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The antiviral restriction factor IFN-induced transmembrane protein 3 prevents cytokine-driven CMV pathogenesis

Stacey, Maria A, Clare, Simon, Clement, Mathew, Marsden, Morgan, Abdul-Karim, Juneid, Kane, Leanne, Harcourt, Katherine, Brandt, Cordelia, Fielding, Ceri A, Smith, Sarah E, Wash, Rachael S, Brias, Silvia Gimeno, Stack, Gabrielle, Notley, George, Cambridge, Emma L, Isherwood, Christopher, Speak, Anneliese O, Johnson, Zoe, Ferlin, Walter, Jones, Simon A, Kellam, Paul and Humphreys, Ian R 2017. The antiviral restriction factor IFN-induced transmembrane protein 3 prevents cytokine-driven CMV pathogenesis. Journal of Clinical Investigation 127 (4) , pp. 1463-1474. 10.1172/JCI84889

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Publisher: American Society for Clinical Investigation
ISSN: 0021-9738
Funders: Wellcome Trust
Date of First Compliant Deposit: 6 March 2017
Date of Acceptance: 5 January 2017
Last Modified: 24 Feb 2019 23:45
URI: http://orca.cf.ac.uk/id/eprint/98758

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