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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. [ABSTRACT FROM AUTHOR]

Lung-resident memory B cells (MBCs) provide localized protection against reinfection in respiratory airways. Currently, the biology of these cells remains largely unexplored. Here, we combined influenza and SARS-CoV-2 infection with fluorescent-reporter mice to identify MBCs regardless of antigen specificity. We found that two main transcriptionally distinct subsets of MBCs colonized the lung peribronchial niche after infection. These subsets arose from different progenitors and were both class switched, somatically mutated, and intrinsically biased in their differentiation fate toward plasma cells. Combined analysis of antigen specificity and B cell receptor repertoire segregated these subsets into "bona fide" virus-specific MBCs and "bystander" MBCs with no apparent specificity for eliciting viruses generated through an alternative permissive process. Thus, diverse transcriptional programs in MBCs are not linked to specific effector fates but rather to divergent strategies of the immune system to simultaneously provide rapid protection from reinfection while diversifying the initial B cell repertoire. [Display omitted] • Influenza and SARS-CoV-2 infection generates bona fide and bystander lung-resident MBCs • Bona fide and bystander MBC subsets differ in their origin and transcriptional programs • Bona fide MBCs are virus specific and produce antibody-secreting cells upon recall • Bystander MBCs are not virus specific but retain exogenous antigens as immune complexes Lung-resident memory B cells (MBCs) provide rapid protection against reinfection with airborne pathogens. Gregoire et al. demonstrate that two MBC subsets with discrete transcriptional programs reside in the lung peribronchial niche: "bona fide" virus-specific MBCs, which dominate recall responses, and "bystander" non-specific MBCs, which locally retain antigens as immune complexes. [ABSTRACT FROM AUTHOR]