The antiviral restriction factor IFN-induced transmembrane protein 3 prevents cytokine-driven CMV pathogenesis
Maria A. Stacey, … , Paul Kellam, Ian R. Humphreys
Maria A. Stacey, … , Paul Kellam, Ian R. Humphreys
Published April 3, 2017; First published February 27, 2017
Citation Information: J Clin Invest. 2017;127(4):1463-1474. https://doi.org/10.1172/JCI84889.
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Research Article Immunology Virology

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

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, Ian R. Humphreys

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Figure 1

IFITM3 affords critical protection from MCMV infection.

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IFITM3 affords critical protection from MCMV infection. WT and Ifitm3–/–...
WT and Ifitm3–/– mice were infected with 3 × 104 PFU MCMV, and survival (A) and weight loss (B) were assessed over time. Survival data include mice culled according to UK Home Office restrictions on virus-induced weight loss. Data shown are from 14 (WT) and 21 (Ifitm3–/–) mice per group merged from 3 experiments. P value in (A) determined by Mantel Cox test. Replicating virus in spleen (C), lung (D), liver (E) and salivary glands (F) on day 4 (C–E) or 14 (F) p.i. was quantified by plaque assay. (G) Spleen morphology in WT and Ifitm3–/– mice 14 days p.i. (H) Spleens were taken 14 days p.i. and sections stained with H&E. Original magnification, ×20; scale bars: 10 μm. Data are representative of at least 3 separate experiments. *P < 0.05 and **P < 0.01, by 1-way ANOVA (B) and by Mann Whitney-U (C–F). Error bars indicate ± SEM.