Iannacone, Matteo, Moseman, E. Ashley, Tonti, Elena, Bosurgi, Lidia, Junt, Tobias, Whelan, Sean P., Guidotti, Luca, von Andrian, Ulrich H. and Henrickson, S.E. (2010) Lymph Node Subcapsular Sinus Macrophages Confer Resistance to CNS Invasion Upon Peripheral Infection With a Neurotropic Virus. Nature, 465 (7301). pp. 1079-1083. ISSN 0028-0836

Abstract

Lymph nodes (LNs) capture microorganisms that breach the body's external barriers and enter draining lymphatics, thereby limiting the systemic spread of such 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 anti-viral humoral immune responses2,3,4. Using vesicular stomatitis virus (VSV), a relative to rabies virus that is typically 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 SCS macrophages, ~60% of mice developed ascending paralysis and died within 7-10 days after subcutaneous infection with a small dose of VSV that was readily cleared by macrophage-sufficient control animals. VSV gained access to the nervous system via peripheral nerves in macrophage-depleted LNs. In contrast, in macrophage-sufficient LNs VSV replicated preferentially within SCS macrophages but failed to replicate in adjacent nerves. Removal of SCS macrophages did not compromise the humoral or T cell responses against VSV, but it dramatically reduced the production of type I interferon (IFN-I) 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 lacking the IFN-I receptor in either hematopoietic or stromal cells revealed that IFN-I must act on both 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.

Item Type:	Article
Related URLs:	http://www.ncbi.nlm.nih.gov/pubmed?term=...
Additional Information:	author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords:	virus infection, macrophages
Related URLs:	http://www.ncbi.nlm.nih.gov/pubmed?term=...
Date Deposited:	13 Oct 2015 13:16
Last Modified:	13 Oct 2015 13:16
URI:	https://oak.novartis.com/id/eprint/2281