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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., Authors affiliations: (1) Centre d'Immunologie de Marseille-Luminy, Aix Marseille Université, Inserm, CNRS, Marseille, France (2) Ecole Normale Supérieure de Lyon, Université Claude Bernard – Lyon I, Université de Lyon, Lyon, France (3)Centre d'Immunophénomique, Aix Marseille Université , Inserm, CNRS, Marseille, France (4) TERI (Tumor Escape, Resistance and Immunity) Department, Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, Université Claude Bernard – Lyon 1, Université de Lyon, Inserm, CNRS, Lyon, France (5) Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA (6) Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China (7) University Paris-Saclay, Inserm U1015, Gustave Roussy Cancer Center, Villejuif, France (8) Singapore Immunology Network, A*STAR, Singapore, Singapore (9) Centre for Inflammation Biology and Cancer Immunology, Cancer Research UK King's Health Partners Centre, School of Immunology and Microbial Sciences, King's College London, London SE1 1UL, UK (10) Lead contact