IFN-β, but not IFN-α, is Responsible for the Pro-Bacterial Effect of Type I Interferon.

Namir Shaabani, Vincent F Vartabedian, Nhan Nguyen, Nadine Honke, Zhe Huang, John R Teijaro

Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 2021 May 14

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During an immune response, type I interferon (IFN-I) signaling induces a wide range of changes, including those which are required to overcome viral infection and those which suppress cytotoxic T cells to avoid immunopathology. During certain bacterial infections, IFN-I signaling exerts largely detrimental effects. Although the IFN-I family of proteins all share one common receptor, biologic responses to signaling vary depending on IFN-I subtype. Here, we asked if one IFN-I subtype dominates the pro-bacterial effect of IFN-I signaling and found that control of Listeria monocytogenes (L.m.) infection is more strongly suppressed by IFN-β than IFN-α. To study this, we measured bacterial titers in IFNAR-/-, IFN-β‑/‑, Stat2-/-, Usp18fl/fl and Usp18fl/fl x CD11c-Cre mice models in addition to IFN-I blocking antibodies. Moreover, we measured interferon stimulated genes in bone marrow derived dendritic cells after treatment with IFN-α4 and IFN-β. Specifically, we show that genetic deletion of IFN-β or antibody-mediated IFN-β neutralization was sufficient to reduce bacterial titers to levels similar to those observed in mice that completely lack IFN-I signaling (IFNAR-/- mice). However, IFN-α blockade failed to significantly reduce L.m. titers, suggesting that IFN-β is the dominant IFN-I subtype responsible for the pro-bacterial effect of IFN-I. Mechanistically, when focusing on IFN-I signals to dendritic cells, we found that IFN-β induces ISGs more robustly than IFN-α, including USP18, the protein we previously identified as driving the pro-bacterial effects of IFN-I. Further, we found that this induction was STAT1/STAT2 heterodimer- or STAT2/STAT2 homodimer-dependent, as STAT2-deficient mice were more resistant to L.m. infection. In conclusion, IFN-Β is the principal member of the IFN-I family responsible for driving the pro-bacterial effect of IFN-I. © Copyright by the Author(s). Published by Cell Physiol Biochem Press.

Citation

Namir Shaabani, Vincent F Vartabedian, Nhan Nguyen, Nadine Honke, Zhe Huang, John R Teijaro. IFN-β, but not IFN-α, is Responsible for the Pro-Bacterial Effect of Type I Interferon. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 2021 May 14;55(3):256-264