Bacteria hijack a meningeal neuroimmune axis to facilitate brain invasion

Abstract

The meninges are densely innervated by nociceptive sensory neurons that mediate pain and headache1,2. How pain and neuroimmune interactions impact meningeal host defense is unclear. Bacterial meningitis causes life-threatening infections of the meninges and central nervous system (CNS), affecting over 2.5 million people a year3-5. Here we find that Nav1.8+ neuron signaling to immune cells in the meninges via the neuropeptide calcitonin gene-related peptide (CGRP) exacerbates bacterial meningitis. Nociceptor ablation reduced meningeal and brain invasion by two bacterial pathogens: Streptococcus pneumoniae and Streptococcus agalactiae. S. pneumoniae activated nociceptors via Pneumolysin to release CGRP, which acts through its receptor RAMP1 on meningeal macrophages to inhibit chemokine expression, neutrophil recruitment and antimicrobial defenses. Macrophage-specific RAMP1 deficiency or blockade of RAMP1 signaling enhanced immune responses and bacterial clearance in meninges and brain. Therefore, targeting a neuro-immune axis in the meninges can enhance host defenses and potentially produce treatments for bacterial meningitis.