The V Protein of Canine Distemper Virus Is Required for Virus Replication in Human Epithelial Cells

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Abstract

Canine distemper virus (CDV) becomes able to use human receptors through a single amino acid substitution in the H protein. In addition, CDV strains possessing an intact C protein replicate well in human epithelial H358 cells. The present study showed that CDV strain 007Lm, which was isolated from lymph node tissue of a dog with distemper, failed to replicate in H358 cells, although it possessed an intact C protein. Sequence analyses suggested that a cysteine-to-tyrosine substitution at position 267 of the V protein caused this growth defect. Analyses using H358 cells constitutively expressing the CDV V protein showed that the V protein with a cysteine, but not that with a tyrosine, at this position effectively blocked the interferon-stimulated signal transduction pathway, and supported virus replication of 007Lm in H358 cells. Thus, the V protein as well as the C protein appears to be functional and essential for CDV replication in human epithelial cells.

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Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures.

Richard E. Randall, Stephen Goodbourn (2008)

The interferon (IFN) system is an extremely powerful antiviral response that is capable of controlling most, if not all, virus infections in the absence of adaptive immunity. However, viruses can still replicate and cause disease in vivo, because they have some strategy for at least partially circumventing the IFN response. We reviewed this topic in 2000 [Goodbourn, S., Didcock, L. & Randall, R. E. (2000). J Gen Virol 81, 2341-2364] but, since then, a great deal has been discovered about the molecular mechanisms of the IFN response and how different viruses circumvent it. This information is of fundamental interest, but may also have practical application in the design and manufacture of attenuated virus vaccines and the development of novel antiviral drugs. In the first part of this review, we describe how viruses activate the IFN system, how IFNs induce transcription of their target genes and the mechanism of action of IFN-induced proteins with antiviral action. In the second part, we describe how viruses circumvent the IFN response. Here, we reflect upon possible consequences for both the virus and host of the different strategies that viruses have evolved and discuss whether certain viruses have exploited the IFN response to modulate their life cycle (e.g. to establish and maintain persistent/latent infections), whether perturbation of the IFN response by persistent infections can lead to chronic disease, and the importance of the IFN system as a species barrier to virus infections. Lastly, we briefly describe applied aspects that arise from an increase in our knowledge in this area, including vaccine design and manufacture, the development of novel antiviral drugs and the use of IFN-sensitive oncolytic viruses in the treatment of cancer.

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The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-beta promoter.

J. Andrejeva, K S Childs, D. Young … (2004)

Most paramyxoviruses circumvent the IFN response by blocking IFN signaling and limiting the production of IFN by virus-infected cells. Here we report that the highly conserved cysteine-rich C-terminal domain of the V proteins of a wide variety of paramyxoviruses binds melanoma differentiation-associated gene 5 (mda-5) product. mda-5 is an IFN-inducible host cell DExD/H box helicase that contains a caspase recruitment domain at its N terminus. Overexpression of mda-5 stimulated the basal activity of the IFN-beta promoter in reporter gene assays and significantly enhanced the activation of the IFN-beta promoter by intracellular dsRNA. Both these activities were repressed by coexpression of the V proteins of simian virus 5, human parainfluenza virus 2, mumps virus, Sendai virus, and Hendra virus. Similar results to the reporter assays were obtained by measuring IFN production. Inhibition of mda-5 by RNA interference or by dominant interfering forms of mda-5 significantly inhibited the activation of the IFN-beta promoter by dsRNA. It thus appears that mda-5 plays a central role in an intracellular signal transduction pathway that can lead to the activation of the IFN-beta promoter, and that the V proteins of paramyxoviruses interact with mda-5 to block its activity.

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Adherens junction protein nectin-4 (PVRL4) is the epithelial receptor for measles virus

Michael D. Mühlebach, Mathieu Mateo, Patrick Sinn … (2011)

Measles (MV) is an aerosol-transmitted virus that affects more than 10 million children each year and accounts for approximately 120,000 deaths 1,2 . While it was long believed to replicate in the respiratory epithelium before disseminating, it was recently shown to initially infect macrophages and dendritic cells of the airways using the signaling lymphocytic activation molecule (SLAM, CD150) as receptor 3-6 . These cells then cross the respiratory epithelium and ferry the infection to lymphatic organs where MV replicates vigorously 7 . How and where the virus crosses back into the airways has remained unknown. Based on functional analyses of surface proteins preferentially expressed on virus-permissive epithelial cell lines, we identified nectin-4 8 (poliovirus-receptor-like-4) as a candidate host exit receptor. This adherens junction protein of the immunoglobulin superfamily interacts with the viral attachment protein with high affinity through its membrane-distal domain. Nectin-4 sustains MV entry and non-cytopathic lateral spread in well-differentiated primary human airway epithelial sheets infected basolaterally. It is down-regulated in infected epithelial cells, including those of macaque tracheas. While other viruses use receptors to enter hosts or transit through their epithelial barriers, we suggest that MV targets nectin-4 to emerge in the airways. Nectin-4 is a cellular marker of several types of cancer 9-11 , which has implications for ongoing MV-based clinical trials of oncolysis 12 .

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Author and article information

Contributors

Kevin Harrod: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2013

Publication date (Electronic): 17 December 2013

Volume: 8

Issue: 12

Electronic Location Identifier: e82343

Affiliations

[1 ]Department of Virology 3, National Institute of Infectious Diseases, Musashimurayama, Tokyo, Japan

[2 ]Laboratory of Bacterial Genomics, Pathogen Genomics Center, National Institute of Infectious Diseases, Shinjyuku, Tokyo, Japan

[3 ]Department of Veterinary Pathology, Faculty of Agriculture, University of Miyazaki, Miyazaki, Miyazaki, Japan

Lovelace Respiratory Research Institute, United States of America

Author notes

* E-mail: otsuki@ 123456nih.go.jp

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: NO MT. Performed the experiments: NO YN TK TS. Analyzed the data: MK NO YN TK TS. Contributed reagents/materials/analysis tools: FS KS RY. Wrote the paper: MT NO.

Article

Publisher ID: PONE-D-13-28109

DOI: 10.1371/journal.pone.0082343

PMC ID: 3866114

PubMed ID: 24358174

SO-VID: 34d7424f-9b5a-4a87-9bfc-fc9bf2673944

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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 9 July 2013

Date accepted : 30 October 2013

Page count

Pages: 8

Funding

This work was supported, in part, by grants from the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labour and Welfare of Japan, and a grant from The Takeda Science Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The V Protein of Canine Distemper Virus Is Required for Virus Replication in Human Epithelial Cells

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Abstract

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Most cited references 47

Interferons and viruses: an interplay between induction, signalling, antiviral responses and virus countermeasures.

The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-beta promoter.

Adherens junction protein nectin-4 (PVRL4) is the epithelial receptor for measles virus

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