A complement–microglial axis drives synapse loss during virus-induced memory impairment
Michael J. Vasek,Charise Garber,Denise A. Dorsey,Douglas M. Durrant,Douglas M. Durrant,Bryan Bollman,Allison Soung,Jinsheng Yu,Carlos J. Perez-Torres,Arnaud Frouin,Daniel K. Wilton,Kristen E. Funk,Bette K. DeMasters,Xiaoping Jiang,James R. Bowen,Steven Mennerick,John K. Robinson,Joel R. Garbow,Kenneth L. Tyler,Mehul S. Suthar,Robert E. Schmidt,Beth Stevens,Robyn S. Klein +22 more
TLDR
It is shown that viral infection of adult hippocampal neurons induces complement-mediated elimination of presynaptic terminals in a murine WNV neuroinvasive disease model, which 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.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.read more
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Microglia emerge as central players in brain disease.
Michael W. Salter,Beth Stevens +1 more
TL;DR: Recent developments in the rapidly expanding understanding of the function, as well as the dysfunction, of microglia in disorders of the CNS are focused on.
Journal ArticleDOI
Microglia and macrophages in brain homeostasis and disease
Qingyun Li,Ben A. Barres +1 more
TL;DR: The current knowledge of how and where brain macrophages are generated is reviewed, with a focus on parenchymal microglia and their normal functions during development and homeostasis are discussed.
Journal ArticleDOI
Microglia in Alzheimer's disease.
TL;DR: Gene expression profiles indicate multiple states of microglial activation in neurodegenerative disease settings, which might explain the disparate roles ofmicroglia in the development and progression of AD pathology.
Journal ArticleDOI
Microglia in neurodegeneration.
TL;DR: The immune checkpoints that control microglial functions are considered and how their imbalance and subsequent neuroinflammation leads to neurodegeneration is discussed.
Journal ArticleDOI
Human Coronaviruses and Other Respiratory Viruses: Underestimated Opportunistic Pathogens of the Central Nervous System?
Marc Desforges,Alain Le Coupanec,Philippe Dubeau,Andréanne Bourgouin,Louise Lajoie,Mathieu Dubé,Mathieu Dubé,Pierre J. Talbot +7 more
TL;DR: A global portrait of some of the most prevalent or emerging human respiratory viruses that have been associated with possible pathogenic processes in CNS infection, with a special emphasis on human coronaviruses.
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