Effects of lipid signaling on innate immune networks during influenza infection. (INM3P.360)

Abstract

Abstract If critical steps in the influenza infection process are identified, druggable targets could be discovered. We have uncovered the role of lipid signaling through phospholipase D (PLD) during influenza infection. Our findings suggest that influenza virus takes advantage of PLD activity to quickly and quietly enter the host cell. By inhibiting PLD with small molecules, we found that endocytosis kinetics were subdued. Slowing influenza entry allowed innate immune proteins to sense the pathogen and mount an effective defense. The molecules required for defense included Rig-I, MxA, and IRF3. When these proteins were knocked down in cells treated with PLD2 inhibitor, protection was lost. Inhibition of PLD2 protected cells from several influenza subtypes, including H5N1 and the newly emerged H7N9. Additionally, viral growth in mice treated with the PLD2 inhibitor was reduced, and mice were more likely to survive when treated with PLD2 inhibitor. Our data suggest that signaling through PLD during influenza infection plays a critical role in innate immune detection and defense mechanisms, and that drugging PLD2, allows a better chance to defend against pathogens using innate molecules. Currently, second generation small molecule inhibitors of PLD2 are proving to be more efficacious and potent. Additionally, further insights are being gained regarding the temporal-spatial regulation of innate immune molecules during the first hours of infection.