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A complement–microglial axis drives synapse loss during virus-induced memory impairment
Open accessAbstract
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.
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“Dysregulation of microglial phagocytosis of synapses has been implicated in the pathology of diverse neurological diseases (Hong et al., 2016; Lui et al., 2016; Vasek et al., 2016), failure to clear myelin debris contributes to CNS regenerative failure (Vargas and Barres, 2007), and problems with microglial uptake and clearance may contribute to aging-associated cognitive decline (Safaiyan et al.,”
From Diverse Requirements for Microglial Survival, Specification, and Function Revealed by Defined-Medium Cultures (2017) · cites this paper as Vasek et al., 2016
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“In WNV and Zika virus (ZIKV) encephalitis, microglia have been identified as orchestrators of spatial-learning impairments seen in the recovery phase after viral neuroinvasion [111, 324].”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [324]
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“Nonetheless, enhanced microglia-mediated synaptic engulfment during insult, infection or injury may well be a protective mechanism, for instance by preventing excitotoxicity and dampening nonsense signalling activity from damaged or injured neurons [342] or, in the context of neurotropic infection, by limiting trans-synaptic viral spread or aberrant calcium signalling by infected neurons [324].”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [324]
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“This is shown by the inappropriate removal of hippocampal synapses leading to circuitry dysfunction and spatial-learning deficits in the clinical recovery phase from WNV and ZIKV neuroinvasive disease [111, 324].”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [324]
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“In particular, C1q, the initiator of the classical complement pathway, which is produced by microglia in the brain, colocalizes with synaptic markers and may contribute to synapse loss in several neurodegenerative models (Hong et al., 2016a; Lui et al., 2016; Vasek et al., 2016”
From Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies (2018) · cites this paper as Vasek et al., 2016
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“recent evidence in various neurodegenerative models points to an important role for synapse loss via microglial phagocytosis (Hong et al., 2016a; Lui et al., 2016; Vasek et al., 2016”
From Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies (2018) · cites this paper as Vasek et al., 2016
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“Both studies show the importance of complement protein C3, the hydrolysed fragment of which, C3a, is recognized by microglial-expressed C3a receptor (C3aR), in the aberrant engulfment of synapses.”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [324]
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“complement activation and synapse loss seems to be a feature of multiple neurological diseases, including progranulin-deficient frontotemporal dementia (Lui et al., 2016”
From Changes in the Synaptic Proteome in Tauopathy and Rescue of Tau-Induced Synapse Loss by C1q Antibodies (2018) · cites this paper as Vasek et al., 2016
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“Physiological housekeeping functions include synaptic remodeling (a function critical for CNS development, homeostasis, and neurodegeneration20–22), migration to sites of neuronal death to phagocytose dead or dying cells23,24 or debris, and maintaining myelin homeostasis25.”
From Microglia in neurodegeneration (2018) · cites this paper as [20]
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“The complement pathway has been implicated in microglia-mediated synapse pruning (Hong et al., 2016; Vasek et al., 2016).”
From Complement C3aR Inactivation Attenuates Tau Pathology and Reverses an Immune Network Deregulated in Tauopathy Models and Alzheimer’s Disease (2018) · cites this paper as Vasek et al., 2016
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“This idea gained further support by a recent report showing a detrimental effect of C3aR in promoting viral-induced synapse loss and cognitive decline (Vasek et al., 2016).”
From Complement C3aR Inactivation Attenuates Tau Pathology and Reverses an Immune Network Deregulated in Tauopathy Models and Alzheimer’s Disease (2018) · cites this paper as Vasek et al., 2016
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Metadata
- Authors
- Vasek, M. J., Garber, C., Dorsey, D., Durrant, D. M., Bollman, B., Soung, A., Yu, J., Perez-Torres, C., Frouin, A., Wilton, D. K., Funk, K., DeMasters, B. K., Jiang, X., Bowen, J. R., Mennerick, S., Robinson, J. K., Garbow, J. R., Tyler, K. L., Suthar, M. S., Schmidt, R. E., Stevens, B., & Klein, R. S.
- Affiliations
- Washington University in St. Louis (US)
- Boston Children's Hospital (US)
- University of Colorado Anschutz (US)
- Emory University (US)
- Stony Brook University (US)
- Corresponding author
- Klein, Robyn S.
- ORCID
- Venue
- Nature
- Published
- 2016-06-22
- Volume
- 534
- Issue
- 7608
- Pages
- 538-543
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5452615
- OpenAlex
- W2471701648
- Cited by
- 671
- References
- 33
- Citations by year
- 2026: 33 · 2025: 44 · 2024: 70 · 2023: 78 · 2022: 87 · 2021: 110 · 2020: 64 · 2019: 63 · 2018: 57 · 2017: 55 · 2016: 8
- FWCI
- 33.42
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Cancer Institute (P30CA091842)
- National Institute of Allergy and Infectious Diseases (U19AI083019, R01AI101400, T32AI052066)
- National Institute of Neurological Disorders and Stroke (R01NS052632, F31NS077640)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD090255)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Mosquito-borne diseases and control
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- West Nile virus, complement system, microglia, synaptic pruning, memory impairment, hippocampus, C1QA, C3a receptor, IL-34, neuroinvasive infection, spatial learning, CA3, neuroinflammation, viral encephalitis, complement C3a
- MeSH terms
- Animals, Complement System Proteins, Complement Activation, Complement Pathway, Classical, Disease Models, Animal, Female, Humans, Male, Memory Disorders, Neuronal Plasticity, Neurons, West Nile Fever, West Nile virus, Microglia, Presynaptic Terminals, Mice, CA3 Region, Hippocampal, Spatial Memory
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