1. Immunology and Inflammation
  2. Microbiology and Infectious Disease

A homeostatic interferon-lambda response to bacterial microbiota stimulates preemptive antiviral defense within discrete pockets of intestinal epithelium

  1. Jacob A Van Winkle
  2. Stefan T Peterson
  3. Elizabeth A Kennedy
  4. Michael J Wheadon
  5. Harshad Ingle
  6. Chandni Desai
  7. Rachel Rodgers
  8. David A Constant
  9. Austin P Wright
  10. Lena Li
  11. Maxim N Artyomov
  12. Sanghyun Lee
  13. Megan T Baldridge  Is a corresponding author
  14. Timothy J Nice  Is a corresponding author
  1. Oregon Health & Science University, United States
  2. Washington University School of Medicine, United States
https://doi.org/10.7554/eLife.74072
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  1. Jacob A Van Winkle
  2. Stefan T Peterson
  3. Elizabeth A Kennedy
  4. Michael J Wheadon
  5. Harshad Ingle
  6. Chandni Desai
  7. Rachel Rodgers
  8. David A Constant
  9. Austin P Wright
  10. Lena Li
  11. Maxim N Artyomov
  12. Sanghyun Lee
  13. Megan T Baldridge
  14. Timothy J Nice
(2022)
A homeostatic interferon-lambda response to bacterial microbiota stimulates preemptive antiviral defense within discrete pockets of intestinal epithelium
eLife 11:e74072.
https://doi.org/10.7554/eLife.74072
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  3. Download .RIS

Abstract

Interferon-lambda (IFN-λ) protects intestinal epithelial cells (IECs) from enteric viruses by inducing expression of antiviral IFN-stimulated genes (ISGs). Here, we find that bacterial microbiota stimulate a homeostatic ISG signature in the intestine of specific pathogen-free mice. This homeostatic ISG expression is restricted to IECs, depends on IEC-intrinsic expression of IFN-λ receptor (Ifnlr1), and is associated with IFN-λ production by leukocytes. Strikingly, imaging of these homeostatic ISGs reveals localization to pockets of the epithelium and concentration in mature IECs. Correspondingly, a minority of mature IECs express these ISGs in public single-cell RNA sequencing datasets from mice and humans. Furthermore, we assessed the ability of orally-administered bacterial components to restore localized ISGs in mice lacking bacterial microbiota. Lastly, we find that IECs lacking Ifnlr1 are hyper-susceptible to initiation of murine rotavirus infection. These observations indicate that bacterial microbiota stimulate ISGs in localized regions of the intestinal epithelium at homeostasis, thereby preemptively activating antiviral defenses in vulnerable IECs to improve host defense against enteric viruses.

Data availability

RNA-seq data were uploaded to the European Nucleotide Archive under accession #PRJEB43446.Source data files are provided for each figure and contain the numerical data used to generate the figures

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Jacob A Van Winkle

    Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Stefan T Peterson

    Department of Medicine, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2984-6400

  3. Elizabeth A Kennedy

    Department of Medicine, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Michael J Wheadon

    Department of Medicine, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2579-3786

  5. Harshad Ingle

    Department of Medicine, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Chandni Desai

    Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Rachel Rodgers

    Department of Medicine, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. David A Constant

    Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.

  9. Austin P Wright

    Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1447-5205

  10. Lena Li

    Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, United States
    Competing interests
    The authors declare that no competing interests exist.

  11. Maxim N Artyomov

    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.

  12. Sanghyun Lee

    Department of Medicine, Washington University School of Medicine, St. Louis, United States
    Competing interests
    The authors declare that no competing interests exist.

  13. Megan T Baldridge

    Department of Medicine, Washington University School of Medicine, St Louis, United States
    For correspondence
    mbaldridge@wustl.edu
    Competing interests
    The authors declare that no competing interests exist.

  14. Timothy J Nice

    Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, United States
    For correspondence
    nice@ohsu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4471-7666

Funding

National Institutes of Health (R01-AI130055)

  • Timothy J Nice

National Institutes of Health (T32-GM071338)

  • Jacob A Van Winkle

National Institutes of Health (T32-AI007472)

  • Jacob A Van Winkle

National Institutes of Health (R01-AI139314)

  • Megan T Baldridge

National Institutes of Health (R01-AI141716)

  • Megan T Baldridge

National Institutes of Health (R01-AI141478)

  • Megan T Baldridge

Pew Charitable Trusts

  • Megan T Baldridge

Washington University School of Medicine in St. Louis (MI-II-2019-790)

  • Megan T Baldridge

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Andrew J MacPherson, University of Bern, Switzerland

Ethics

Animal experimentation: All mice were maintained in specific-pathogen-free facilities at Oregon Health & Science University (OHSU) and Washington University in St. Louis (WUSTL). Animal protocols were approved by the Institutional Animal Care and Use Committee at OHSU (protocol #IP00000228) and WUSTL (protocol #20190162) in accordance with standards provided in the Animal Welfare Act.

Version history

  1. Preprint posted: June 2, 2021 (view preprint)
  2. Received: September 21, 2021
  3. Accepted: February 4, 2022
  4. Accepted Manuscript published: February 9, 2022 (version 1)
  5. Version of Record published: February 17, 2022 (version 2)

Copyright

© 2022, Van Winkle et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Jacob A Van Winkle
  2. Stefan T Peterson
  3. Elizabeth A Kennedy
  4. Michael J Wheadon
  5. Harshad Ingle
  6. Chandni Desai
  7. Rachel Rodgers
  8. David A Constant
  9. Austin P Wright
  10. Lena Li
  11. Maxim N Artyomov
  12. Sanghyun Lee
  13. Megan T Baldridge
  14. Timothy J Nice
(2022)
A homeostatic interferon-lambda response to bacterial microbiota stimulates preemptive antiviral defense within discrete pockets of intestinal epithelium
eLife 11:e74072.
https://doi.org/10.7554/eLife.74072

Share this article

https://doi.org/10.7554/eLife.74072

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