1. The antiviral restriction factor IFN-induced transmembrane protein 3 prevents cytokine-driven CMV pathogenesis
- Author
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Maria A, Stacey, Simon, Clare, Mathew, Clement, Morgan, Marsden, Juneid, Abdul-Karim, Leanne, Kane, Katherine, Harcourt, Cordelia, Brandt, Ceri A, Fielding, Sarah E, Smith, Rachael S, Wash, Silvia Gimeno, Brias, Gabrielle, Stack, George, Notley, Emma L, Cambridge, Christopher, Isherwood, Anneliese O, Speak, Zoë, Johnson, Walter, Ferlin, Simon A, Jones, Paul, Kellam, and Ian R, Humphreys
- Subjects
INFLUENZA-VIRUS ,INTERFERON ,Muromegalovirus ,Mice, 129 Strain ,viruses ,Immunology ,Research & Experimental Medicine ,Virus Replication ,NATURAL-KILLER-CELLS ,Mice ,MURINE CYTOMEGALOVIRUS-INFECTION ,Animals ,IFITM3 RESTRICTS ,DENGUE VIRUS ,Cells, Cultured ,11 Medical and Health Sciences ,Mice, Knockout ,Immunity, Cellular ,Mice, Inbred BALB C ,Science & Technology ,Membrane Proteins ,Herpesviridae Infections ,Virus Internalization ,R1 ,Receptors, Interleukin-6 ,INNATE IMMUNE-RESPONSE ,WEST NILE VIRUS ,Mice, Inbred C57BL ,Medicine, Research & Experimental ,IL-10 ,T-CELLS ,Cytokines ,Life Sciences & Biomedicine ,Research Article ,Signal Transduction - 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.
- Published
- 2017