Meningeal macrophages protect against viral neuroinfection

The surface of the central nervous system (CNS) is protected by the meninges, which contain a dense network of meningeal macrophages (MMs). Here, we examined the role of tissue-resident MM in viral infection. MHC-II− MM were abundant neonatally, whereas MHC-II+ MM appeared over time. These barrier macrophages differentially responded to in vivo peripheral challenges such as LPS, SARS-CoV-2, and lymphocytic choriomeningitis virus (LCMV). Peripheral LCMV infection, which was asymptomatic, led to a transient infection and activation of the meninges. Mice lacking macrophages but conserving brain microglia, or mice bearing macrophage-specific deletion of Stat1 or Ifnar, exhibited extensive viral spread into the CNS. Transcranial pharmacological depletion strategies targeting MM locally resulted in several areas of the meninges becoming infected and fatal meningitis. Low numbers of MHC-II+ MM, which is seen upon LPS challenge or in neonates, corelated with higher viral load upon infection. Thus, MMs protect against viral infection and may present targets for therapeutic manipulation. [Display omitted] •MM populations respond to peripheral microbial challenge•MMs protect the brain against fatal viral infection•IFNAR, but not MHC-II, is required for MM antiviral functions Rebejac et al. used transcriptomics and imaging techniques to analyze the behavior of meningeal macrophages (MMs) localized at the brain surface, upon systemic viral infection. Depletion of MMs and of their interferon-I receptor converts a benign infection into a fatal brain disease. MMs thus represent guardians of brain integrity.