title: Subcapsular sinus macrophages prevent CNS invasion on peripheral infection with a neurotropic virus.
abstract: Lymph nodes (LNs) capture microorganisms that breach the body's 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.
authors.affiliation: Immune Disease Institute and Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA. Matteo_Iannacone@hms.harvard.edu
authors.forename: Matteo
authors.initials: M
authors.lastname: Iannacone
authors.forename: E Ashley
authors.initials: EA
authors.lastname: Moseman
authors.forename: Elena
authors.initials: E
authors.lastname: Tonti
authors.forename: Lidia
authors.initials: L
authors.lastname: Bosurgi
authors.forename: Tobias
authors.initials: T
authors.lastname: Junt
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Henrickson
authors.forename: Sean P
authors.initials: SP
authors.lastname: Whelan
authors.forename: Luca G
authors.initials: LG
authors.lastname: Guidotti
authors.forename: Ulrich H
authors.initials: UH
authors.lastname: von Andrian
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000166:cytology / Q000276:immunology* / Q000821:virology*; D003713:Dendritic Cells / Q000276:immunology; D007267:Injections; D007370:Interferon Type I / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology* / Q000294:innervation / Q000821:virology*; D008264:Macrophages / Q000276:immunology* / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010243:Paralysis / Q000150:complications / Q000821:virology; D010525:Peripheral Nerves / Q000821:virology; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency; D018353:Rhabdoviridae Infections / Q000150:complications / Q000276:immunology* / Q000821:virology; D015996:Survival Rate; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology; D054260:Vesicular stomatitis New Jersey virus / Q000276:immunology / Q000472:pathogenicity / Q000502:physiology; D018116:Vesiculovirus / Q000276:immunology* / Q000472:pathogenicity / Q000502:physiology
chemical_list: C508032:Ifnar1 protein, mouse; D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta