An Antiviral Branch of the IL-1 Signaling Pathway Restricts Immune-Evasive Virus Replication

Virulent pathogens often cause the release of host-derived damage-associated molecular patterns (DAMPs) from infected cells. During encounters with immune-evasive viruses that block inflammatory gene expression, preformed DAMPs provide backup inflammatory signals that ensure protective immunity. Whe...

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Bibliographic Details
Published in:Molecular cell 2018-09, Vol.71 (5), p.825-840.e6
Main Authors: Orzalli, Megan H., Smith, Avi, Jurado, Kellie A., Iwasaki, Akiko, Garlick, Jonathan A., Kagan, Jonathan C.
Format: Article
Language:English
Subjects:
Animals
antiviral defense
Cell Line
Cercopithecus aethiops
Female
Fibroblasts - immunology
Fibroblasts - virology
Gene Expression - immunology
HEK293 Cells
Human Umbilical Vein Endothelial Cells
Humans
Immune Evasion - immunology
innate immunity
interferon regulatory factors
Interleukin-1 - immunology
IRF1
ISGs
Male
Mice
Mice, Inbred C57BL
Signal Transduction - immunology
Skin - immunology
Skin - virology
Vero Cells
Virus Replication - immunology
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Summary:Virulent pathogens often cause the release of host-derived damage-associated molecular patterns (DAMPs) from infected cells. During encounters with immune-evasive viruses that block inflammatory gene expression, preformed DAMPs provide backup inflammatory signals that ensure protective immunity. Whether DAMPs exhibit additional backup defense activities is unknown. Herein, we report that viral infection of barrier epithelia (keratinocytes) elicits the release of preformed interleukin-1 (IL-1) family cytokines, including the DAMP IL-1α. Mechanistic studies revealed that IL-1 acts on skin fibroblasts to induce an interferon (IFN)-like state that restricts viral replication. We identified a branch in the IL-1 signaling pathway that induces IFN-stimulated gene expression in infected cells and found that IL-1 signaling is necessary to restrict viral replication in human skin explants. These activities are most important to control immune-evasive virus replication in fibroblasts and other barrier cell types. These findings highlight IL-1 as an important backup antiviral system to ensure barrier defense. [Display omitted] •Keratinocytes release IL-1 cytokines in response to PRR-evasive virus infection•IL-1 cytokines induce an antiviral state in human fibroblasts and endothelial cells•This antiviral response is important during encounters with immune-evasive viruses•IL-1 stimulates this antiviral response through an IRF1/gp130/STAT1 signaling axis Keratinocytes are a barrier cell type that contribute to antiviral host defense. Orzalli et al. report that IL-1 cytokines released from infected keratinocytes induce antiviral responses in stromal cells. Mechanistic studies identified a genetic requirement for an IRF1-dependent signaling axis that regulates antiviral gene expression downstream of the IL-1R.
ISSN:1097-2765
1097-4164
DOI:10.1016/j.molcel.2018.07.009