skip to main content
DOE PAGES title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Sialic acid-dependent cell entry of human enterovirus D68

Abstract

Human enterovirus D68 (EV-D68) is a causative agent of childhood respiratory diseases and has now emerged as a global public health threat. Nevertheless, knowledge of the tissue tropism and pathogenesis of EV-D68 has been hindered by a lack of studies on the receptor-mediated EV-D68 entry into host cells. Here we demonstrate that cell surface sialic acid is essential for EV-D68 to bind to and infect susceptible cells. Crystal structures of EV-D68 in complex with sialylated glycan receptor analogues show that they bind into the ‘canyon’ on the virus surface. The sialic acid receptor induces a cascade of conformational changes in the virus to eject a fatty-acid-like molecule that regulates the stability of the virus. Furthermore, virus binding to a sialic acid receptor and to immunoglobulin-like receptors used by most other enteroviruses share a conserved mechanism for priming viral uncoating and facilitating cell entry.

Authors:
 [1];  [1];  [2];  [1];  [3];  [2];  [2];  [1]
  1. Purdue Univ., West Lafayette, IN (United States)
  2. Utrecht Univ., Utrecht (The Netherlands)
  3. Univ. of Texas at El Paso, El Paso, TX (United States)
Publication Date:
Research Org.:
Purdue Univ., West Lafayette, IN (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1239678
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 6; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; biological sciences; virology

Citation Formats

Liu, Yue, Sheng, Ju, Baggen, Jim, Meng, Geng, Xiao, Chuan, Thibaut, Hendrik J., van Kuppeveld, Frank J. M., and Rossmann, Michael G. Sialic acid-dependent cell entry of human enterovirus D68. United States: N. p., 2015. Web. doi:10.1038/ncomms9865.
Liu, Yue, Sheng, Ju, Baggen, Jim, Meng, Geng, Xiao, Chuan, Thibaut, Hendrik J., van Kuppeveld, Frank J. M., & Rossmann, Michael G. Sialic acid-dependent cell entry of human enterovirus D68. United States. doi:10.1038/ncomms9865.
Liu, Yue, Sheng, Ju, Baggen, Jim, Meng, Geng, Xiao, Chuan, Thibaut, Hendrik J., van Kuppeveld, Frank J. M., and Rossmann, Michael G. Fri . "Sialic acid-dependent cell entry of human enterovirus D68". United States. doi:10.1038/ncomms9865. https://www.osti.gov/servlets/purl/1239678.
@article{osti_1239678,
title = {Sialic acid-dependent cell entry of human enterovirus D68},
author = {Liu, Yue and Sheng, Ju and Baggen, Jim and Meng, Geng and Xiao, Chuan and Thibaut, Hendrik J. and van Kuppeveld, Frank J. M. and Rossmann, Michael G.},
abstractNote = {Human enterovirus D68 (EV-D68) is a causative agent of childhood respiratory diseases and has now emerged as a global public health threat. Nevertheless, knowledge of the tissue tropism and pathogenesis of EV-D68 has been hindered by a lack of studies on the receptor-mediated EV-D68 entry into host cells. Here we demonstrate that cell surface sialic acid is essential for EV-D68 to bind to and infect susceptible cells. Crystal structures of EV-D68 in complex with sialylated glycan receptor analogues show that they bind into the ‘canyon’ on the virus surface. The sialic acid receptor induces a cascade of conformational changes in the virus to eject a fatty-acid-like molecule that regulates the stability of the virus. Furthermore, virus binding to a sialic acid receptor and to immunoglobulin-like receptors used by most other enteroviruses share a conserved mechanism for priming viral uncoating and facilitating cell entry.},
doi = {10.1038/ncomms9865},
journal = {Nature Communications},
number = ,
volume = 6,
place = {United States},
year = {2015},
month = {11}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 17 works
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

Kinetics and Thermodynamics of Virus Binding to Receptor.: STUDIES WITH RHINOVIRUS, INTERCELLULAR ADHESION MOLECULE-1 (ICAM-1), AND SURFACE PLASMON RESONANCE
journal, June 1995

  • Casasnovas, José M.; Springer, Timothy A.
  • Journal of Biological Chemistry, Vol. 270, Issue 22
  • DOI: 10.1074/jbc.270.22.13216

Sialylated glycans as receptor and inhibitor of enterovirus 71 infection to DLD-1 intestinal cells
journal, January 2009


The major and minor group receptor families contain all but one human rhinovirus serotype
journal, February 1991


Viral cell recognition and entry
journal, October 1994


Nectin-Like Interactions between Poliovirus and Its Receptor Trigger Conformational Changes Associated with Cell Entry
journal, January 2015

  • Strauss, Mike; Filman, David J.; Belnap, David M.
  • Journal of Virology, Vol. 89, Issue 8
  • DOI: 10.1128/JVI.03101-14

Glycomic Analysis of Human Respiratory Tract Tissues and Correlation with Influenza Virus Infection
journal, March 2013


Interpretation of electron density with stereographic roadmap projections
journal, May 2007


Enterovirus 70 Receptor Utilization Is Controlled by Capsid Residues That Also Regulate Host Range and Cytopathogenicity
journal, May 2007


Enterovirus 70 Binds to Different Glycoconjugates Containing  2,3-Linked Sialic Acid on Different Cell Lines
journal, May 2005


Crystallography & NMR System: A New Software Suite for Macromolecular Structure Determination
journal, September 1998

  • Brünger, A. T.; Adams, P. D.; Clore, G. M.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 54, Issue 5
  • DOI: 10.1107/S0907444998003254

Structural and Virological Studies of the Stages of Virus Replication That Are Affected by Antirhinovirus Compounds
journal, September 2004


Antigenic and Receptor Binding Properties of Enterovirus 68
journal, December 2013

  • Imamura, T.; Okamoto, M.; Nakakita, S. -i.
  • Journal of Virology, Vol. 88, Issue 5
  • DOI: 10.1128/JVI.03070-13

Cellular tropism of human enterovirus D species serotypes EV-94, EV-70, and EV-68 in vitro: Implications for pathogenesis
journal, September 2010

  • Smura, Teemu; Ylipaasto, Petri; Klemola, Päivi
  • Journal of Medical Virology, Vol. 82, Issue 11
  • DOI: 10.1002/jmv.21894

Structural factors that control conformational transitions and serotype specificity in type 3 poliovirus.
journal, May 1989


Two Distinct Binding Affinities of Poliovirus for Its Cellular Receptor
journal, April 2000

  • McDermott, Brian M.; Rux, Ann H.; Eisenberg, Roselyn J.
  • Journal of Biological Chemistry, Vol. 275, Issue 30
  • DOI: 10.1074/jbc.M002146200

Viruses and sialic acids: rules of engagement
journal, October 2011

  • Neu, Ursula; Bauer, Johannes; Stehle, Thilo
  • Current Opinion in Structural Biology, Vol. 21, Issue 5
  • DOI: 10.1016/j.sbi.2011.08.009

The CCP4 suite programs for protein crystallography
journal, September 1994


Haploid Genetic Screens in Human Cells Identify Host Factors Used by Pathogens
journal, November 2009

  • Carette, Jan E.; Guimaraes, Carla P.; Varadarajan, Malini
  • Science, Vol. 326, Issue 5957
  • DOI: 10.1126/science.1178955

Software for handling macromolecular envelopes
journal, April 1999

  • Kleywegt, G. Jacob; Jones, Thomas A.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 55, Issue 4
  • DOI: 10.1107/S0907444999001031

Sialic Acid Is a Cellular Receptor for Coxsackievirus A24 Variant, an Emerging Virus with Pandemic Potential
journal, January 2008

  • Nilsson, E. C.; Jamshidi, F.; Johansson, S. M. C.
  • Journal of Virology, Vol. 82, Issue 6
  • DOI: 10.1128/JVI.02470-07

Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
journal, December 2001


Heparan Sulfates and Coxsackievirus-Adenovirus Receptor: Each One Mediates Coxsackievirus B3 PD Infection
journal, August 2003


Identification of the pocket factors in a picornavirus
journal, May 2003


Anti-enterovirus activity and structure–activity relationship of a series of 2,6-dihalophenyl-substituted 1H,3H-thiazolo[3,4-a]benzimidazoles
journal, February 2007

  • Palma, Armando M. De; Heggermont, Ward; Leyssen, Pieter
  • Biochemical and Biophysical Research Communications, Vol. 353, Issue 3
  • DOI: 10.1016/j.bbrc.2006.12.063

A Probable new Human Picornavirus Associated with Respiratory Disease1
journal, March 1967


MolProbity : all-atom structure validation for macromolecular crystallography
journal, December 2009

  • Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1
  • DOI: 10.1107/S0907444909042073

Picornavirus uncoating intermediate captured in atomic detail
journal, June 2013

  • Ren, Jingshan; Wang, Xiangxi; Hu, Zhongyu
  • Nature Communications, Vol. 4, Issue 1
  • DOI: 10.1038/ncomms2889

A novel outbreak enterovirus D68 strain associated with acute flaccid myelitis cases in the USA (2012–14): a retrospective cohort study
journal, June 2015

  • Greninger, Alexander L.; Naccache, Samia N.; Messacar, Kevin
  • The Lancet Infectious Diseases, Vol. 15, Issue 6
  • DOI: 10.1016/S1473-3099(15)70093-9

Features and development of Coot
journal, March 2010

  • Emsley, P.; Lohkamp, B.; Scott, W. G.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4
  • DOI: 10.1107/S0907444910007493

Sialic Acid Functions in Enterovirus 70 Binding and Infection
journal, November 2002


Three-dimensional structure of poliovirus at 2.9 A resolution
journal, September 1985


Enterovirus 71 Uses Cell Surface Heparan Sulfate Glycosaminoglycan as an Attachment Receptor
journal, October 2012

  • Tan, C. W.; Poh, C. L.; Sam, I. -C.
  • Journal of Virology, Vol. 87, Issue 1
  • DOI: 10.1128/JVI.02226-12

Two cases of acute severe flaccid myelitis associated with enterovirus D68 infection in children, Norway, autumn 2014
journal, March 2015


Picornavirus–receptor interactions
journal, July 2002


Cell surface sialylation affects binding of enterovirus 71 to rhabdomyosarcoma and neuroblastoma cells
journal, January 2012


PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010

  • Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
  • DOI: 10.1107/S0907444909052925

Rapid routine detection of enterovirus RNA in cerebrospinal fluid by a one-step real-time RT-PCR assay
journal, May 2008

  • Dierssen, Uta; Rehren, Fabienne; Henke-Gendo, Cornelia
  • Journal of Clinical Virology, Vol. 42, Issue 1
  • DOI: 10.1016/j.jcv.2007.11.016

VIPERdb2: an enhanced and web API enabled relational database for structural virology
journal, January 2009

  • Carrillo-Tripp, M.; Shepherd, C. M.; Borelli, I. A.
  • Nucleic Acids Research, Vol. 37, Issue Database
  • DOI: 10.1093/nar/gkn840

A Sialic Acid Binding Site in a Human Picornavirus
journal, October 2014


Not your average density
journal, December 1997


Worldwide emergence of multiple clades of enterovirus 68
journal, June 2012

  • Tokarz, R.; Firth, C.; Madhi, S. A.
  • Journal of General Virology, Vol. 93, Issue Pt_9
  • DOI: 10.1099/vir.0.043935-0

Structure of a human common cold virus and functional relationship to other picornaviruses
journal, September 1985

  • Rossmann, Michael G.; Arnold, Edward; Erickson, John W.
  • Nature, Vol. 317, Issue 6033
  • DOI: 10.1038/317145a0

Structure and inhibition of EV-D68, a virus that causes respiratory illness in children
journal, January 2015


Cryo-Electron Microscopy Reconstruction Shows Poliovirus 135S Particles Poised for Membrane Interaction and RNA Release
journal, November 2013

  • Butan, C.; Filman, D. J.; Hogle, J. M.
  • Journal of Virology, Vol. 88, Issue 3
  • DOI: 10.1128/JVI.01949-13

    Works referencing / citing this record:

    Current Understanding of Human Enterovirus D68
    journal, May 2019

    • Sun, Jing; Hu, Xiao-Yi; Yu, Xiao-Fang
    • Viruses, Vol. 11, Issue 6
    • DOI: 10.3390/v11060490

    Cell surface α2,3-linked sialic acid facilitates Zika virus internalization
    journal, January 2019


    Cell surface α2,3-linked sialic acid facilitates Zika virus internalization
    journal, January 2019


    Current Understanding of Human Enterovirus D68
    journal, May 2019

    • Sun, Jing; Hu, Xiao-Yi; Yu, Xiao-Fang
    • Viruses, Vol. 11, Issue 6
    • DOI: 10.3390/v11060490

    The association between acute flaccid myelitis (AFM) and Enterovirus D68 (EV-D68) – what is the evidence for causation?
    journal, January 2018