title: 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.affiliation: Department of Medicine, Faculty of Science, University of Fribourg, 1700 Fribourg, Switzerland; Division of Clinical Pharmacology, Center for Integrated Protein Science Munich, Ludwig-Maximilian-University Munich, 80336 Munich, Germany; and.
authors.forename: Christian
authors.identifier: http://orcid.org/0000-0001-6148-9821
authors.initials: C
authors.lastname: Hotz
authors.affiliation: Division of Clinical Pharmacology, Center for Integrated Protein Science Munich, Ludwig-Maximilian-University Munich, 80336 Munich, Germany; and.
authors.forename: Laurin C
authors.initials: LC
authors.lastname: Roetzer
authors.affiliation: Division of Clinical Pharmacology, Center for Integrated Protein Science Munich, Ludwig-Maximilian-University Munich, 80336 Munich, Germany; and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Huber
authors.affiliation: Division of Clinical Pharmacology, Center for Integrated Protein Science Munich, Ludwig-Maximilian-University Munich, 80336 Munich, Germany; and.
authors.forename: Andreas
authors.initials: A
authors.lastname: Sailer
authors.affiliation: Department of Medicine, Faculty of Science, University of Fribourg, 1700 Fribourg, Switzerland;
authors.forename: Anne
authors.initials: A
authors.lastname: Oberson
authors.affiliation: Department of Medicine, Faculty of Science, University of Fribourg, 1700 Fribourg, Switzerland;
authors.forename: Marina
authors.initials: M
authors.lastname: Treinies
authors.affiliation: Division of Clinical Pharmacology, Center for Integrated Protein Science Munich, Ludwig-Maximilian-University Munich, 80336 Munich, Germany; and III Medical Department, Technical University Munich, 81675 Munich, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Heidegger
authors.affiliation: Department of Medicine, Faculty of Science, University of Fribourg, 1700 Fribourg, Switzerland;
authors.forename: Tina
authors.initials: T
authors.lastname: Herbst
authors.affiliation: Division of Clinical Pharmacology, Center for Integrated Protein Science Munich, Ludwig-Maximilian-University Munich, 80336 Munich, Germany; and.
authors.forename: Stefan
authors.initials: S
authors.lastname: Endres
authors.affiliation: Department of Medicine, Faculty of Science, University of Fribourg, 1700 Fribourg, Switzerland; Division of Clinical Pharmacology, Center for Integrated Protein Science Munich, Ludwig-Maximilian-University Munich, 80336 Munich, Germany; and carole.bourquin@unifr.ch.
authors.forename: Carole
authors.identifier: http://orcid.org/0000-0003-3862-4583
authors.initials: C
authors.lastname: Bourquin
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D015151:Immunoblotting; D016898:Interferon-alpha / Q000276:immunology / Q000378:metabolism; D016899:Interferon-beta / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000821:virology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011070:Poly I-C / Q000276:immunology / Q000494:pharmacology; D051192:Receptors, Pattern Recognition / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029082:Sendai virus / Q000276:immunology / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014777:Virus Diseases / Q000276:immunology*
chemical_list: D016898:Interferon-alpha; D015850:Interleukin-6; D051192:Receptors, Pattern Recognition; D051193:Toll-Like Receptors; D016753:Interleukin-10; D016899:Interferon-beta; C503356:Ddx58 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D011070:Poly I-C