Identification of a mechanical signaling pathway activating type 1 fimbriae via a ZraSR two-component system in neonatal meningitis-associated Escherichia coli

Escherichia coli K1 (E. coli K1) meningitis develops after the bacteria cross the blood−brain barrier (BBB); however, the molecular mechanisms underlying this process remain incompletely understood. Adhesion to human brain microvascular endothelial cells (HBMECs), which constitute the BBB, is considered important in E. coli K1 bacterial penetration into the central nervous system. Here, we report a complete signal regulatory pathway in which the ZraSR two-component system (TCS) senses mechanical cues-specifically, physical forces and envelope perturbations generated by the initial attachment of E. coli K1 to host cells-and directly binds to fimS, the invertible promoter element of the fim operon (fimAICDFGH). This interaction promotes fimS inversion to the phase-ON orientation, thereby activating the expression of type 1 fimbriae, specifically the FimH adhesin. This activation enhances E. coli K1 invasion into HBMECs. Disruption of this signaling pathway severely attenuates the progression of meningitis and reduces the production of proinflammatory factors triggered by E. coli K1 infection in vivo. These findings suggest that components of this pathway may serve as potential targets for novel therapeutic strategies against E. coli K1 infection.