Caspase-8 drove apoptosis of BMECs to promote neutrophil infiltration and DE205B clearance in meningitis.

Abstract

Avian pathogenic Escherichia coli (APEC), a significant virulence reservoir for human extraintestinal pathogenic E. coli (ExPEC), poses an escalating zoonotic risk through the food chain. Our previous study demonstrated that the poultry-derived strain DE205B shared high genetic similarity with the neonatal meningitis-associated E. coli (NMEC) strain RS218 and induced meningitis in a rat model. Here, we further demonstrated that DE205B crossed the blood-brain barrier (BBB) via a transcellular pathway without compromising barrier integrity. During this process, brain microvascular endothelial cells (BMECs) trigger limited RIPK1-independent apoptosis. Mechanistically, caspase-8 activation in BMECs drove the release of proinflammatory mediators, thereby promoting neutrophil recruitment into the cerebrospinal fluid (CSF). These neutrophils facilitated bacterial clearance through the formation of neutrophil extracellular traps (NETs). In vivo pharmacological inhibition of caspase-8 attenuated the ability of BMECs to recruit neutrophils, exacerbating meningitis progression. These findings suggested that limited apoptosis of BMECs contributed positively to APEC clearance in the brain. Collectively, this study systematically elucidated mechanisms underlying DE205B-mediated BBB invasion and host immune responses, providing insights into its cross-species pathogenic potential and zoonotic implications.