title: The antiviral restriction factor IFN-induced transmembrane protein 3 prevents cytokine-driven CMV pathogenesis.
abstract: The antiviral restriction factor IFN-induced transmembrane protein 3 (IFITM3) inhibits cell entry of a number of viruses, and genetic diversity within IFITM3 determines susceptibility to viral disease in humans. Here, we used the murine CMV (MCMV) model of infection to determine that IFITM3 limits herpesvirus-associated pathogenesis without directly preventing virus replication. Instead, IFITM3 promoted antiviral cellular immunity through the restriction of virus-induced lymphopenia, apoptosis-independent NK cell death, and loss of T cells. Viral disease in Ifitm3-/- mice was accompanied by elevated production of cytokines, most notably IL-6. IFITM3 inhibited IL-6 production by myeloid cells in response to replicating and nonreplicating virus as well as following stimulation with the TLR ligands Poly(I:C) and CpG. Although IL-6 promoted virus-specific T cell responses, uncontrolled IL-6 expression in Ifitm3-/- mice triggered the loss of NK cells and subsequently impaired control of MCMV replication. Thus, IFITM3 represents a checkpoint regulator of antiviral immunity that controls cytokine production to restrict viral pathogenesis. These data suggest the utility of cytokine-targeting strategies in the treatment of virus-infected individuals with impaired IFITM3 activity.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Stacey
authors.forename: Simon
authors.initials: S
authors.lastname: Clare
authors.forename: Mathew
authors.initials: M
authors.lastname: Clement
authors.forename: Morgan
authors.initials: M
authors.lastname: Marsden
authors.forename: Juneid
authors.initials: J
authors.lastname: Abdul-Karim
authors.forename: Leanne
authors.initials: L
authors.lastname: Kane
authors.forename: Katherine
authors.initials: K
authors.lastname: Harcourt
authors.forename: Cordelia
authors.initials: C
authors.lastname: Brandt
authors.forename: Ceri A
authors.initials: CA
authors.lastname: Fielding
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Smith
authors.forename: Rachael S
authors.initials: RS
authors.lastname: Wash
authors.forename: Silvia Gimeno
authors.initials: SG
authors.lastname: Brias
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Stack
authors.forename: George
authors.initials: G
authors.lastname: Notley
authors.forename: Emma L
authors.initials: EL
authors.lastname: Cambridge
authors.forename: Christopher
authors.initials: C
authors.lastname: Isherwood
authors.forename: Anneliese O
authors.initials: AO
authors.lastname: Speak
authors.forename: Zoë
authors.initials: Z
authors.lastname: Johnson
authors.forename: Walter
authors.initials: W
authors.lastname: Ferlin
authors.forename: Simon A
authors.initials: SA
authors.lastname: Jones
authors.forename: Paul
authors.initials: P
authors.lastname: Kellam
authors.forename: Ian R
authors.initials: IR
authors.lastname: Humphreys
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology*; D006566:Herpesviridae Infections / Q000276:immunology / Q000378:metabolism*; D007111:Immunity, Cellular; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000502:physiology; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D015398:Signal Transduction; D053586:Virus Internalization; D014779:Virus Replication
chemical_list: D016207:Cytokines; D008565:Membrane Proteins; D019947:Receptors, Interleukin-6; C462181:fragilis protein, mouse