title: Concomitant TLR/RLH signaling of radioresistant and radiosensitive cells is essential for protection against vesicular stomatitis virus infection.
abstract: Several studies indicated that TLR as well as retinoic acid-inducible gene I-like helicase (RLH) signaling contribute to vesicular stomatitis virus (VSV)-mediated triggering of type I IFN (IFN-I) responses. Nevertheless, TLR-deficient MyD88(-/-)Trif(-/-) mice and RLH-deficient caspase activation and recruitment domain adaptor inducing IFN-β (Cardif)(-/-) mice showed only marginally enhanced susceptibility to lethal VSV i.v. infection. Therefore, we addressed whether concomitant TLR and RLH signaling, or some other additional mechanism, played a role. To this end, we generated MyD88(-/-)Trif(-/-)Cardif(-/-) (MyTrCa(-/-)) mice that succumbed to low-dose i.v. VSV infection with similar kinetics as IFN-I receptor-deficient mice. Three independent approaches (i.e., analysis of IFN-α/β serum levels, experiments with IFN-β reporter mice, and investigation of local IFN-stimulated gene induction) revealed that MyTrCa(-/-) mice did not mount IFN-I responses following VSV infection. Of note, treatment with rIFN-α protected the animals, qualifying MyTrCa(-/-) mice as a model to study the contribution of different immune cell subsets to the production of antiviral IFN-I. Upon adoptive transfer of wild-type plasmacytoid dendritic cells and subsequent VSV infection, MyTrCa(-/-) mice displayed significantly reduced viral loads in peripheral organs and showed prolonged survival. On the contrary, adoptive transfer of wild-type myeloid dendritic cells did not have such effects. Analysis of bone marrow chimeric mice revealed that TLR and RLH signaling of radioresistant and radiosensitive cells was required for efficient protection. Thus, upon VSV infection, plasmacytoid dendritic cell-derived IFN-I primarily protects peripheral organs, whereas concomitant TLR and RLH signaling of radioresistant stroma cells as well as of radiosensitive immune cells is needed to effectively protect against lethal disease.
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research, Braunschweig, and the Hannover Medical School, 30625 Hannover, Germany;
authors.forename: Julia
authors.initials: J
authors.lastname: Spanier
authors.affiliation: Department of Molecular Immunology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany;
authors.forename: Stefan
authors.initials: S
authors.lastname: Lienenklaus
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research, Braunschweig, and the Hannover Medical School, 30625 Hannover, Germany;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Paijo
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research, Braunschweig, and the Hannover Medical School, 30625 Hannover, Germany;
authors.forename: Annett
authors.initials: A
authors.lastname: Kessler
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research, Braunschweig, and the Hannover Medical School, 30625 Hannover, Germany;
authors.forename: Katharina
authors.initials: K
authors.lastname: Borst
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research, Braunschweig, and the Hannover Medical School, 30625 Hannover, Germany;
authors.forename: Sabrina
authors.initials: S
authors.lastname: Heindorf
authors.affiliation: Biogen Idec, Cambridge, MA 02142;
authors.forename: Darren P
authors.initials: DP
authors.lastname: Baker
authors.affiliation: Research Group on Innate Immunity and Infection, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany; and.
authors.forename: Andrea
authors.initials: A
authors.lastname: Kröger
authors.affiliation: Department of Molecular Immunology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany;
authors.forename: Siegfried
authors.initials: S
authors.lastname: Weiss
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research, Braunschweig, and the Hannover Medical School, 30625 Hannover, Germany;
authors.forename: Claudia N
authors.initials: CN
authors.lastname: Detje
authors.affiliation: Department of Virology, Institute for Medical Microbiology and Hygiene, Albert-Ludwigs-Universität, 79104 Freiburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Staeheli
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research, Braunschweig, and the Hannover Medical School, 30625 Hannover, Germany; ulrich.kalinke@twincore.de.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalinke
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 / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation; D016219:Immunotherapy, Adoptive; D016898:Interferon-alpha / Q000097:blood / Q000235:genetics / Q000276:immunology; D016899:Interferon-beta / Q000097:blood / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology / Q000637:transplantation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics; D011836:Radiation Tolerance; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D017154:Stromal Cells / Q000276:immunology / Q000528:radiation effects; D051193:Toll-Like Receptors / Q000235:genetics*; D054243:Vesicular Stomatitis / Q000276:immunology* / Q000821:virology; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D016898:Interferon-alpha; D016899:Interferon-beta; D053594:Myeloid Differentiation Factor 88; D053633:Receptor, Interferon alpha-beta; D051193:Toll-Like Receptors; C512612:MAVS protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C503356:Ddx58 protein, mouse