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  • Review Article
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The life cycle of non-polio enteroviruses and how to target it

Nature Reviews Microbiology volume 16, pages 368–381 (2018)Cite this article

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A Publisher Correction to this article was published on 03 May 2018

This article has been updated

Abstract

The genus Enterovirus (EV) of the family Picornaviridae includes poliovirus, coxsackieviruses, echoviruses, numbered enteroviruses and rhinoviruses. These diverse viruses cause a variety of diseases, including non-specific febrile illness, hand-foot-and-mouth disease, neonatal sepsis-like disease, encephalitis, paralysis and respiratory diseases. In recent years, several non-polio enteroviruses (NPEVs) have emerged as serious public health concerns. These include EV-A71, which has caused epidemics of hand-foot-and-mouth disease in Southeast Asia, and EV-D68, which recently caused a large outbreak of severe lower respiratory tract disease in North America. Infections with these viruses are associated with severe neurological complications. For decades, most research has focused on poliovirus, but in recent years, our knowledge of NPEVs has increased considerably. In this Review, we summarize recent insights from enterovirus research with a special emphasis on NPEVs. We discuss virion structures, host–receptor interactions, viral uncoating and the recent discovery of a universal enterovirus host factor that is involved in viral genome release. Moreover, we briefly explain the mechanisms of viral genome replication, virion assembly and virion release, and describe potential targets for antiviral therapy. We reflect on how these recent discoveries may help the development of antiviral therapies and vaccines.

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Fig. 1: Schematic overview of the enterovirus life cycle.
Fig. 2: Picornavirus structure.
Fig. 3: The enterovirus uncoating mechanism.

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Change history

  • 03 May 2018

    In the version of this Review originally published, co-author Hendrik Jan Thibaut’s name was incorrectly indexed as “Jan Thibaut, H”. It should have appeared as “Thibaut, HJ”. This has now been corrected in all versions of the Review. The publisher apologizes to the authors and to readers for this error.

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Acknowledgements

Research in the authors’ laboratory is supported by grants from the Netherlands Organisation for Scientific Research (NWO-VICI-91812628 and NWO-ECHO-711.017.002 to F.J.M.v.K.) and from the European Union (Horizon2020 Marie Sklodowska Curie ETN ‘ANTIVIRALS’ grant agreement number 642434 to F.J.M.v.K.).

Reviewer information

Nature Reviews Microbiology thanks S. Hafenstein, Q. Li and S.-R. Shih for their contributions to the peer review of this work.

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Author notes

  1. These authors contributed equally: Jim Baggen, Hendrik Jan Thibaut

Authors and Affiliations

  1. Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands

    Jim Baggen, Hendrik Jan Thibaut, Jeroen R. P. M. Strating & Frank J. M. van Kuppeveld

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  1. Jim Baggen
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J.B., H.J.T., J.R.P.M.S. and F.J.M.v.K. researched data for the article and substantially contributed to discussion of content, wrote the article and reviewed and edited the manuscript before submission.

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Correspondence to Frank J. M. van Kuppeveld.

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Related links

RCSB Protein Databank http://www.rcsb.org/pdb/home/home.do

Glossary

Acute flaccid paralysis

A type of paralysis that is characterized by a sudden weakness or loss of muscle tone.

Hand-foot-and-mouth disease

A viral disease in which characteristic vesicular lesions appear on the hands, feet and inside the mouth.

Herpangina

A viral infection of the mouth that is characterized by blisters in the throat.

Pleurodynia

A viral disease that is characterized by a sudden pain in the muscles between the ribs.

Pericarditis

An inflammation of the pericardium, the membrane that surrounds the heart and the beginning of the great vessels.

Myocarditis

An inflammation of the heart muscle.

Bronchiolitis

An inflammation of the bronchioles that is caused by a viral infection.

Replication organelles

Virus-induced membranous structures that are generated from remodelled host membranes that accumulate in the cytoplasmic area of the cell and that are thought to support replication by scaffolding the replication machinery and occluding the viral RNA from antiviral defence systems.

Protomers

Assembly intermediates of an enterovirus capsid that is composed of one copy of each of the structural proteins VP0, VP1 and VP3.

Chronic shedders

Immunodeficient people who excrete vaccine-derived poliovirus for prolonged times.

Myristoylation

A saturated fatty acid that is linked to the N terminus of structural protein VP4 and has a role in both the entry and assembly process.

Poly-l-proline type II helices

Helical protein structures that consist of repeating proline residues and are frequently involved in protein–protein and protein–nucleic acid interactions.

High-speed fixed-target X-ray crystallography at X-ray free-electron lasers

A novel method in which X-ray free-electron lasers that generate high-intensity X-ray pulses and sample fixation on a micro-patterned pore-containing chip are combined to allow very fast structure determination with limited beam time and sample material.

Telencephalic grey matter

An area of the cerebral cortex that contains the nerve bodies.

Sedimentation coefficients

Quantities that describe the sedimentation rate of a particle when centrifuged in a fluid medium, which depends on particle size, density and shape.

GH loop

A structural loop in structural protein VP1 that forms the border between the hydrophobic pocket and the bottom of the canyon.

Phospholipase A2 group XVI

(PLA2G16). A lipid-modifying enzyme that catalyses the release of fatty acids from phospholipids in adipose tissue and has been proposed to have acyltransferase activity.

Phospholipase A2 domain

A domain with phospholipase A2 catalytic activity; that is, it cleaves off fatty acids from the second hydroxyl group of the glycerol backbone of a phospholipid.

Internal ribosome entry site

(IRES). A highly structured RNA element in the 5′ UTR that allows cap-independent initiation of translation.

IRES trans-acting factors

(ITAFs). Host RNA-binding proteins that bind to the enteroviral IRES and stimulate translation (for example, polypyrimidine tract-binding protein 2, poly(rC)-binding protein 2, polyadenylate-binding protein 1, La and serine/arginine-rich splicing factor 3).

Poly(rC)-binding protein 2

(PCBP2). A host RNA-binding protein that functions as an ITAF to stimulate IRES-mediated translation and that binds to a replication element in the 5′ UTR to stimulate viral RNA replication.

Polyadenylate-binding protein 1

(PABP1). A host protein that binds the viral poly(A) tail and interacts with poly(rC)-binding protein 2 to mediate circularization of the viral genome and initiate negative-strand RNA synthesis.

Heterogeneous nuclear ribonucleoprotein C

(HNRNPC). A host protein that binds the 5′ and 3′ ends of enterovirus genomes and stabilizes interactions between them.

Acyl-CoA-binding domain-containing 3

(ACBD3). A protein that regulates function and structure of the Golgi complex through its interaction with the integral membrane protein giantin.

Phosphatidylinositol 4-kinase-β

(PI4KB). A Golgi-localized lipid kinase that phosphorylates phosphatidylinositol to yield phosphatidylinositol-4-phosphate.

Oxysterol-binding protein

(OSBP). A protein that exchanges phosphatidylinositol-4-phosphate lipids and cholesterol at membrane contact sites.

Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1

(GBF1). A guanine nucleotide exchange factor for ADP-ribosylation factor (ARF) proteins that plays important roles in intracellular membrane transport and homeostasis.

Autophagy

A cellular catabolic process in which intracellular parts of the cell are engulfed by membranes and targeted for breakdown, which yields energy or building blocks or clears aged or damaged parts of a cell.

Soaking

An approach in crystallography in which a protein is crystallized, followed by addition of a ligand to form a co-crystal, allowing determination of the structure of the complex.

Co-crystallization

An approach in crystallography in which a protein and its ligand are crystallized together, forming a co-crystal that is used to determine the structure of the complex.

Glutathione

A tripeptide composed of glutamate, cysteine and glycine that has an important role in cellular redox reactions and as an antioxidant.

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Baggen, J., Thibaut, H.J., Strating, J.R.P.M. et al. The life cycle of non-polio enteroviruses and how to target it. Nat Rev Microbiol 16, 368–381 (2018). https://doi.org/10.1038/s41579-018-0005-4

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