Low leucine levels in the blood enhance the pathogenicity of neonatal meningitis-causing Escherichia coli.

Summary

This mechanistic study identifies a host-nutrient cue—low blood leucine—that augments NMEC bacteremia and meningitis via an Lrp-dependent repression of sRNA NsrP, derepressing purD and de novo purine biosynthesis. Genetic perturbations validate causality, and intravenous leucine attenuates disease in vivo, suggesting a potential prophylactic/adjunctive strategy.

Key Findings

• Low blood leucine promotes NMEC survival/replication in vivo, increasing bacteremia and meningitis.
• Leucine scarcity suppresses sRNA NsrP via Lrp; reduced NsrP derepresses purD and activates de novo purine biosynthesis.
• NsrP deletion increases, while purD deletion decreases, NMEC bacteremia/meningitis in animal models.
• Intravenous leucine blocks the Lrp–NsrP–purD pathway and reduces NMEC bacteremia/meningitis.

Clinical Implications

Although preclinical, the data suggest exploring controlled leucine supplementation or targeting the Lrp–sRNA–purine axis to prevent or attenuate NMEC bacteremia/meningitis, with careful neonatal safety and dosing evaluation.

Limitations

• Preclinical animal and molecular data without human clinical validation
• Pathogen-specific mechanism (NMEC); generalizability to other sepsis pathogens is uncertain

Future Directions

Evaluate safety/PK of leucine in neonatal models, test prophylaxis/adjunctive strategies clinically, and probe whether analogous nutrient–sRNA–metabolism axes exist in other pathogens.