Anthrax Edema Toxin Co-Opts IGF1R and EGFR Signaling to Promote Cell-Cell Barrier Dysfunction

Abstract

Cell-cell barrier dysfunction induced by the anthrax edema toxin (ET) is central to bacterial dissemination and lethal vascular collapse during disease progression. Available treatments including antimicrobial and early-stage antitoxin measures do not prevent lethal anthrax toxemia during fulminant stages of infection. This study identifies cell-based therapeutic measures that target the late-stage intracellular activities of ET and their potential to mitigate consequences of ET toxemia. We uncover a critical involvement of IGF1R and EGFR in promoting ET-dependent barrier disruption through effects on cellular F-actin network that are separate from, but have an impact upon, previously characterized cAMP-mediated inhibition of vesicular trafficking. ET rapidly trans-activates IGF1R and EGFR, resulting in the activation of downstream effectors PI3K and MEK, and subsequently a Rac1- and cofilin-dependent actin remodeling. Finally, we provide in vivo pre-clinical validation of the therapeutic potential of PI3K, MEK and Rac1 inhibitors in preventing ET-dependent edema in a mouse footpad model.