Research ArticleINFECTIOUS DISEASES

The probacterial effect of type I interferon signaling requires its own negative regulator USP18

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Science Immunology  28 Sep 2018:
Vol. 3, Issue 27, eaau2125
DOI: 10.1126/sciimmunol.aau2125

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Turning the tables on interferon

An early step in the host response to viral infection involves a burst of synthesis of type I interferons that allow cells to quickly fight back against the offending viruses. Shaabani et al. investigated how the same interferon-stimulated genes (ISGs) that usually help against viruses surprisingly dampen the host’s ability to resist many bacterial infections. Deletion of a single ISG known as Usp18 in mouse dendritic cells was sufficient to enhance host control of infections with two strains of Gram-positive bacteria. Normal induction of USP18 after infection impaired antibacterial responses mediated by tumor necrosis factor. These findings spotlight USP18 as a new potential target for therapeutics aimed at improving control of serious bacterial infections.

Abstract

Type I interferon (IFN-I) signaling paradoxically impairs host immune responses during many primary and secondary bacterial infections. Lack of IFN-I receptor reduces bacterial replication and/or bacterial persistence during infection with several bacteria. However, the mechanisms that mediate the adverse IFN-I effect are incompletely understood. Here, we show that Usp18, an interferon-stimulated gene that negatively regulates IFN-I signaling, is primarily responsible for the deleterious effect of IFN-I signaling during infection of mice with Listeria monocytogenes or Staphylococcus aureus. Mechanistically, USP18 promoted bacterial replication by inhibiting antibacterial tumor necrosis factor–α (TNF-α) signaling. Deleting IFNAR1 or USP18 in CD11c-Cre+ cells similarly reduced bacterial titers in multiple organs and enhanced survival. Our results demonstrate that inhibiting USP18 function can promote control of primary and secondary bacterial infection by enhancing the antibacterial effect of TNF-α, which correlates with induction of reactive oxygen species (ROS). These findings suggest that USP18 could be targeted therapeutically in patients to ameliorate disease caused by serious bacterial infections.

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