Subcapsular Sinus Macrophages Prevent CNS Invasion Upon Peripheral Infection With a Neurotropic Virus

Lymph nodes (LNs) capture microorganisms that breach the body’s external barriers and enter draining lymphatics, limiting the systemic spread of pathogens1. Recent work has shown that CD11b(+)CD169(+) macrophages, which populate the subcapsular sinus (SCS) of LNs, are critical for clearance of viruses from the lymph and for initiating antiviral humoral immune responses2,3,4. Using vesicular stomatitis virus (VSV), a relative of rabies virus transmitted by insect bites, we show here that SCS macrophages perform a third vital function: they prevent lymph-borne neurotropic viruses from infecting the CNS. Upon local depletion of LN macrophages, ~60% of mice developed ascending paralysis and died 7–10 days after subcutaneous infection with a small dose of VSV, while macrophage-sufficient animals remained asymptomatic and cleared the virus. VSV gained access to the nervous system via peripheral nerves in macrophage-depleted LNs. In contrast, within macrophage-sufficient LNs VSV replicated preferentially within SCS macrophages but not in adjacent nerves. Removal of SCS macrophages did not compromise adaptive immune responses against VSV, but reduced type I interferon (IFN-I) production within infected LNs. VSV-infected macrophages recruited IFN-I producing plasmacytoid dendritic cells to the SCS and additionally were a major source of IFN-I themselves. Experiments in bone marrow chimeric mice revealed that IFN-I must act on both hematopoietic and stromal compartments, including the intranodal nerves, to prevent lethal VSV infection. These results identify SCS macrophages as crucial gatekeepers to the CNS that prevent fatal viral neuroinvasion upon peripheral infection.