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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4520-4527 |
| Number of pages | 8 |
| Journal | Journal of Immunology |
| Volume | 189 |
| Issue number | 9 |
| DOIs | |
| State | Published - Nov 1 2012 |
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Genetic depletion of complement receptors CD21/35 prevents terminal prion disease in a mouse model of chronic wasting disease. / Michel, Brady; Ferguson, Adam; Johnson, Theodore; Bender, Heather; Meyerett-Reid, Crystal; Pulford, Bruce; Von Teichman, Adriana; Seelig, Davis; Weis, John H.; Telling, Glenn C.; Aguzzi, Adriano; Zabel, Mark D.
In: Journal of Immunology, Vol. 189, No. 9, 01.11.2012, p. 4520-4527.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Genetic depletion of complement receptors CD21/35 prevents terminal prion disease in a mouse model of chronic wasting disease
AU - Michel, Brady
AU - Ferguson, Adam
AU - Johnson, Theodore
AU - Bender, Heather
AU - Meyerett-Reid, Crystal
AU - Pulford, Bruce
AU - Von Teichman, Adriana
AU - Seelig, Davis
AU - Weis, John H.
AU - Telling, Glenn C.
AU - Aguzzi, Adriano
AU - Zabel, Mark D.
PY - 2012/11/1
Y1 - 2012/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84867911587&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84867911587&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1201579
DO - 10.4049/jimmunol.1201579
M3 - Article
C2 - 23002439
AN - SCOPUS:84867911587
VL - 189
SP - 4520
EP - 4527
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 9
ER -