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

## TL;DR

A zoonotic Streptococcus species uses glucose import to grow in cerebrospinal fluid and cause meningitis.

## Contribution

The study identifies the bacterial PTSman system as critical for glucose uptake and growth in cerebrospinal fluid during meningitis.

## Key findings

- Only a few Streptococcus clones invade the meninges and replicate extensively.
- The PTSman system enables glucose acquisition at low concentrations in cerebrospinal fluid.
- Glucose import inhibits the stringent response and supports pathogen replication.

## Abstract

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 ~107-fold. Subsequent transposon insertion sequencing experiments, plus validation work with bacterial mannose phosphotransferase system (PTSman)-defective strains, identified the PTSman, which imports glucose, as essential for S.
zooepidemicus proliferation in CSF. The S.
zooepidemicus PTSman promoter confers species-specific constitutive transcription of PTSman, 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 PTSman in the control of S.
zooepidemicus metabolism enables this pathogen to adapt to and replicate in CSF during meningitis.

Streptococcus equi subsp. zooepidemicus imports glucose via the bacterial mannose phosphotransferase system (PTSman), which inhibits stringent response, supports growth in cerebrospinal fluid and promotes brain damage during meningitis.