Bacteria hijack a neuro-immune axis in the meninges to facilitate brain invasion

Abstract The meninges are densely innervated by nociceptors that mediate pain and headache. Bacterial meningitis is a life-threatening infection of the meninges and central nervous system (CNS) that affects over one million people a year. However, whether pain and neuro-immune interactions impact CNS bacterial invasion is unclear. Here we find that nociceptor signaling to immune cells 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. Bacteria directly activated nociceptors to release CGRP, which acts through its receptor RAMP1 on meningeal macrophages to inhibit chemokine expression and immune defenses. Macrophage-specific RAMP1 deficiency or blockade of RAMP1 signaling enhanced immune responses and bacterial clearance in the meninges and brain. Therefore, targeting a neuro-immune axis in the meninges can enhance host defenses and may be a potential treatment for bacterial meningitis.