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

ABSTRACT: The meninges are densely innervated by nociceptive sensory neurons that mediate pain and headache. How pain and neuro-immune interactions impact meningeal host defenses is unclear. Bacterial meningitis causes life-threatening infections of the meninges and central nervous system (CNS), affecting over one million people a year. 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 may be a potential treatment for bacterial meningitis.

ORGANISM(S): Mus musculus

PROVIDER: GSE221681 | GEO | 2022/12/23

REPOSITORIES: GEO

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Project description:The meningeal space is an important structure in the brain borders, which provides immunosurveillance for the central nervous system, but the impact of infections on the meningeal immune landscape is far from being fully understood. Trypanosoma brucei, the causative agents of Human African Trypanosomiasis or sleeping sickness, accumulates in the meningeal spaces, inducing severe meningitis and resulting in death if left untreated. Thus, sleeping sickness represents an attractive model to study immunological dynamics in the meninges during infection. Here, combining single cell transcriptomics and mass cytometry by time of flight (CyTOF), coupled with in vivo interventions, we found that chronic T. brucei infection triggers the development of ectopic lymphoid aggregates (ELAs) in the murine meninges during chronic infection. These infection-induced ectopic structures are defined by the presence of ER-TR7+ fibroblastic reticular cells (FRCs) and follicular dendritic cells (FDCs) that initiate a signalling cascade driving local T cell activation towards a T follicular helper (TFH)-like phenotype, as well as B cell class switching. Furthermore, the meningeal-resident plasma cells display activity typically associated with germinal centre reactions and are able to produce antibodies able to recognise mouse brain antigens, which correlates with cortical (and white matter) demyelination. Lastly, we found that systemic lymphotoxin (LT) signalling blockade led to a significant depletion of meningeal FDCs and autoreactive B cells, indicating that LTsignalling is critical to induce and maintain local responses in the meninges. Taken together, we provide evidence that the meningeal immune response results in the acquisition of lymphoid tissue-like properties during chronic T. brucei infection. These findings have broader implications for understanding the mechanisms underlying the formation ELAs during chronic inflammation resulting in autoimmunity, as observed in other demyelinating neurodegenerative disorders such as multiple sclerosis.

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

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