A homeostatic interferon-lambda response to bacterial microbiota stimulates preemptive antiviral defense within discrete pockets of intestinal epithelium
- Oregon Health & Science University, United States
- Washington University School of Medicine, United States
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
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ena-STUDY-WASHINGTON UNIVERSITY SCHOOL OF MEDICINE-04-03-2021-20:01:57:156-1305European Nucleotide Archive, PRJEB43446.
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A single-cell survey of the small intestinal epitheliumNCBI Gene Expression Omnibus, GSE92332.
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Single-cell sequencing of developing human gut reveals transcriptional links to childhood Crohn's diseaseEuropean Nucleotide Archive, PRJEB37689.
Article and author information
Author details
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
- 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
- Preprint posted: June 2, 2021 (view preprint)
- Received: September 21, 2021
- Accepted: February 4, 2022
- Accepted Manuscript published: February 9, 2022 (version 1)
- 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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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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