferon r...

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RNA‐virus proteases counteracting host innate immunity

Lei

Hilgenfeld

2017

FEBS Letters

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Virus invasion triggers host immune responses, in particular, innate immune responses. Pathogen‐associated molecular patterns of viruses (such as dsRNA, ssRNA, or viral proteins) released during virus replication are detected by the corresponding pattern‐recognition receptors of the host, and innate immune responses are induced. Through production of type‐I and type‐III interferons as well as various other cytokines, the host innate immune system forms the frontline to protect host cells and inhibit virus infection. Not surprisingly, viruses have evolved diverse strategies to counter this antiviral system. In this review, we discuss the multiple strategies used by proteases of positive‐sense single‐stranded RNA viruses of the families Picornaviridae, Coronaviridae, and Flaviviridae, when counteracting host innate immune responses.

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

Cited by 66 publications

References 40 publications

Coxsackievirus counters the host innate immune response by blocking type III interferon expression

Coxsackievirus counters the host innate immune response by blocking type III interferon expression

3C Protease of Enterovirus D68 Inhibits Cellular Defense Mediated by Interferon Regulatory Factor 7

RNA‐virus proteases counteracting host innate immunity

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