Type I Interferon Signaling Prevents IL-1β-Driven Lethal Systemic Hyperinflammation during Invasive Bacterial Infection of Soft Tissue

Virginia Castiglia, Alessandra Piersigilli, Florian Ebner, Dagmar Stoiber, Pavel Kovarik

Cell Host & Microbe, 2016. 19, 375–387

Speaker: Yi Tein (田 依)                                              Time: 15:00~16:00, May 18, 2016

Commentator: Dr. Ching-Hao Teng (鄧景浩老師)      Place: Room 601

Abstract:

The role of type I interferons (IFN-Is) in the protection against viral infections has been known, but in bacterial infection is less clear. Streptococcus pyogenes is an important human pathogen and can cause severe invasive manifestations clinically. In previous study, it is been demonstrated that S. pyogenes activates IFN-I production in innate immune cells, and IFN-I receptor 1 (Ifnar1)-deficient mice are highly susceptible to S. pyogenes infection.[1] Hence, the authors want to explore the role of IFN-Is in severe S. pyogenes infection. First, the author used reporter mice allowing Cre-Lox-regulated cell type-specific monitoring of the Ifnb promoter activity , indicated that IFN-I induction is Irf5 dependent by S. pyogenes infection in vivo and occurs mostly in LysM⁺ or CD11c⁺ myeloid cell. However, Ifnar1 ablation in both CD11c⁺ and LysM⁺ cells resulted in significantly decreased survival, but no difference in bacterial burden between WT and Ifnar1^-/- mice. Using clinical parameters, the tissue sections and ELISA assay revealed that increased leukocyte infiltration and organ damage upon with systemic levels of IL-1β in S. pyogenes-infected Ifnar1^-/- mice. At the site of infection in Ifnar1^-/- Mice, neutrophils were the major infiltrating cells .This finding suggested that neutrophil probably contribute to IL-1βproduction. Forthermore, they detected the IL-1β mRNA level in S. pyogenes-infected Ifnar1^-/- BMDMs, DCs and neutrophils with adding exogenous IFN-β. The authors found that IFN-I signaling inhibits Il1b gene transcription in myeloid cells. At last, they investigated that the survival decreased in IL-1receptor 1 gene (Il1r1) deficient mice and caspase-1 and caspase-11 double deficient mice compared with WT mice. Moreover, treating Ifnar1^-/-mice with Ac-YVAD-CHO (caspase-1 and caspase-4 inhibitor) resulted in full protection against S. pyogenes infection. This study shows that activation of IFN-Is signaling in the context of Streptococcus pyogenes infection controls IL-1β levels and limits systemic inflammation and tissue damage.

References:

1. Nina Gratz, et al., Group A Streptococcus Activates Type I Interferon Production and MyD88- dependent Signaling without Involvement of TLR2, TLR4, and TLR9. Science, 2008 vol 321