title: Genetic depletion of complement receptors CD21/35 prevents terminal prion disease in a mouse model of chronic wasting disease.
abstract: The complement system has been shown to facilitate peripheral prion pathogenesis. Mice lacking complement receptors CD21/35 partially resist terminal prion disease when infected i.p. with mouse-adapted scrapie prions. Chronic wasting disease (CWD) is an emerging prion disease of captive and free-ranging cervid populations that, similar to scrapie, has been shown to involve the immune system, which probably contributes to their relatively facile horizontal and environmental transmission. In this study, we show that mice overexpressing the cervid prion protein and susceptible to CWD (Tg(cerPrP)5037 mice) but lack CD21/35 expression completely resist clinical CWD upon peripheral infection. CD21/35-deficient Tg5037 mice exhibit greatly impaired splenic prion accumulation and replication throughout disease, similar to CD21/35-deficient murine prion protein mice infected with mouse scrapie. TgA5037;CD21/35(-/-) mice exhibited little or no neuropathology and deposition of misfolded, protease-resistant prion protein associated with CWD. CD21/35 translocate to lipid rafts and mediates a strong germinal center response to prion infection that we propose provides the optimal environment for prion accumulation and replication. We further propose a potential role for CD21/35 in selecting prion quasi-species present in prion strains that may exhibit differential zoonotic potential compared with the parental strains.
authors.affiliation: Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University Prion Research Center, Fort Collins, CO 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: Bruce
authors.initials: B
authors.lastname: Pulford
authors.forename: Adriana
authors.initials: A
authors.lastname: von Teichman
authors.forename: Davis
authors.initials: D
authors.lastname: Seelig
authors.forename: John H
authors.initials: JH
authors.lastname: Weis
authors.forename: Glenn C
authors.initials: GC
authors.lastname: Telling
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
authors.forename: Mark D
authors.initials: MD
authors.lastname: Zabel
mesh_terms: D000818:Animals; D003670:Deer; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques / Q000379:methods; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017096:Prion Diseases / Q000276:immunology / Q000401:mortality / Q000517:prevention & control; D011951:Receptors, Complement / Q000172:deficiency* / Q000235:genetics*; D017463:Receptors, Complement 3b / Q000172:deficiency* / Q000235:genetics*; D017464:Receptors, Complement 3d / Q000172:deficiency* / Q000235:genetics*; D034081:Wasting Disease, Chronic / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*
chemical_list: D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D017464:Receptors, Complement 3d