title: Inflammatory monocytes require type I interferon receptor signaling to activate NK cells via IL-18 during a mucosal viral infection.
abstract: The requirement of type I interferon (IFN) for natural killer (NK) cell activation in response to viral infection is known, but the underlying mechanism remains unclear. Here, we demonstrate that type I IFN signaling in inflammatory monocytes, but not in dendritic cells (DCs) or NK cells, is essential for NK cell function in response to a mucosal herpes simplex virus type 2 (HSV-2) infection. Mice deficient in type I IFN signaling,Ifnar-/-andIrf9-/-mice, had significantly lower levels of inflammatory monocytes, were deficient in IL-18 production, and lacked NK cell-derived IFN-γ. Depletion of inflammatory monocytes, but not DCs or other myeloid cells, resulted in lower levels of IL-18 and a complete abrogation of NK cell function in HSV-2 infection. Moreover, this resulted in higher susceptibility to HSV-2 infection. AlthoughIl18-/-mice had normal levels of inflammatory monocytes, their NK cells were unresponsive to HSV-2 challenge. This study highlights the importance of type I IFN signaling in inflammatory monocytes and the induction of the early innate antiviral response.
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Lee
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
authors.forename: Branson
authors.identifier: 0000-0002-4224-0753
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
authors.forename: Marianne V
authors.initials: MV
authors.lastname: Chew
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
authors.forename: Nicole G
authors.identifier: 0000-0002-2605-0845
authors.initials: NG
authors.lastname: Barra
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
authors.forename: Mira M
authors.initials: MM
authors.lastname: Shenouda
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
authors.forename: Tina
authors.initials: T
authors.lastname: Nham
authors.affiliation: Department of Molecular Cell Biology, Vrije University Medical Center, 1081 HV Amsterdam, Netherlands.
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
authors.forename: Manel
authors.identifier: 0000-0002-5861-5994
authors.initials: M
authors.lastname: Jordana
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Mossman
authors.affiliation: Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Robert D
authors.identifier: 0000-0001-6311-0432
authors.initials: RD
authors.lastname: Schreiber
authors.affiliation: RCI Regensburg Center for Interventional Immunology, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mack
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario L8S 4K1, Canada ashkara@mcmaster.ca.
authors.forename: Ali A
authors.identifier: 0000-0003-1139-1468
authors.initials: AA
authors.lastname: Ashkar
mesh_terms: D000818:Animals; D006561:Herpes Simplex / Q000276:immunology*; D018258:Herpesvirus 2, Human / Q000276:immunology; D007113:Immunity, Innate; D007370:Interferon Type I / Q000502:physiology*; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000502:physiology; D007371:Interferon-gamma / Q000096:biosynthesis; D019409:Interleukin-15 / Q000502:physiology; D020382:Interleukin-18 / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000502:physiology*; D053633:Receptor, Interferon alpha-beta / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D007370:Interferon Type I; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D007371:Interferon-gamma; D019409:Interleukin-15; D020382:Interleukin-18; D053633:Receptor, Interferon alpha-beta; C508032:Ifnar1 protein, mouse; C494228:Isgf3g protein, mouse