title: Complement protein C3 exacerbates prion disease in a mouse model of chronic wasting disease.
abstract: Accumulating evidence shows a critical role of the complement system in facilitating attachment of prions to both B cells and follicular dendritic cells and assisting in prion replication. Complement activation intensifies disease in prion-infected animals, and elimination of complement components inhibits prion accumulation, replication and pathogenesis. Chronic wasting disease (CWD) is a highly infectious prion disease of captive and free-ranging cervid populations that utilizes the complement system for efficient peripheral prion replication and most likely efficient horizontal transmission. Here we show that complete genetic or transient pharmacological depletion of C3 prolongs incubation times and significantly delays splenic accumulation in a CWD transgenic mouse model. Using a semi-quantitative prion amplification scoring system we show that C3 impacts disease progression in the early stages of disease by slowing the rate of prion accumulation and/or replication. The delayed kinetics in prion replication correlate with delayed disease kinetics in mice deficient in C3. Taken together, these data support a critical role of C3 in peripheral CWD prion pathogenesis.
authors.affiliation: Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University Prion Research Center, Fort Collins, Colorado 80523, USA.
authors.forename: Brady
authors.initials: B
authors.lastname: Michel
authors.forename: Adam
authors.initials: A
authors.lastname: Ferguson
authors.forename: Theodore
authors.initials: T
authors.lastname: Johnson
authors.forename: Heather
authors.initials: H
authors.lastname: Bender
authors.forename: Crystal
authors.initials: C
authors.lastname: Meyerett-Reid
authors.forename: A Christy
authors.initials: AC
authors.lastname: Wyckoff
authors.forename: Bruce
authors.initials: B
authors.lastname: Pulford
authors.forename: Glenn C
authors.initials: GC
authors.lastname: Telling
authors.forename: Mark D
authors.initials: MD
authors.lastname: Zabel
mesh_terms: D000818:Animals; D003176:Complement C3 / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D018450:Disease Progression; D051379:Mice; D018345:Mice, Knockout; D011328:Prions / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D034081:Wasting Disease, Chronic / Q000235:genetics / Q000276:immunology* / Q000401:mortality
chemical_list: D003176:Complement C3; D011328:Prions
keywords: CWD; PrPres; innate immunity
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