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 Bacillus anthracis. 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 in vivo pre-clinical validation of their therapeutic potential.