title: IFN-γ Primes Keratinocytes for HSV-1-Induced Inflammasome Activation.
abstract: Inflammasomes are immune complexes that induce an inflammatory response upon sensing of different stress signals. This effect is mainly mediated by activation and secretion of the proinflammatory cytokines proIL-1β and -18. Here we report that infection of human primary keratinocytes with the double-stranded DNA viruses modified vaccinia virus Ankara (MVA) or herpes simplex virus type 1 (HSV-1)-induced secretion of mature IL-1β and -18. This secretion was dependent on several inflammasome complexes; however, the absent in melanoma 2 (AIM2) inflammasome, which is activated by binding of double-stranded DNA, played the most important role. Whereas prestimulation of keratinocytes with IFN-γ moderately increased MVA-induced IL-1β and IL-18 secretion, it was essential for substantial secretion of these cytokines in response to herpes simplex virus type 1 infection. IFN-γ partially restored HSV-1 suppressed proIL-1β expression and was also required for inflammasome activation. Most importantly, IFN-γ strongly suppressed virus replication in keratinocytes in vitro and ex vivo, which was independent of inflammasome activation. Our results suggest that, similar to Herpesviridae infection in mice, HSV-1 replication in human skin is controlled by a positive feedback loop of keratinocyte-derived IL-1/IL-18 and IFN-γ expressed by immune cells.
authors.affiliation: Department of Dermatology, University Hospital, University of Zurich, Zurich, Switzerland.
authors.forename: Gerhard E
authors.initials: GE
authors.lastname: Strittmatter
authors.affiliation: Department of Dermatology, University Hospital, University of Zurich, Zurich, Switzerland.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sand
authors.affiliation: Institute of Virology, Saarland University, Homburg/Saar, Germany.
authors.forename: Marlies
authors.initials: M
authors.lastname: Sauter
authors.affiliation: Institute of Virology, University of Zurich, Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Seyffert
authors.affiliation: Infectious Disease Division, Bavarian Nordic GmbH, Martinsried, Germany.
authors.forename: Robin
authors.initials: R
authors.lastname: Steigerwald
authors.affiliation: Institute of Virology, University of Zurich, Zurich, Switzerland.
authors.forename: Cornel
authors.initials: C
authors.lastname: Fraefel
authors.affiliation: Institute of Virology, Saarland University, Homburg/Saar, Germany.
authors.forename: Sigrun
authors.initials: S
authors.lastname: Smola
authors.affiliation: Department of Dermatology, University Hospital, University of Zurich, Zurich, Switzerland.
authors.forename: Lars E
authors.initials: LE
authors.lastname: French
authors.affiliation: Department of Dermatology, University Hospital, University of Zurich, Zurich, Switzerland. Electronic address: Hans-Dietmar.Beer@usz.ch.
authors.forename: Hans-Dietmar
authors.initials: HD
authors.lastname: Beer
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured / Q000276:immunology / Q000821:virology*; D006561:Herpes Simplex / Q000276:immunology / Q000503:physiopathology; D018259:Herpesvirus 1, Human / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology; D058847:Inflammasomes / Q000276:immunology* / Q000378:metabolism; D020382:Interleukin-18 / Q000276:immunology* / Q000378:metabolism; D015603:Keratinocytes / Q000276:immunology* / Q000378:metabolism; D051379:Mice
chemical_list: D058847:Inflammasomes; D020382:Interleukin-18