A single vertebrate DNA virus protein disarms invertebrate immunity to RNA virus infection

  1. Don B Gammon
  2. Sophie Duraffour
  3. Daniel K Rozelle
  4. Heidi Hehnly
  5. Rita Sharma
  6. Michael E Sparks
  7. Cara C West
  8. Ying Chen
  9. James J Moresco
  10. Graciela Andrei
  11. John C Connor
  12. Darryl Conte
  13. Dawn E Gundersen-Rindal
  14. William L Marshall
  15. John Yates
  16. Neal Silverman
  17. Craig C Mello  Is a corresponding author
  1. University of Massachusetts Medical School, United States
  2. KU Leuven, Belgium
  3. Boston University, United States
  4. Walter Reed Army Institute of Research, United States
  5. The Scripps Research Institute, United States
  6. United States Department of Agriculture, United States
  7. Merck, United States

Abstract

Virus-host interactions drive a remarkable diversity of immune responses and countermeasures. We found that two RNA viruses with broad host ranges, vesicular stomatitis virus (VSV) and Sindbis virus (SINV), are completely restricted in their replication after entry into Lepidopteran cells. This restriction is overcome when cells are co-infected with vaccinia virus (VACV), a vertebrate DNA virus. Using RNAi screening, we show that Lepidopteran RNAi, Nuclear Factor-κB, and ubiquitin-proteasome pathways restrict RNA virus infection. Surprisingly, a highly-conserved, uncharacterized VACV protein, A51R, can partially overcome this virus restriction. We show that A51R is also critical for VACV replication in vertebrate cells and for pathogenesis in mice. Interestingly, A51R colocalizes with, and stabilizes, host microtubules and also associates with ubiquitin. We show that A51R promotes viral protein stability, possibly by preventing ubiquitin-dependent targeting of viral proteins for destruction. Importantly, our studies reveal exciting new opportunities to study virus-host interactions in experimentally-tractable Lepidopteran systems.

Article and author information

Author details

  1. Don B Gammon

    University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Sophie Duraffour

    KU Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  3. Daniel K Rozelle

    Boston University, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Heidi Hehnly

    University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Rita Sharma

    University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Michael E Sparks

    Walter Reed Army Institute of Research, Silver Spring, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Cara C West

    University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Ying Chen

    University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. James J Moresco

    The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Graciela Andrei

    KU Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
  11. John C Connor

    Boston University, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Darryl Conte

    University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Dawn E Gundersen-Rindal

    United States Department of Agriculture, Beltsville, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. William L Marshall

    Merck, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. John Yates

    The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Neal Silverman

    University of Massachusetts Medical School, Worcester, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Craig C Mello

    University of Massachusetts Medical School, Worcester, United States
    For correspondence
    craig.mello@umassmed.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All animal work was approved by the Katholieke Universiteit Leuven Ethics Committee for Animal Care and Use (Permit number: P044-2010) and all animal guidelines and policies were in accordance with the Belgian Royal Decree of 14 November 1993 and the European Directive 86-609-EEC.When necessary, animals were euthanized by administering pentobarbital sodium.

Reviewing Editor

  1. Ruslan Medzhitov, Yale University School of Medicine, United States

Publication history

  1. Received: March 26, 2014
  2. Accepted: June 25, 2014
  3. Accepted Manuscript published: June 25, 2014 (version 1)
  4. Accepted Manuscript updated: June 26, 2014 (version 2)
  5. Version of Record published: July 29, 2014 (version 3)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Don B Gammon
  2. Sophie Duraffour
  3. Daniel K Rozelle
  4. Heidi Hehnly
  5. Rita Sharma
  6. Michael E Sparks
  7. Cara C West
  8. Ying Chen
  9. James J Moresco
  10. Graciela Andrei
  11. John C Connor
  12. Darryl Conte
  13. Dawn E Gundersen-Rindal
  14. William L Marshall
  15. John Yates
  16. Neal Silverman
  17. Craig C Mello
(2014)
A single vertebrate DNA virus protein disarms invertebrate immunity to RNA virus infection
eLife 3:e02910.
https://doi.org/10.7554/eLife.02910

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