Zoonotic Streptococcus imports glucose to inhibit stringent response and promote growth during meningitis

Proliferation of the emerging zoonotic pathogen Streptococcus equi subsp. zooepidemicus in the meninges is linked to mortality in pigs and morbidity in humans. The mechanisms underlying the remarkable capacity of hypervirulent S. zooepidemicus to proliferate in cerebrospinal fluid (CSF) are largely undefined. Here, using genetically barcoded S. zooepidemicus , we found that following systemic infection of mice, only ~1–10 S. zooepidemicus clones invade the meninges where they subsequently replicate ~10 7 -fold. Subsequent transposon insertion sequencing experiments, plus validation work with bacterial mannose phosphotransferase system (PTS man )-defective strains, identified the PTS man , which imports glucose, as essential for S. zooepidemicus proliferation in CSF. The S. zooepidemicus PTS man promoter confers species-specific constitutive transcription of PTS man , enabling glucose acquisition at low glucose concentrations and limiting activation of the stringent response, leading to pathogen replication in CSF. Our findings reveal how the rewiring of PTS man in the control of S. zooepidemicus metabolism enables this pathogen to adapt to and replicate in CSF during meningitis.