Anthrax ET activates Rac1 and RTK signaling to induce F-actin reorganization and endothelial permeability

Endothelial permeability induced by the potent adenylate cyclase edema toxin (ET) is central to bacterial dissemination and lethal vascular collapse during infections caused by <i>Bacillus anthracis</i>. Antibiotic and antitoxin treatments are ineffective against anthrax lethal toxemia once high doses of toxins have been released. This study uncovers a critical cAMP-dependent disruption of the F-actin network by ET in human brain microvascular endothelial cells (HBMECs), mediated by Rac1 and cofilin. Rac1 activation by ET leads to a loss of cell area and monolayer permeability. These effects are preceded by the rapid cAMP-independent activation of IGF1R and EGFR and their respective downstream effectors PI3K/AKT and MEK/ERK, which contribute to F-actin remodeling and permeability induced by ET. Consistent with these findings, Rac1, PI3K, and MEK inhibitors prevent ET-induced edema in a mouse footpad model, providing the <i>in vivo</i> pre-clinical validation of their therapeutic potential.