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Published on: September 12, 2016
Subcapsular sinus macrophages prevent CNS invasion on peripheral infection with a neurotropic virus
Matteo Iannacone1, E Ashley Moseman, Elena Tonti
1Immune Disease Institute and Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA. Matteo_Iannacone@hms.harvard.edu
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.
Insights
Subcapsular sinus macrophages in lymph nodes prevent neurotropic viruses from reaching the central nervous system. Depleting these macrophages leads to fatal paralysis, highlighting their critical gatekeeper role in antiviral defense.
Area of Science:
- Immunology
- Virology
- Neuroscience
Background:
- Lymph nodes (LNs) are crucial for pathogen capture and immune response initiation.
- Subcapsular sinus (SCS) macrophages are known to clear viruses and initiate antiviral humoral immunity.
- The role of SCS macrophages in preventing neurotropic viral invasion of the central nervous system (CNS) is not well understood.
Purpose of the Study:
- To investigate the role of SCS macrophages in preventing lymph-borne neurotropic virus entry into the CNS.
- To elucidate the mechanisms by which SCS macrophages confer protection against neurotropic viral infections.
Main Methods:
- Utilized vesicular stomatitis virus (VSV), a neurotropic virus, in mouse models.
- Employed local depletion of LN macrophages to assess their necessity in preventing VSV neuroinvasion.
- Conducted experiments using bone marrow chimaeric mice to investigate the roles of different cellular compartments and type I interferon (IFN-I).
Main Results:
- Depletion of LN macrophages resulted in VSV neuroinvasion via peripheral nerves and fatal ascending paralysis in approximately 60% of mice.
- In macrophage-sufficient LNs, VSV replicated within SCS macrophages but did not infect adjacent nerves.
- SCS macrophages were identified as a major source of type I interferon (IFN-I) and recruited IFN-I-producing plasmacytoid dendritic cells, crucial for preventing lethal VSV infection.
Conclusions:
- SCS macrophages act as critical gatekeepers, preventing lymph-borne neurotropic viruses from accessing the CNS.
- IFN-I signaling, acting on both hematopoietic and stromal compartments including intranodal nerves, is essential for protection mediated by SCS macrophages.
- These findings reveal a novel and vital function of SCS macrophages in protecting the CNS from viral infections originating peripherally.
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