Targeting E. coli invasion of the blood-brain barrier for investigating the pathogenesis and therapeutic development of E. coli meningitis.

Escherichia coliis the most common Gram-negative bacillary organism causing neonatal meningitis.Escherichia colimeningitis remains an important cause of mortality and morbidity, but the pathogenesis ofE. colipenetration of the blood-brain barrier remains incompletely understood.Escherichia colientry into the brain occurs in the meningeal and cortex capillaries, not in the choroid plexus, and exploits epidermal growth factor receptor (EGFR) and cysteinyl leukotrienes (CysLTs) for invasion of the blood-brain barrier. The present study examined whether EGFR and CysLTs are inter-related in their contribution toE. coliinvasion of the blood-brain barrier and whether counteracting EGFR and CysLTs is a beneficial adjunct to antibiotic therapy ofE. colimeningitis. We showed that (a) meningitis isolates ofE. coliexploit EGFR and CysLTs for invasion of the blood-brain barrier, (b) the contribution of EGFR is upstream of that of CysLTs, and (c) counteracting EGFR and CysLTs as an adjunctive therapy improved the outcome (survival, neuronal injury and memory impairment) of animals withE. colimeningitis. These findings suggest that investigation of host factors contributing toE. coliinvasion of the blood-brain barrier will help in enhancing the pathogenesis and development of new therapeutic targets forE. colimeningitis in the era of increasing resistance to conventional antibiotics.