TLR and RLR Signaling Are Reprogrammed in Opposite Directions after Detection of Viral Infection.

Abstract

Innate immune recognition of RNA is key for the initiation of immunity in response to viral infection. Although the factors controlling the detection of viral RNA by innate immune receptors in host cells are increasingly well understood, little is known about the dynamic changes in signaling after the initial triggering of these receptors. In this study, we report that preconditioning with the synthetic dsRNA polyinosinic-polycytidylic acid [poly(I:C)], a mimetic of viral RNA, rapidly reprograms murine APCs by simultaneously augmenting sensitivity of endosomal TLRs and inhibiting activation of RIG-I-like receptors (RLRs) in an IFN-β-dependent manner. These changes in receptor sensitivity were also seen in vivo after treatment of mice with poly(I:C). Mechanistically, the increased sensitivity of the TLR pathway was associated with elevated MAPK and NF-κB activity. The RLR response was inhibited downstream of TANK-binding kinase-1, resulting in decreased IFN regulatory factor 3 phosphorylation. Reprogramming of pattern-recognition receptor signaling also occurred after viral infection, because infection of host cells with Sendai virus or their exposure to supernatant from virus-infected cells induced the same changes in TLR and RLR sensitivity as poly(I:C). Thus, innate recognition of viral infection critically modifies responses to pattern-recognition receptor stimulation. These dynamic adaptations to infection may reinforce antiviral immunity and at the same time serve to limit pathological inflammation.

• Authors: Christian Hotz, Laurin C Roetzer, Thomas Huber, Andreas Sailer, Anne Oberson, Marina Treinies, Simon Heidegger, Tina Herbst, Stefan Endres, Carole Bourquin
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 195 Issue 9 Pg. 4387-95 (Nov 01 2015) ISSN: 1550-6606 [Electronic] United States
• PMID: 26392465 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by The American Association of Immunologists, Inc.

Chemical References

• Interferon-alpha
• Interleukin-6
• Receptors, Pattern Recognition
• Toll-Like Receptors
• Interleukin-10
• Interferon-beta
• Ddx58 protein, mouse
• DEAD Box Protein 58
• DEAD-box RNA Helicases
• Poly I-C

Topics

• Animals
• Cell Line
• Cell Line, Tumor
• DEAD Box Protein 58
• DEAD-box RNA Helicases (genetics, immunology, metabolism)
• Gene Expression (drug effects, immunology)
• Immunoblotting
• Interferon-alpha (immunology, metabolism)
• Interferon-beta (immunology, metabolism)
• Interleukin-10 (immunology, metabolism)
• Interleukin-6 (immunology, metabolism)
• Macrophages (drug effects, immunology, virology)
• Mice, 129 Strain
• Mice, Inbred C57BL
• Mice, Knockout
• Poly I-C (immunology, pharmacology)
• Receptors, Pattern Recognition (immunology)
• Reverse Transcriptase Polymerase Chain Reaction
• Sendai virus (immunology, physiology)
• Signal Transduction (drug effects, immunology)
• Toll-Like Receptors (genetics, immunology, metabolism)
• Virus Diseases (immunology)