Resistance to Chronic Wasting Disease in Transgenic Mice Expressing a Naturally Occurring Allelic Variant of Deer Prion Protein

Abstract

Prion protein (PrP) is a required factor for susceptibility to transmissible spongiform encephalopathy or prion diseases. In transgenic mice, expression of prion protein (PrP) from another species often confers susceptibility to prion disease from that donor species. For example, expression of deer or elk PrP in transgenic mice has induced susceptibility to chronic wasting disease (CWD), the prion disease of cervids. In the current experiments, transgenic mice expressing two naturally occurring allelic variants of deer PrP with either glycine (G) or serine (S) at residue 96 were found to differ in susceptibility to CWD infection. G96 mice were highly susceptible to infection, and disease appeared starting as early as 160 days postinfection. In contrast, S96 mice showed no evidence of disease or generation of disease-associated protease-resistant PrP (PrPres) over a 600-day period. At the time of clinical disease, G96 mice showed typical vacuolar pathology and deposition of PrPres in many brain regions, and in some individuals, extensive neuronal loss and apoptosis were noted in the hippocampus and cerebellum. Extraneural accumulation of PrPres was also noted in spleen and intestinal tissue of clinically ill G96 mice. These results demonstrate the importance of deer PrP polymorphisms in susceptibility to CWD infection. Furthermore, this deer PrP transgenic model is the first to demonstrate extraneural accumulation of PrPres in spleen and intestinal tissue and thus may prove useful in studies of CWD pathogenesis and transmission by oral or other natural routes of infection.

Prion agent diversity and species barrier

“…This apparent lack of species barrier after homotypic transmission -i.e. when the host expresses a PrP gene identical to that of the infecting species -has led to the development of a long list of mice transgenic for sheep [60,197,203], bovine [20,41,48,175], human [5,22,113,190], cervid [30,82,113,117,134,188] and mink [206] PrP. Most of such lines were obtained by additional transgenesis, and have an endogenous PrP null (PrP 0/0 ) background, in order to avoid any interfering effect of the resident murine PrP gene [39,190].…”

“…Two other 'absolute' species barriers in mice have recently been broken. Expression of mink PrP [206] and cervid PrP [30,82,113,117,134,188] in transgenic mice render them susceptible to TME and CWD, respectively. It is noteworthy that the use of transgenic mice overexpressing mouse PrP C also allowed the propagation of the CWD agent [179].…”

A prion disease of cervids: Chronic wasting disease

“…Transgenic mice expressing cervid PrP of either allelic variant, denoted here as tg(CerPrP96G) and tg(CerPrP96S), were exposed to deer CWD [52]. Whereas the tg(CerPrP96G) mice were highly susceptible to infection and developed disease at 160 days post-infection, the tg(CerPrP96S) mice were completely resistant, with no clinical disease or PrP Sc deposits even at 600 dpi.…”

“…Several transgenic mice expressing cervid PrP have since been produced using different constructs and sequences [10,41,44,52,84] (detailed in Tab. I).…”

“…The widespread occurrence of CWD in farmed and free-ranging cervids has led to a surge in CWD research, focused on understanding species susceptibility, transmission and pathogenesis, spatial epidemiology, diagnostic tools, strains, and cervid PrP structure. Transgenic mice expressing cervid PrP have been generated in five laboratories [10,41,44,52,84], providing useful tools for CWD research. In this review, the latest advances in CWD research are discussed.…”