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.

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

  • 3,852
    views
  • 329
    downloads
  • 19
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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

Share this article

https://doi.org/10.7554/eLife.02910

Further reading

    1. Immunology and Inflammation
    Arijit Chakraborty, Arunava Bandyopadhaya ... Laurence G Rahme
    Research Article

    How bacterial pathogens exploit host metabolism to promote immune tolerance and persist in infected hosts remains elusive. To achieve this, we show that Pseudomonas aeruginosa (PA), a recalcitrant pathogen, utilizes the quorum sensing (QS) signal 2’-aminoacetophenone (2-AA). Here, we unveil how 2-AA-driven immune tolerization causes distinct metabolic perturbations in murine macrophages’ mitochondrial respiration and bioenergetics. We present evidence indicating that these effects stem from decreased pyruvate transport into mitochondria. This reduction is attributed to decreased expression of the mitochondrial pyruvate carrier (Mpc1), which is mediated by diminished expression and nuclear presence of its transcriptional regulator, estrogen-related nuclear receptor alpha (Esrra). Consequently, Esrra exhibits weakened binding to the Mpc1 promoter. This outcome arises from the impaired interaction between Esrra and the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Ppargc1a). Ultimately, this cascade results in diminished pyruvate influx into mitochondria and, consequently reduced ATP production in tolerized murine and human macrophages. Exogenously added ATP in infected macrophages restores the transcript levels of Mpc1 and Esrra and enhances cytokine production and intracellular bacterial clearance. Consistent with the in vitro findings, murine infection studies corroborate the 2-AA-mediated long-lasting decrease in ATP and acetyl-CoA and its association with PA persistence, further supporting this QS signaling molecule as the culprit of the host bioenergetic alterations and PA persistence. These findings unveil 2-AA as a modulator of cellular immunometabolism and reveal an unprecedented mechanism of host tolerance to infection involving the Ppargc1a/Esrra axis in its influence on Mpc1/OXPHOS-dependent energy production and PA clearance. These paradigmatic findings pave the way for developing treatments to bolster host resilience to pathogen-induced damage. Given that QS is a common characteristic of prokaryotes, it is likely that 2-AA-like molecules with similar functions may be present in other pathogens.

    1. Immunology and Inflammation
    Alessandra Machado Araujo, Joseph D Dekker ... Haley O Tucker
    Research Article

    We identified a novel mouse plasmacytoid dendritic cell (pDC) lineage derived from the common lymphoid progenitors (CLPs) that is dependent on expression of Bcl11a. These CLP-derived pDCs, which we refer to as ‘B-pDCs’, have a unique gene expression profile that includes hallmark B cell genes, normally not expressed in conventional pDCs. Despite expressing most classical pDC markers such as SIGLEC-H and PDCA1, B-pDCs lack IFN-α secretion, exhibiting a distinct inflammatory profile. Functionally, B-pDCs induce T cell proliferation more robustly than canonical pDCs following Toll-like receptor 9 (TLR9) engagement. B-pDCs, along with another homogeneous subpopulation of myeloid-derived pDCs, display elevated levels of the cell surface receptor tyrosine kinase AXL, mirroring human AXL+ transitional DCs in function and transcriptional profile. Murine B-pDCs therefore represent a phenotypically and functionally distinct CLP-derived DC lineage specialized in T cell activation and previously not described in mice.