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 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 5

Ifitm3–/– myeloid cells are hyperresponsive to replication-deficient virus and endosomal TLR ligand stimulation.

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Ifitm3–/– myeloid cells are hyperresponsive to replication-deficient vi...
(A and B) GM-CSF– and FLT3L-differentiated myeloid cells were infected or not with irradiated MCMV, and IL-6 protein in the supernatants was analyzed by ELISA 24 hours later. (C and D) GM-CSF– and FLT3L-differentiated myeloid cells were stimulated or not with a control CPG or CPG (both 0.5 μg/ml) or with Poly(I:C) (10 μg/ml) for 24 hours, and IL-6 protein in the supernatants was analyzed by ELISA. Data represent the mean ± SEM of quadruplet wells for 2 (C and D) or 3 (A and B) experiments. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-tailed Students t test.