Inhibiting the Inflammatory Response Following Influenza Virus Infection utilizing Sphingosine-1-phosphate receptor 1 signaling (92.4)

Abstract

Abstract Emerging pathogenic strains of influenza A virus have caused significant morbidity and mortality in humans. During influenza virus infection, severe damage of lung tissue directly correlates with innate and adaptive cellular immune responses in addition to elevated pro-inflammatory cytokine responses. We reported previously that intra-tracheal treatment with a sphingosine analog, AAL-R, inhibits the production of pro-inflammatory cytokines and T cell accumulation within lung tissue without altering B cell responses or viral clearance (Marsolais, et al., 2008). Now we report that intra-tracheal treatment with AAL-R has profound S1P1-specific effects on innate immune responses. AAL-R inhibits neutrophil, NK and macrophage activation and recruitment into the lung via S1P1 signaling. In addition, AAL-R modulation of pro-inflammatory cytokines was also specific to S1P1 receptor signaling, as treatment with an S1P1 specific agonist significantly reduces early pro-inflammatory cytokine production after influenza virus challenge. Finally, we demonstrate that inhibition of T cell accumulation within the infected lung was independent of S1P1 receptor signaling. Here we provide mechanistic evidence for previously unrecognized inhibition of influenza virus innate and pro-inflammatory immune responses via S1P1 signaling. These findings have profound implications for designing therapeutic strategies to mitigate harmful immune responses during pathogenic influenza virus infection.