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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 pathogens1. 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 responses2,3,4. 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.

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Figure 1: Lymph node macrophages confer resistance to fatal invasion of the CNS on peripheral low-dose infection with VSV.
Figure 2: SCS macrophages are the primary targets for lymph-borne VSV and prevent infection of adjacent nerves.
Figure 3: Regulation of VSV-induced IFN-I production by SCS macrophages.

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Acknowledgements

We thank G. Cheng and M. Flynn for technical support; J. Alton for secretarial assistance; D. Cureton for help and advice with VSV preparations; H. Leung for help with image quantification; R. M. Zinkernagel and H. Hengartner for providing tg7 mice; R. Bronson for help with reading neuropathology; S. Cohen for advice on nerve staining; N. van Rooijen for clodronate liposomes; and the members of the von Andrian laboratory for discussion. This work was supported by National Institutes of Health (NIH) grants AI069259, AI072252, AI078897 and AR42689 (to U.H.v.A.), the Giovanni Armenise-Harvard Foundation (to M.I.) and a NIH T32 Training Grant in Hematology (to E.A.M.).

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M.I., E.A.M. and U.H.v.A. designed the study. M.I., E.A.M., E.T., L.B. and T.J. performed experiments. M.I., E.A.M., E.T. and L.B. collected and analysed data. S.P.W. provided reagents and performed the RT–PCR experiment. S.E.H. contributed to the nerve imaging. L.G.G. provided mice and gave conceptual advice. M.I., E.A.M. and U.H.v.A. wrote the manuscript. M.I. and E.A.M contributed equally to this work.

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Correspondence to Matteo Iannacone or Ulrich H. von Andrian.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-13 with legends and legends for Supplementary Movies 1-2. (PDF 1161 kb)

Supplementary Movie 1

This movie shows a three-dimensional rotation view followed by Z-stack projection of the MP-IVM stack used to generate Fig. 2e (see Supplementary Information file for full legend). (MOV 12971 kb)

Supplementary Movie 2

This movie shows a three-dimensional rotation view followed by Z-stack projection of the MP-IVM stack used to generate Fig. 2f (see Supplementary Information file for full legend). (MOV 8989 kb)

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Iannacone, M., Moseman, E., Tonti, E. et al. Subcapsular sinus macrophages prevent CNS invasion on peripheral infection with a neurotropic virus. Nature 465, 1079–1083 (2010). https://doi.org/10.1038/nature09118

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