title: Thogoto virus infection induces sustained type I interferon responses that depend on RIG-I-like helicase signaling of conventional dendritic cells.
abstract: Type I interferon (IFN-α/β) induction upon viral infection contributes to the early antiviral host defense and ensures survival until the onset of adaptive immunity. Many viral infections lead to an acute, transient IFN expression which peaks a few hours after infection and reverts to initial levels after 24 to 36 h. Robust IFN expression often is conferred by specialized plasmacytoid dendritic cells (pDC) and may depend on positive-feedback amplification via the type I IFN receptor (IFNAR). Here, we show that mice infected with Thogoto virus (THOV), which is an influenza virus-like orthomyxovirus transmitted by ticks, mounted sustained IFN responses that persisted up to 72 h after infection. For this purpose, we used a variant of THOV lacking its IFN-antagonistic protein ML, an elongated version of the matrix (M) protein [THOV(ΔML)]. Of note, large amounts of type I IFN were also found in the serum of mice lacking the IFNAR. Early IFN-α expression seemed to depend on Toll-like receptor (TLR) signaling, whereas prolonged IFN-α responses strictly depended on RIG-I-like helicase (RLH) signaling. Unexpectedly, THOV(ΔML)-infected bone marrow-derived pDC (BM-pDC) produced only moderate IFN levels, whereas myeloid DC (BM-mDC) showed massive IFN induction that was IPS-1-dependent, suggesting that BM-mDC are involved in the massive, sustained IFN production in THOV(ΔML)-infected animals. Thus, our data are compatible with the model that THOV(ΔML) infection is sensed in the acute phase via TLR and RLH systems, whereas at later time points only RLH signaling is responsible for the induction of sustained IFN responses.
authors.affiliation: Abteilung Virologie, Institut für Medizinische Mikrobiologie und Hygiene, Universität Freiburg, Freiburg, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Kochs
authors.forename: Stefanie
authors.initials: S
authors.lastname: Bauer
authors.forename: Carola
authors.initials: C
authors.lastname: Vogt
authors.forename: Theresa
authors.initials: T
authors.lastname: Frenz
authors.forename: Jürg
authors.initials: J
authors.lastname: Tschopp
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalinke
authors.forename: Zoe
authors.initials: Z
authors.lastname: Waibler
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics; D000818:Animals; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018448:Models, Immunological; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D018117:Thogotovirus / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D007370:Interferon Type I; D053594:Myeloid Differentiation Factor 88; C512612:MAVS protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C503356:Ddx58 protein, mouse