Macrophage metabolic regulation by phosphoglucomutase 1 shapes the host immune response in pneumococcal meningitis

Pneumococcal meningitis remains a life-threatening disease despite antibiotic and anti-inflammatory therapy, with unfavourable outcome driven by excessive inflammation and impaired bacterial clearance. Host genetic variation influences disease outcome in pneumococcal meningitis, though the underlaying mechanisms remain unclear. In a genome-wide association study, we identified the single nucleotide polymorphism (SNP) rs12081070 as a risk factor for unfavourable outcome in bacterial meningitis (Minor allele frequency (MAF) = 0.43; odds ratio (OR) = 1.63; p = 2.0 × 10 ^− 8 ). Chromatin conformation capture analysis linked this variant to phosphoglucomutase 1 ( PGM1) , which encodes a key enzyme in glucose metabolism and glycosylation in immune cells. In a nationwide cohort study of 1200 patients with bacterial meningitis, we show that individuals carrying the rs12081070 risk allele exhibited elevated proinflammatory cytokine responses to Streptococcus pneumoniae ( S. pneumoniae ) and an increased risk of unfavourable functional outcome. Using a murine model of pneumococcal meningitis, we show that myeloid-specific Pgm1 deletion amplifies inflammation, impairs bacterial clearance, and exacerbates brain injury. Mechanistically, Pgm1 -deficient macrophages exhibit disrupted glycolysis and mitochondrial respiration, and enhanced cytokine and nitrogen oxygen production. Our findings identify Pgm1 as a regulator of macrophage metabolism and inflammation in pneumococcal meningitis, highlighting a potential target for immune-modulation in bacterial disease.