PGK1 contributes to blood-brain barrier integrity via PI3K-AKT-mTOR pathway in early pneumococcal meningitis.

Pneumococcal meningitis continues to be a devastating disease associated with high mortality and neurological sequelae, largely due to disruption of the blood-brain barrier (BBB). Emerging evidence implicates that metabolic reprogramming within the neurovascular unit constitutes a critical pathophysiological mechanism. Phosphoglycerate kinase 1 (PGK1), a glycolytic enzyme, may play a role beyond energy metabolism, but its involvement in BBB protection during meningitis is undefined. Here, we demonstrate that PGK1 preserves BBB integrity via the PI3K-Akt-mTOR pathway in early pneumococcal meningitis. Transcriptomic and in vitro analyses revealed that early Streptococcus pneumoniae infection induces profound metabolic reprogramming in the BBB microvasculature, characterized by significant upregulation of glycolytic enzymes including PGK1. Furthermore, PGK1 overexpression in bEnd.3 ells enhanced expression of tight junction proteins (ZO-1, Occludin). Mechanistically, PGK1 conferred barrier protection by fueling ATP production and subsequently activating the PI3K-AKT-mTOR signaling pathway. This conclusion is supported by the finding that inhibition of this pathway abolished the PGK1-dependent upregulation of tight junctions. These findings identify PGK1 as an essential host mediator safeguarding BBB function through the PI3K-AKT-mTOR-tight junction protein axis during early pneumococcal meningitis, highlightingPGK1 and its downstream effectors as novel therapeutic targets to preserve BBB integrity and mitigate neurological damage.