Fig. 1.

IFN-I signaling enhances cytokine/chemokine amplification, innate immune cell recruitment, and immune pathology during respiratory viral infections. (A) Viral infection in the lung with Influenza or SARS-CoV promotes the induction of delayed IFN-I production which enhances cytokine/chemokine production, recruitment of NK cells, and neutrophils and inflammatory macrophage/monocytes all which contribute to lung immune-mediated pathology. (B) Blockade or genetic deletion of IFNAR1 blunts cytokine/chemokine amplification, inhibits recruitment of NK cells, neutrophils, and inflammatory macrophages/monocytes resulting in reduced immunopathology, and improved survival. Treatment of mice with S1P1R agonists early during influenza virus infection suppresses IFN-I amplification from plasmacytoid dendritic cells which lowers IFN-I levels. The end result is blunting of cytokine/chemokine amplification, inhibition of NK cell, neutrophil, and inflammatory macrophage/monocyte recruitment into the lung, reduced immunopathology, and improved survival.