Cerebrospinal Fluid as a Window into Neuroimmune Responses During Brain Infection

Understanding neuroimmune responses during brain infections remains challenging because the site of disease (i.e., the brain) is difficult to access, immune responses within the central nervous system (CNS) are spatially and temporally compartmentalized, and peripheral immune cells have largely served as a proxy for the neuroimmune response. Cerebrospinal fluid (CSF) occupies a unique anatomical and immunological position at the interface between the brain parenchyma, CNS border compartments, and the peripheral immune system, making it an important window through which neuroinflammatory processes can be investigated in living patients. In this review, we examine evidence from CNS infections, with particular emphasis on tuberculous meningitis, demonstrating that CSF contains cellular and transcriptional profiles that differ from those observed in peripheral blood and vary according to the anatomical sampling site. We consider how CNS-resident cells, border-associated immune populations, and recruited leukocytes contribute to the neuroimmune environment of CSF. Importantly, we distinguish evidence derived from cells directly recovered from CSF from soluble biomarkers that may reflect activity in parenchymal or border compartments, and from cellular processes inferred from transcriptomic studies. We also discuss how CSF sampling and analytical approaches influence interpretation and highlight the potential of high-dimensional profiling to resolve compartmentalized neuroimmune responses during CNS infection.