Homeostatic interferon-lambda response to bacterial microbiota stimulates preemptive antiviral defense within discrete pockets of intestinal epithelium
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...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-02-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/74072 |
| _version_ | 1811252881902272512 |
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| author | Jacob A Van Winkle Stefan T Peterson Elizabeth A Kennedy Michael J Wheadon Harshad Ingle Chandni Desai Rachel Rodgers David A Constant Austin P Wright Lena Li Maxim N Artyomov Sanghyun Lee Megan T Baldridge Timothy J Nice |
| author_facet | Jacob A Van Winkle Stefan T Peterson Elizabeth A Kennedy Michael J Wheadon Harshad Ingle Chandni Desai Rachel Rodgers David A Constant Austin P Wright Lena Li Maxim N Artyomov Sanghyun Lee Megan T Baldridge Timothy J Nice |
| author_sort | Jacob A Van Winkle |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T16:41:19Z |
| format | Article |
| id | doaj.art-49f905267f26475caccf534d5cf8c0dd |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:41:19Z |
| publishDate | 2022-02-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-49f905267f26475caccf534d5cf8c0dd2022-12-22T03:24:46ZengeLife Sciences Publications LtdeLife2050-084X2022-02-011110.7554/eLife.74072Homeostatic interferon-lambda response to bacterial microbiota stimulates preemptive antiviral defense within discrete pockets of intestinal epitheliumJacob A Van Winkle0Stefan T Peterson1https://orcid.org/0000-0002-2984-6400Elizabeth A Kennedy2Michael J Wheadon3https://orcid.org/0000-0002-2579-3786Harshad Ingle4Chandni Desai5Rachel Rodgers6David A Constant7Austin P Wright8https://orcid.org/0000-0002-1447-5205Lena Li9Maxim N Artyomov10Sanghyun Lee11Megan T Baldridge12https://orcid.org/0000-0002-7030-6131Timothy J Nice13https://orcid.org/0000-0002-4471-7666Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, United StatesDepartment of Medicine, Washington University School of Medicine, St. Louis, United StatesDepartment of Medicine, Washington University School of Medicine, St. Louis, United StatesDepartment of Medicine, Washington University School of Medicine, St. Louis, United StatesDepartment of Medicine, Washington University School of Medicine, St. Louis, United StatesDepartment of Pathology and Immunology, Washington University School of Medicine, St. Louis, United StatesDepartment of Medicine, Washington University School of Medicine, St. Louis, United StatesDepartment of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, United StatesDepartment of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, United StatesDepartment of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, United StatesDepartment of Pathology and Immunology, Washington University School of Medicine, St Louis, United StatesDepartment of Medicine, Washington University School of Medicine, St. Louis, United StatesDepartment of Medicine, Washington University School of Medicine, St Louis, United StatesDepartment of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, United StatesInterferon-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.https://elifesciences.org/articles/74072interferonmicrobiotarotavirusintestineepitheliuminnate immunity |
| spellingShingle | Jacob A Van Winkle Stefan T Peterson Elizabeth A Kennedy Michael J Wheadon Harshad Ingle Chandni Desai Rachel Rodgers David A Constant Austin P Wright Lena Li Maxim N Artyomov Sanghyun Lee Megan T Baldridge Timothy J Nice Homeostatic interferon-lambda response to bacterial microbiota stimulates preemptive antiviral defense within discrete pockets of intestinal epithelium eLife interferon microbiota rotavirus intestine epithelium innate immunity |
| title | Homeostatic interferon-lambda response to bacterial microbiota stimulates preemptive antiviral defense within discrete pockets of intestinal epithelium |
| title_full | Homeostatic interferon-lambda response to bacterial microbiota stimulates preemptive antiviral defense within discrete pockets of intestinal epithelium |
| title_fullStr | Homeostatic interferon-lambda response to bacterial microbiota stimulates preemptive antiviral defense within discrete pockets of intestinal epithelium |
| title_full_unstemmed | Homeostatic interferon-lambda response to bacterial microbiota stimulates preemptive antiviral defense within discrete pockets of intestinal epithelium |
| title_short | Homeostatic interferon-lambda response to bacterial microbiota stimulates preemptive antiviral defense within discrete pockets of intestinal epithelium |
| title_sort | homeostatic interferon lambda response to bacterial microbiota stimulates preemptive antiviral defense within discrete pockets of intestinal epithelium |
| topic | interferon microbiota rotavirus intestine epithelium innate immunity |
| url | https://elifesciences.org/articles/74072 |
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