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 H 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 H Connor

    Boston University, Boston, 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.

Metrics

  • 3,740
    Page views
  • 302
    Downloads
  • 9
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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 H 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

Further reading

    1. Cell Biology
    2. Immunology and Inflammation
    Ana J Caetano, Yushi Redhead ... Paul T Sharpe
    Research Article Updated

    The interplay among different cells in a tissue is essential for maintaining homeostasis. Although disease states have been traditionally attributed to individual cell types, increasing evidence and new therapeutic options have demonstrated the primary role of multicellular functions to understand health and disease, opening new avenues to understand pathogenesis and develop new treatment strategies. We recently described the cellular composition and dynamics of the human oral mucosa; however, the spatial arrangement of cells is needed to better understand a morphologically complex tissue. Here, we link single-cell RNA sequencing, spatial transcriptomics, and high-resolution multiplex fluorescence in situ hybridisation to characterise human oral mucosa in health and oral chronic inflammatory disease. We deconvolved expression for resolution enhancement of spatial transcriptomic data and defined highly specialised epithelial and stromal compartments describing location-specific immune programs. Furthermore, we spatially mapped a rare pathogenic fibroblast population localised in a highly immunogenic region, responsible for lymphocyte recruitment through CXCL8 and CXCL10 and with a possible role in pathological angiogenesis through ALOX5AP. Collectively, our study provides a comprehensive reference for the study of oral chronic disease pathogenesis.

    1. Immunology and Inflammation
    Jiro Sakai, Jiyeon Yang ... Mustafa Akkoyunlu
    Research Article

    Newborns are unable to reach the adult-level humoral immune response partly due to the potent immunoregulatory role of IL-10. Increased IL-10 production by neonatal B cells has been attributed to the larger population of IL-10-producting CD43+ B-1 cells in neonates. Here, we show that neonatal mouse CD43- non-B-1 cells also produce substantial amounts of IL-10 following B cell antigen receptor (BCR) activation. In neonatal mouse CD43- non-B-1 cells, BCR engagement activated STAT5 under the control of phosphorylated forms of signaling molecules Syk, Btk, PKC, FAK and Rac1. Neonatal STAT5 activation led to IL-6 production, which in turn was responsible for IL-10 production in an autocrine/paracrine fashion through the activation of STAT3. In addition to the increased IL-6 production in response to BCR stimulation, elevated expression of IL-6Rα expression in neonatal B cells rendered them highly susceptible to IL-6 mediated STAT3 phosphorylation and IL-10 production. Finally, IL-10 secreted from neonatal mouse CD43- non-B-1 cells was sufficient to inhibit TNF-α secretion by macrophages. Our results unveil a distinct mechanism of IL-6-dependent IL-10 production in BCR-stimulated neonatal CD19+CD43- B cells.