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A High Resolution Method to Monitor Phosphorylation-dependent Activation of IRF3
Published on: January 24, 2016
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.
Insights
Interferon-induced transmembrane protein 3 (IFITM3) limits viral disease by controlling cytokine production, not by blocking virus replication. IFITM3 restricts IL-6, preventing immune cell loss and promoting antiviral immunity.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- Interferon-induced transmembrane protein 3 (IFITM3) is an antiviral restriction factor known to inhibit viral entry.
- Genetic variations in IFITM3 influence human susceptibility to viral diseases.
- The precise mechanisms by which IFITM3 modulates pathogenesis beyond direct viral inhibition are not fully understood.
Purpose of the Study:
- To investigate the role of IFITM3 in limiting herpesvirus pathogenesis using a murine model.
- To elucidate how IFITM3 influences antiviral cellular immunity and cytokine production during infection.
- To determine the impact of IFITM3 deficiency on immune cell populations and viral control.
Main Methods:
- Utilized the murine cytomegalovirus (MCMV) infection model in wild-type and Ifitm3 knockout mice.
- Assessed viral replication, pathogenesis, and immune cell dynamics (lymphopenia, NK cell death, T cell loss).
- Quantified cytokine production, particularly IL-6, by myeloid cells in response to viral stimuli and TLR ligands (Poly(I:C), CpG).
Main Results:
- IFITM3 limits MCMV-associated pathogenesis without directly inhibiting viral replication.
- Mice lacking IFITM3 (Ifitm3-/-) exhibited restricted antiviral immunity, characterized by lymphopenia, apoptosis-independent NK cell death, and T cell loss.
- Viral disease in Ifitm3-/- mice correlated with elevated IL-6 production, which IFITM3 was found to inhibit in myeloid cells.
- While IL-6 can promote T cell responses, its uncontrolled production in Ifitm3-/- mice led to NK cell loss and impaired viral control.
Conclusions:
- IFITM3 acts as a checkpoint regulator of antiviral immunity by controlling cytokine production, specifically inhibiting IL-6.
- IFITM3's mechanism involves preserving immune cell populations (NK and T cells) and preventing excessive inflammation.
- Targeting cytokines like IL-6 may be a therapeutic strategy for virus-infected individuals with compromised IFITM3 activity.
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