Early P2X7 receptor activation mitigates neonatal group B Streptococcus infection severity and long-term neurodevelopmental impairment.

Neonatal invasive Group B Streptococcus (GBS) infection remains a leading cause of mortality and long-term neurodevelopmental impairment. Effective treatment for neonatal GBS sepsis is critically hampered by a dysregulated immune response that fails to clear the infection and induces neuroinflammation. The P2X7 receptor (P2X7R) plays a key role in inflammatory responses and neuroinflammation during infection. Here, we investigated the effects of systemic P2X7R modulation on immune and neuronal dysfunction in a neonatal GBS infection model. Neonatal mice born to GBS-colonized dams were treated with a P2X7R agonist (Bz-ATP) or antagonist (A740003) from postnatal day 1 to 4. Survival rates, bacterial dissemination, inflammatory cytokines (TNF-α, IL-1β, IL-10), neutrophil recruitment, glial activation, brain pathology, neurodevelopmental milestones, and long-term cognitive and anxiety-like behaviors were assessed. P2X7R activation significantly reduced mortality, disease severity, and bacterial burden by shifting the immune response from an IL-10-dominant anti-inflammatory profile to a TNF-α-driven pro-inflammatory state, a protective effect that remained fully preserved under pharmacological inhibition of NLRP3. This immune reprogramming was associated with enhanced neutrophil recruitment and reduced disease severity. Importantly, P2X7R activation mitigated GBS-induced brain damage, preventing neuronal loss in the hippocampal CA1-CA3 regions and limiting early astrocyte reactivity while promoting microglial activation. These neuroprotective effects persisted into adulthood, improving cognitive performance and reducing anxiety-like behavior. In contrast, P2X7R blockade failed to confer protection. Our findings demonstrate that early P2X7R activation modulates immune responses to prevent neonatal GBS related mortality and long-term neurodevelopmental impairments. Given the substantial burden of early-life infections on brain development, targeting P2X7R may represent a promising neuroimmune therapeutic strategy to improve neurodevelopmental outcomes following early-life infections.