The antiviral restriction factor IFN-induced transmembrane protein 3 prevents cytokine-driven CMV pathogenesis
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
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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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 6

IL-6 is a critical regulator of MCMV-induced pathology in Ifitm3–/– mice.

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IL-6 is a critical regulator of MCMV-induced pathology in Ifitm3–/– mice...
WT and Ifitm3–/– mice were infected with 3 × 104 PFU MCMV and treated with IgG or anti–IL-6R (2B10) on days 0 and 4 p.i. (A) Weight loss was measured over a 7-day period. Data represent the mean ± SEM of 4 to 11 mice per group. (B) Viral load in the spleen was quantified by plaque assay 4 days p.i. Data represent individual mice ± the median for 2 experiments. (C) Viable splenocytes were counted on day 4 p.i. Data represent the mean ± SEM of 2 merged experiments using 9–11 mice per group. (D) Representative bivariate plots of NK1.1 versus CD3 expression in WT (left) and Ifitm3–/– (right) mice 4 days p.i. after IgG (top) or anti–IL-6R (αIL-6R) (bottom) treatment. Viable NK cells (E) and annexin V+7AAD+ NK cells (F) were quantified 4 days p.i. (G) Correlation between viral load and NK1.1+CD3– cells in chimeric WT/Ifitm3–/– mice treated with IgG or anti–IL-6R. (H and I) After 7 days, viable splenic T cells and NK1.1+ cells were quantified and expressed as the mean ± SEM for 4 to 6 mice per group (H), and viral load in the spleen was measured (I). All results represent 2–3 experiments. *P < 0.05, **P < 0.01, and ***P < 0.001, by 1-way ANOVA (A); 1-way ANOVA with Bonferonni’s multiple comparison post-test analysis (B); 2-tailed Students t test (C, E, F); Mann Whitney-U (I); 1-way ANOVA (H); Spearman’s rank (G).