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

Area of Science:

• Microbiology
• Pathogen Biology
• Zoonotic Diseases

Background:

• Streptococcus equi subsp. zooepidemicus is an emerging zoonotic pathogen causing significant mortality in pigs and morbidity in humans.
• The mechanisms enabling hypervirulent S. zooepidemicus to proliferate in cerebrospinal fluid (CSF) during meningitis are poorly understood.

Purpose of the Study:

• To elucidate the molecular mechanisms S. zooepidemicus employs to adapt and replicate within the CSF.
• To identify key factors contributing to the pathogen's success in the central nervous system.

Main Methods:

• Utilized genetically barcoded S. zooepidemicus strains to track clonal expansion in vivo.
• Performed transposon insertion sequencing (Tn-Seq) to identify essential genes for CSF proliferation.
• Validated findings using bacterial mannose phosphotransferase system (PTS_man)-defective strains.

Main Results:

• Only a small number of S. zooepidemicus clones (~1-10) successfully invade the meninges and replicate extensively (~10⁷-fold) in the CSF.
• The mannose phosphotransferase system (PTS_man), responsible for glucose import, was identified as essential for S. zooepidemicus proliferation in CSF.
• The S. zooepidemicus PTS_man promoter drives constitutive transcription, facilitating glucose uptake in low-glucose environments and preventing stringent response activation.

Conclusions:

• The rewiring of the PTS_man system is crucial for S. zooepidemicus adaptation to the CSF environment.
• This metabolic adaptation enables efficient glucose acquisition and pathogen replication, contributing to meningitis pathogenesis.
• Understanding these mechanisms offers insights into controlling S. zooepidemicus infections.