Subcapsular sinus macrophages prevent CNS invasion on peripheral infection with a neurotropic virus

Matteo Iannacone, E. Ashley Moseman, Elena Tonti, Lidia Bosurgi, Tobias Junt, Sarah E. Henrickson, Sean P. Whelan, Luca G. Guidotti, Ulrich H. Von Andrian

Research output: Contribution to journalArticlepeer-review

Abstract

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

Original languageEnglish
Pages (from-to)1079-1083
Number of pages5
JournalNature
Volume465
Issue number7301
DOIs
Publication statusPublished - Jun 24 2010

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Subcapsular sinus macrophages prevent CNS invasion on peripheral infection with a neurotropic virus'. Together they form a unique fingerprint.

Cite this