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. https://doi.org/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. https://doi.org/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 = {Fri Nov 13 00:00:00 EST 2015},
month = {Fri Nov 13 00:00:00 EST 2015}
}

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

Citation Metrics:
Cited by: 79 works
Citation information provided by
Web of Science

Save / Share:

Works referenced in this record:

Viral cell recognition and entry
book, May 2014


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

Viral cell recognition and entry
journal, October 1994


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


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

  • Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
  • Apollo - University of Cambridge Repository
  • DOI: 10.17863/cam.45787

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


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

Picornavirus–receptor interactions
journal, July 2002


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


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


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

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


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

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


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

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

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


Formation of rhinovirus-soluble ICAM-1 complexes and conformational changes in the virion.
journal, January 1993


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


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


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

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

  • Nilsson, Emma C.; Jamshidi, Fariba; Johansson, Susanne M. C.
  • Journal of Virology, Vol. 82, Issue 10
  • DOI: 10.1128/jvi.00615-08

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

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


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

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

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

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


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

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

Viral cell recognition and entry
journal, October 1994


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

  • Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
  • Apollo - University of Cambridge Repository
  • DOI: 10.17863/cam.45787

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


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

Exploring the gas access routes in a [NiFeSe] hydrogenase using crystals pressurized with krypton and oxygen
journal, August 2020

  • Zacarias, Sónia; Temporão, Adriana; Carpentier, Philippe
  • JBIC Journal of Biological Inorganic Chemistry, Vol. 25, Issue 6
  • DOI: 10.1007/s00775-020-01814-y

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

Conformational exchange in the potassium channel blocker ShK
journal, December 2019


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


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


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

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


Neutralization of poliovirus by cell receptors expressed in insect cells.
journal, January 1990


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


PARP1 exhibits enhanced association and catalytic efficiency with γH2A.X-nucleosome
journal, December 2019


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

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


Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation
journal, February 2021


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

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

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

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

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


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

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


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


Not your average density
journal, December 1997


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


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

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

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


Pleconaril
book, January 1999


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


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

A Fatal Central Nervous System Enterovirus 68 Infection
journal, June 2011

  • Kreuter, Justin D.; Barnes, Arti; McCarthy, James E.
  • Archives of Pathology & Laboratory Medicine, Vol. 135, Issue 6
  • DOI: 10.5858/2010-0174-CR.1

Neutralization of poliovirus by cell receptors expressed in insect cells.
journal, January 1990


Formation of rhinovirus-soluble ICAM-1 complexes and conformational changes in the virion.
journal, January 1993


Works referencing / citing this record:

Neurotropism of Enterovirus D68 Isolates Is Independent of Sialic Acid and Is Not a Recently Acquired Phenotype
journal, October 2019

  • Rosenfeld, Amy B.; Warren, Audrey L.; Racaniello, Vincent R.
  • mBio, Vol. 10, Issue 5
  • DOI: 10.1128/mbio.02370-19

Understanding Enterovirus D68-Induced Neurologic Disease: A Basic Science Review
journal, September 2019

  • Hixon, Alison M.; Frost, Joshua; Rudy, Michael J.
  • Viruses, Vol. 11, Issue 9, p. 821
  • DOI: 10.3390/v11090821

Understanding Enterovirus D68-Induced Neurologic Disease: A Basic Science Review
journal, September 2019

  • Hixon, Alison M.; Frost, Joshua; Rudy, Michael J.
  • Viruses, Vol. 11, Issue 9, p. 821
  • DOI: 10.3390/v11090821

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


CRISPR/Cas9-mediated gene knockout screens and target identification via whole-genome sequencing uncover host genes required for picornavirus infection
journal, April 2017

  • Kim, Heon Seok; Lee, Kyungjin; Bae, Sangsu
  • Journal of Biological Chemistry, Vol. 292, Issue 25
  • DOI: 10.1074/jbc.m117.782425

Molecular basis for the acid-initiated uncoating of human enterovirus D68
journal, December 2018

  • Liu, Yue; Sheng, Ju; van Vliet, Arno L. W.
  • Proceedings of the National Academy of Sciences, Vol. 115, Issue 52
  • DOI: 10.1073/pnas.1803347115

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
text, January 2019


Recent advances on the role of host factors during non-poliovirus enteroviral infections
journal, June 2019


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


CRISPR/Cas9-mediated gene knockout screens and target identification via whole-genome sequencing uncover host genes required for picornavirus infection
journal, April 2017

  • Kim, Heon Seok; Lee, Kyungjin; Bae, Sangsu
  • Journal of Biological Chemistry, Vol. 292, Issue 25
  • DOI: 10.1074/jbc.m117.782425

Atomic structures of enterovirus D68 in complex with two monoclonal antibodies define distinct mechanisms of viral neutralization
journal, November 2018


A Novel Neutralizing Antibody Specific to the DE Loop of VP1 Can Inhibit EV-D68 Infection in Mice
journal, October 2018

  • Zheng, Huiwen; Wang, Jingjing; Li, Bingxiang
  • The Journal of Immunology, Vol. 201, Issue 9
  • DOI: 10.4049/jimmunol.1800655

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


Recent advances on the role of host factors during non-poliovirus enteroviral infections
journal, June 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

Contemporary Circulating Enterovirus D68 Strains Infect and Undergo Retrograde Axonal Transport in Spinal Motor Neurons Independent of Sialic Acid
journal, June 2019

  • Hixon, Alison M.; Clarke, Penny; Tyler, Kenneth L.
  • Journal of Virology, Vol. 93, Issue 16
  • DOI: 10.1128/jvi.00578-19

Respiratory Enterovirus (like Parainfluenza Virus) Can Cause Chronic Lung Disease if Protection by Airway Epithelial STAT1 Is Lost
journal, February 2019

  • Zhang, Yong; Mao, Dailing; Keeler, Shamus P.
  • The Journal of Immunology, Vol. 202, Issue 8
  • DOI: 10.4049/jimmunol.1801491

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


Enterovirus D-68 Infection, Prophylaxis, and Vaccination in a Novel Permissive Animal Model, the Cotton Rat (Sigmodon hispidus)
journal, November 2016


The life cycle of non-polio enteroviruses and how to target it
journal, April 2018

  • Baggen, Jim; Thibaut, Hendrik Jan; Strating, Jeroen R. P. M.
  • Nature Reviews Microbiology, Vol. 16, Issue 6
  • DOI: 10.1038/s41579-018-0005-4

A 3.0-Angstrom Resolution Cryo-Electron Microscopy Structure and Antigenic Sites of Coxsackievirus A6-Like Particles
journal, November 2017

  • Chen, Jinhuan; Zhang, Chao; Zhou, Yu
  • Journal of Virology, Vol. 92, Issue 2
  • DOI: 10.1128/jvi.01257-17

Atomic structure of a rhinovirus C, a virus species linked to severe childhood asthma
journal, July 2016

  • Liu, Yue; Hill, Marchel G.; Klose, Thomas
  • Proceedings of the National Academy of Sciences, Vol. 113, Issue 32
  • DOI: 10.1073/pnas.1606595113

Viral chimeras decrypt the role of enterovirus capsid proteins in viral tropism, acid sensitivity and optimal growth temperature
journal, April 2018

  • Royston, Léna; Essaidi-Laziosi, Manel; Pérez-Rodríguez, Francisco J.
  • PLOS Pathogens, Vol. 14, Issue 4
  • DOI: 10.1371/journal.ppat.1006962

Enterovirus pathogenesis requires the host methyltransferase SETD3
journal, September 2019


Multifunctionality of structural proteins in the enterovirus life cycle
journal, September 2019


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


Viral chimeras decrypt the role of enterovirus capsid proteins in viral tropism, acid sensitivity and optimal growth temperature
journal, April 2018

  • Royston, Léna; Essaidi-Laziosi, Manel; Pérez-Rodríguez, Francisco J.
  • PLOS Pathogens, Vol. 14, Issue 4
  • DOI: 10.1371/journal.ppat.1006962