title: A complement-microglial axis drives synapse loss during virus-induced memory impairment.
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.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Vasek
authors.affiliation: Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Charise
authors.initials: C
authors.lastname: Garber
authors.affiliation: Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Denise
authors.initials: D
authors.lastname: Dorsey
authors.affiliation: Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.|Biological Sciences Department, California State Polytechnic University, 3801 West Temple Avenue, Pomona, California 91768, USA.
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Durrant
authors.affiliation: Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: Bollman
authors.affiliation: Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Soung
authors.affiliation: Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Jinsheng
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Radiology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Perez-Torres
authors.affiliation: Department of Neurology, F. M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Frouin
authors.affiliation: Department of Neurology, F. M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Wilton
authors.affiliation: Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Funk
authors.affiliation: Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
authors.forename: Bette K
authors.initials: BK
authors.lastname: DeMasters
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Jiang
authors.affiliation: 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.
authors.forename: James R
authors.initials: JR
authors.lastname: Bowen
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Mennerick
authors.affiliation: Department of Psychology, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: John K
authors.initials: JK
authors.lastname: Robinson
authors.affiliation: Department of Radiology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Joel R
authors.initials: JR
authors.lastname: Garbow
authors.affiliation: Department of Neurology, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Tyler
authors.affiliation: 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.
authors.forename: Mehul S
authors.initials: MS
authors.lastname: Suthar
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Schmidt
authors.affiliation: Department of Neurology, F. M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Stevens
authors.affiliation: Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.|Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA.|Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
authors.forename: Robyn S
authors.initials: RS
authors.lastname: Klein
mesh_terms: D000818:Animals; D056654:CA3 Region, Hippocampal / Q000276:immunology / Q000473:pathology / Q000821:virology; D003167:Complement Activation; D003171:Complement Pathway, Classical / Q000276:immunology; D003165:Complement System Proteins / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology / Q000821:virology*; D051379:Mice; D017628:Microglia / Q000276:immunology*; D009473:Neuronal Plasticity; D009474:Neurons / Q000276:immunology / Q000473:pathology / Q000821:virology; D017729:Presynaptic Terminals / Q000276:immunology / Q000473:pathology*; D065852:Spatial Memory; D014901:West Nile Fever / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D014902:West Nile virus / Q000276:immunology / Q000472:pathogenicity*
chemical_list: D003165:Complement System Proteins