ICAM-5/Telencephalin Is a Functional Entry Receptor for Enterovirus D68

Wei, Wei; Guo, Hao; Chang, Junliang; Yu, Yizhi; Liu, Guanchen; Zhang, Nannan; Willard, Stephen H.; Zheng, Shu; Yu, Xiao Fang

doi:10.1016/j.chom.2016.09.013

Cited by 101 publications

(99 citation statements)

References 37 publications

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“…Indeed, similar pathological changes caused by coxsackievirus B3 hippocampal infection have been documented (33). Most interestingly, a recent report on the identification of the EV-D68 receptor suggested that hippocampal neurons are susceptible to EV-D68 (34). It should be noted that induced expression of hWARS could be detected on the plasma membrane of hippocampal neurons in a disease model (32).…”

Section: Discussionmentioning

confidence: 59%

Human tryptophanyl-tRNA synthetase is an IFN-γ–inducible entry factor for Enterovirus

Yeung¹,

Jia²,

Yip³

et al. 2018

Journal of Clinical Investigation

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Enterovirus A71 (EV-A71) receptors that have been identified to date cannot fully explain the pathogenesis of EV-A71, which is an important global cause of hand, foot, and mouth disease and life-threatening encephalitis. We identified an IFN-γ-inducible EV-A71 cellular entry factor, human tryptophanyl-tRNA synthetase (hWARS), using genome-wide RNAi library screening. The importance of hWARS in mediating virus entry and infectivity was confirmed by virus attachment, in vitro pulldown, antibody/antigen blocking, and CRISPR/Cas9-mediated deletion. Hyperexpression and plasma membrane translocation of hWARS were observed in IFN-γ-treated semipermissive (human neuronal NT2) and cDNA-transfected nonpermissive (mouse fibroblast L929) cells, resulting in their sensitization to EV-A71 infection. Our hWARS-transduced mouse infection model showed pathological changes similar to those seen in patients with severe EV-A71 infection. Expression of hWARS is also required for productive infection by other human enteroviruses, including the clinically important coxsackievirus A16 (CV-A16) and EV-D68. This is the first report to our knowledge on the discovery of an entry factor, hWARS, that can be induced by IFN-γ for EV-A71 infection. Given that we detected high levels of IFN-γ in patients with severe EV-A71 infection, our findings extend the knowledge of the pathogenicity of EV-A71 in relation to entry factor expression upon IFN-γ stimulation and the therapeutic options for treating severe EV-A71-associated complications.

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Section: Discussionmentioning

confidence: 59%

Human tryptophanyl-tRNA synthetase is an IFN-γ–inducible entry factor for Enterovirus

Yeung¹,

Jia²,

Yip³

et al. 2018

Journal of Clinical Investigation

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“…We also extended this mouse model to studies of a human viral pathogen in the form of enterovirus D68 (EV-D68), a member of the Picornaviridae family that (unlike other enteroviruses) shares characteristics with human rhinovirus (RV) members of this family. In concert with shared viral features, EV-D68 can also cause respiratory infection, and this infection can result in severe illness in susceptible populations, particularly asthmatics (18-23) as well as acute flaccid myelitis in other patients, based possibly on neuronal receptor binding (24). The severity of EV-D68-driven illness might be based on the viral capacity to subvert the IFN-based immune response (25,26), raising the possibility that any further IFN deficiency might no longer influence the infection.…”

mentioning

confidence: 99%

Respiratory Enterovirus (like Parainfluenza Virus) Can Cause Chronic Lung Disease if Protection by Airway Epithelial STAT1 Is Lost

Zhang

Mao

Keeler

et al. 2019

The Journal of Immunology

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Epithelial barrier cells are proposed to be critical for host defense, and airway epithelial cell capacity for IFN signal transduction is presumed to protect against respiratory viral infection. However, it has been difficult to fully test these concepts given the absence of tools to analyze IFN signaling specific to airway epithelial cells in vivo. To address these issues, we generated a new line of transgenic mice with Cre-driver genes (Foxj1 and Scgb1a1) for a floxed-Stat1 allele (designated Foxj1-Scgb1a1-Cre-Stat1f/f mice) to target the master IFN signal regulator STAT1 in airway epithelial cells and tested these mice for control of infection because of mouse parainfluenza (Sendai) virus and human enterovirus D68 (EV-D68). Indeed, both types of infections showed increases in viral titers and severity of acute illness in Foxj1-Scgb1a1-Cre-Stat1f/f mice and conventional Stat1−/− mice compared with wild-type mice. In concert, the chronic lung disease that develops after Sendai virus infection was also increased in Foxj1-Scgb1a1-Cre-Stat1f/f and Stat1–/– mice, marked by airway and adjacent parenchymal immune cell infiltration and mucus production for at least 7 wk postinfection. Unexpectedly, relatively mild EV-D68 infection also progressed to chronic lung disease in Foxj1-Scgb1a1-Cre-Stat1f/f and Stat1−/− mice but was limited (like viral replication) to airways. The results thereby provide proof-of-concept for a critical role of barrier epithelial cells in protection from acute illness and chronic disease after viral infection and suggest a specific role for airway epithelial cells given the limitation of EV-D68 replication and acute and chronic manifestations of disease primarily to airway tissue.

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“…Our data indicate that contemporary strains of EV-D68 are better fit to replicate at 37°C than historic strains. Extrapolation of this data suggests that temperature is no barrier for the viruses to infect both upper and lower airways of the human respiratory tract.While recent studies have given insight into the ability of EV-D68 to infect neuronal cell lines in vitro and in animal models as it pertains to receptors, the mechanisms by which EV-D68 infects the central nervous system to cause AFM remain unclear [78][79][80][81][82][83]. Other picornaviruses capable of causing AFM such as poliovirus, EV-71, and CVB all replicate at high physiological temperatures.…”

Section: Discussionmentioning

confidence: 99%

Contemporary Enterovirus D68 strains show enhanced replication and translation at 37°C

Smith

Pekosz

2020

Preprint

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Enterovirus D68 (EV-D68) emerged in 2014 as an important pathogen linked to severe lower respiratory disease and acute flaccid myelitis outbreaks. Historically associated with mild common-cold-like symptoms, clusters of severe disease attributed to EV-D68 appeared during a series of outbreaks in 2014, 2016, and 2018. Previous studies of historic EV-D68 strains demonstrated attenuated replication at temperatures of the lower respiratory tract (37°C), when compared to the upper respiratory tract (32°C). By testing a panel of historic and contemporary EV-D68 strains at 32°C and 37°C, we demonstrate that contemporary strains of EV-D68 undergo little to no attenuation at increased temperatures. Contemporary strains produced higher levels of viral proteins at 32°C and 37°C than historic strains, although both strains infected similar numbers of cells and had comparable amounts of replication complexes. IRES activity assays with dual-luciferase reporter plasmids demonstrated enhanced translation in recent EV-D68 strains mapped to regions of variability in the 5' UTR found only in contemporary strains. Using an infectious clone system, we demonstrate that the translation advantage dictated by the 5' UTR does not solely mediate temperature sensitivity. The strain-dependent effects of temperature on the EV-D68 life cycle gives insight into the susceptibility of the lower respiratory system to contemporary strains. IMPORTANCEEnterovirus-D68 (EV-D68) emerged in 2014 as a causative agent of biannual severe pediatric respiratory disease and acute flaccid myelitis (AFM). We show that recent EV-D68 viruses have gained the ability to replicate at 37⁰C. Enhanced virus protein translation seemed to correlate with enhanced virus replication at 37⁰C but other genetic factors are also contributing to this phenotype. An enhanced ability to replicate at core body temperature may have allowed EV-D68 to penetrate both lower in the respiratory tract and into the central nervous system, explaining the recent surge in severe disease associated with virus infection.

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ICAM-5/Telencephalin Is a Functional Entry Receptor for Enterovirus D68

Cited by 101 publications

References 37 publications

Human tryptophanyl-tRNA synthetase is an IFN-γ–inducible entry factor for Enterovirus

Human tryptophanyl-tRNA synthetase is an IFN-γ–inducible entry factor for Enterovirus

Respiratory Enterovirus (like Parainfluenza Virus) Can Cause Chronic Lung Disease if Protection by Airway Epithelial STAT1 Is Lost

Contemporary Enterovirus D68 strains show enhanced replication and translation at 37°C

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