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 intraperitoneally with mouse-adapted scrapie prions. Chronic wasting disease (CWD) is an emerging prion disease of captive and free-ranging cervid populations that, like scrapie, has been shown to involve the immune system, which probably contributes to their relatively facile horizontal and environmental transmission. Here 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 PrP mice infected with mouse scrapie. TgA5037;CD21/35-/- mice exhibited little or no neuropathology and deposition of misfolded, protease-resistant PrP associated with CWD. CD21/35 translocates 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 to the parental strains.

Murine complement receptor 1 is required for germinal center B cell maintenance but not initiation

“…FDC are responsible for the trapping of antigen via C and Fc receptors (Tew, et al, 1997, Roozendaal, et al, 2009) and for orchestrating the GC reaction (Wang, et al, 2011, Donius, et al, 2013). The recent development of a mouse specifically deficient for the Cr1 isoform of Cr2 , the Cr1KO mouse, and the revelation that Cr1 is the nearly exclusive isoform expressed by the stromal compartment FDCs, suggested that the Cr1-deficiency ( Cr1KO ) may result in a significant reduction in GC output of high affinity antibody producing cells and memory B cells (Donius, et al, 2013, Michel, et al, 2012). …”

Clay Components in Soil Dictate Environmental Stability and Bioavailability of Cervid Prions in Mice

“…Tg(CerPrP)5037 mice express elk PrP C and are susceptible to PrP CWD infection by multiple routes (Angers et al, 2009; Michel et al, 2012a). Mice were used in this experiment as opposed to the natural host due to shorter incubation times, smaller space requirements, much lower cost, greater tolerance to handling (Groschup and Buschmann, 2008), feasibly larger group sizes and, most importantly, no a priori exposure to potential PrP CWD environmental contamination.…”

“…One hemisphere of cervid each brain was separately homogenized to a 10% dilution with sPMCA buffer (4 mM EDTA, 150 mM NaCl in PBS) in a commercial blender as previously described (Michel et al, 2012a) and aliquots were stored at −80°C until needed. E2 was the primary CWD isolate used in this study; D10 was used in previous studies.…”

“…We used sPMCA to detect PrP CWD in frozen brains and feces after homogenization as previously described (7). Fixed tissues were assessed by histological techniques including H&E, GFAP, and IHC analysis (Michel et al, 2012a). Mice found positive by either sPMCA or IHC were considered CWD-positive, regardless of clinical signs.…”

Complement Regulatory Protein Factor H Is a Soluble Prion Receptor That Potentiates Peripheral Prion Pathogenesis

“…CD21/35- and PrP C -expressing follicular dendritic cells (FDC) and B cells capture pathogens opsonized with C3 and C4 cleavage products, decreasing the threshold to activate B cells to induce antibody production. Both FDCs and B cells promote prion disease (5–11). Many studies suggest Complement promotes trafficking of infectious prions to cells expressing PrP C , a substrate for prion replication, in lymphoid follicles.…”