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Nature. 2016 Jun 23;534(7608):538-43. doi: 10.1038/nature18283.

A complement-microglial axis drives synapse loss during virus-induced memory impairment.

Author information

1
Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.
2
Biological Sciences Department, California State Polytechnic University, 3801 West Temple Avenue, Pomona, California 91768, USA.
3
Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63110, USA.
4
Department of Radiology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
5
Department of Neurology, F. M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
6
Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
7
Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri 63110, USA.
8
Department of Pediatrics and Children's Healthcare of Atlanta, Emory Vaccine Center, Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, Georgia 30329, USA.
9
Department of Psychology, Stony Brook University, Stony Brook, New York 11794, USA.
10
Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
11
Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, Missouri 63110, USA.

Abstract

Over 50% of patients who survive neuroinvasive infection with West Nile virus (WNV) exhibit chronic cognitive sequelae. Although thousands of cases of WNV-mediated memory dysfunction accrue annually, the mechanisms responsible for these impairments are unknown. The classical complement cascade, a key component of innate immune pathogen defence, mediates synaptic pruning by microglia during early postnatal development. Here we show that viral infection of adult hippocampal neurons induces complement-mediated elimination of presynaptic terminals in a murine WNV neuroinvasive disease model. Inoculation of WNV-NS5-E218A, a WNV with a mutant NS5(E218A) protein leads to survival rates and cognitive dysfunction that mirror human WNV neuroinvasive disease. WNV-NS5-E218A-recovered mice (recovery defined as survival after acute infection) display impaired spatial learning and persistence of phagocytic microglia without loss of hippocampal neurons or volume. Hippocampi from WNV-NS5-E218A-recovered mice with poor spatial learning show increased expression of genes that drive synaptic remodelling by microglia via complement. C1QA was upregulated and localized to microglia, infected neurons and presynaptic terminals during WNV neuroinvasive disease. Murine and human WNV neuroinvasive disease post-mortem samples exhibit loss of hippocampal CA3 presynaptic terminals, and murine studies revealed microglial engulfment of presynaptic terminals during acute infection and after recovery. Mice with fewer microglia (Il34(-/-) mice with a deficiency in IL-34 production) or deficiency in complement C3 or C3a receptor were protected from WNV-induced synaptic terminal loss. Our study provides a new murine model of WNV-induced spatial memory impairment, and identifies a potential mechanism underlying neurocognitive impairment in patients recovering from WNV neuroinvasive disease.

PMID:
27337340
PMCID:
PMC5452615
DOI:
10.1038/nature18283
[Indexed for MEDLINE]
Free PMC Article

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