Meningitic Escherichia Coli α-Hemolysin Facilitates Blood-Brain Barrier Disruption Via Targeting Tgfβ1-Induced Hedgehog Signaling

Meningitic Escherichia coli is the major etiological agent of bacterial meningitis in neonatal stage, which is a life-threatening infection disease with severe neurological sequelae and high mortality. Blood-brain barrier (BBB) disruption is an important hallmark during this infection. Here, we showed that astrocyte-derived TGFβ1 maintained the BBB integrity via activating hedgehog signaling in endothelium, while meningitic E. coli infection could effectively subvert BBB by attenuating TGFBRII/Gli2-mediated such signaling. By high-throughput screening, we demonstrated E. coli α-hemolysin was the key determinant responsible for this attenuation through Sp1-dependent TGFBRII reduction, as well as triggering Ca2+ influx and protein kinase A activation, thus leading to Gli2 suppression. Additionally, the exogenous hedgehog agonist SAG showed a promising protection against meningitic E. coli-caused BBB dysfunction. Our work revealed a hedgehog-involved mechanism of E. coli-caused BBB disruption, and suggested that activating hedgehog signaling could be a potential protective strategy for future therapy of bacterial meningitis.