Atomic structures of enterovirus D68 in complex with two monoclonal antibodies define distinct mechanisms of viral neutralization

Zheng, Qingbing; Zhu, Rui; Xu, Longfa; He, Maozhou; Yan, Xiaodong; Liu, Dongxiao; Yin, Zhichao; Wu, Yangtao; Li, Yongchao; Yang, Lijie; Hou, Wangheng; Li, Shuxuan; Li, Zizhen; Chen, Zhenqin; Li, Zhihai; Yu, Hai; Gu, Ying; Zhang, Jun; Baker, Timothy S.; Zhou, Z. Hong; Graham, Barney S.; Cheng, Tong; Li, Shaowei; Xia, Ningshao

doi:10.1038/s41564-018-0275-7

Cited by 47 publications

(63 citation statements)

References 51 publications

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“…Nevertheless, the identification of ICAM-5 may prove to be an important step in the discovery of additional EV-D68 neuronal receptors. Recent attempts to cocrystallize EV-D68 bound to ICAM-5 have been unsuccessful, consistent with a very low binding affinity of EV-D68 to ICAM-5 (50). ICAM-5 is a member of the immunoglobulin superfamily of proteins, and the majority of enteroviruses utilize this family of protein receptors for infection in various tissues (51).…”

Section: Discussionmentioning

confidence: 99%

Contemporary Circulating Enterovirus D68 Strains Infect and Undergo Retrograde Axonal Transport in Spinal Motor Neurons Independent of Sialic Acid

Hixon

Clarke²,

Tyler

2019

J Virol

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Enterovirus D68 (EV-D68) is an emerging virus that has been identified as a cause of recent outbreaks of acute flaccid myelitis (AFM), a poliomyelitis-like spinal cord syndrome that can result in permanent paralysis and disability. In experimental mouse models, EV-D68 spreads to, infects, and kills spinal motor neurons following infection by various routes of inoculation. The topography of virus-induced motor neuron loss correlates with the pattern of paralysis. The mechanism(s) by which EV-D68 spreads to target motor neurons remains unclear. We sought to determine the capacity of EV-D68 to spread by the neuronal route and to determine the role of known EV-D68 receptors, sialic acid and intracellular adhesion molecule 5 (ICAM-5), in neuronal infection. To do this, we utilized a microfluidic chamber culture system in which human induced pluripotent stem cell (iPSC) motor neuron cell bodies and axons can be compartmentalized for independent experimental manipulation. We found that EV-D68 can infect motor neurons via their distal axons and spread by retrograde axonal transport to the neuronal cell bodies. Virus was not released from the axons via anterograde axonal transport after infection of the cell bodies. Prototypic strains of EV-D68 depended on sialic acid for axonal infection and transport, while contemporary circulating strains isolated during the 2014 EV-D68 outbreak did not. The pattern of infection did not correspond with the ICAM-5 distribution and expression in either human tissue, the mouse model, or the iPSC motor neurons. IMPORTANCE Enterovirus D68 (EV-D68) infections are on the rise worldwide. Since 2014, the United States has experienced biennial spikes in EV-D68-associated acute flaccid myelitis (AFM) that have left hundreds of children paralyzed. Much remains to be learned about the pathogenesis of EV-D68 in the central nervous system (CNS). Herein we investigated the mechanisms of EV-D68 CNS invasion through neuronal pathways. A better understanding of EV-D68 infection in experimental models may allow for better prevention and treatment strategies of EV-D68 CNS disease.

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Section: Discussionmentioning

confidence: 99%

Contemporary Circulating Enterovirus D68 Strains Infect and Undergo Retrograde Axonal Transport in Spinal Motor Neurons Independent of Sialic Acid

Hixon

Clarke²,

Tyler

2019

J Virol

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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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“…Thus far, 3D reconstructions of virus-Fab complexes at atomic resolution are available for some picornaviruses, including rhinovirus B14 (RV-B14) (Dong et al 2017), human parechovirus 3 (HPeV3) (Domanska et al 2019), hepatovirus A (HAV) (Cao et al 2019) and enterovirus D68 (EV-D68) (Zheng et al 2019) (Table 1). The atomic models of the capsid protein were well-fitted in the cryo-EM density map for HPeV3 (Fig.…”

Section: Antibodies For Cryo-em Studiesmentioning

confidence: 99%

“…Site 1 is located near the icosahedral fivefold axis of EV-A71 (MA28-7), CV-A6 (1D5)) and EV-D68 (11G1)(Zheng et al 2019). While site 2 maps to the VP1 GH-loop across the twofold axis of EV-A71 (22A12 and D5)(Shingler et al 2015;Ye et al 2016), site 3 is situated near the threefold axis of EV-A71 (E18, E19 and A9)(Plevka et al 2014;Zhu L et al 2018b) and EV-D68 (15C5)(Zheng et al 2019). Site 4 is adjacent to the quasi threefold axis of CV-A10 (2G8)(Zhu R et al 2018).Some clinically relevant viruses in the Flaviviridae family, such as dengue virus (DENV), West Nile virus (WNV), Japanese encephalitis virus (JEV), tick-borne encephalitis virus (TBEV) and Zika virus (ZIKV)…”

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confidence: 99%

Cryo-EM Studies of Virus-Antibody Immune Complexes

et al. 2020

Virol. Sin.

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Antibodies play critical roles in neutralizing viral infections and are increasingly used as therapeutic drugs and diagnostic tools. Structural studies on virus-antibody immune complexes are important for better understanding the molecular mechanisms of antibody-mediated neutralization and also provide valuable information for structure-based vaccine design. Cryo-electron microscopy (cryo-EM) has recently matured as a powerful structural technique for studying bio-macromolecular complexes. When combined with X-ray crystallography, cryo-EM provides a routine approach for structurally characterizing the immune complexes formed between icosahedral viruses and their antibodies. In this review, recent advances in the structural understanding of virus-antibody interactions are outlined for whole virions with icosahedral T = pseudo 3 (picornaviruses) and T = 3 (flaviviruses) architectures, focusing on the dynamic nature of viral shells in different functional states. Glycoprotein complexes from pleomorphic enveloped viruses are also discussed as immune complex antigens. Improving our understanding of viral epitope structures using virus-based platforms would provide a fundamental road map for future vaccine development.

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Atomic structures of enterovirus D68 in complex with two monoclonal antibodies define distinct mechanisms of viral neutralization

Cited by 47 publications

References 51 publications

Contemporary Circulating Enterovirus D68 Strains Infect and Undergo Retrograde Axonal Transport in Spinal Motor Neurons Independent of Sialic Acid

Contemporary Circulating Enterovirus D68 Strains Infect and Undergo Retrograde Axonal Transport in Spinal Motor Neurons Independent of Sialic Acid

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

Cryo-EM Studies of Virus-Antibody Immune Complexes

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