Passage of chronic wasting disease prion into transgenic mice expressing Rocky Mountain elk (Cervus elaphus nelsoni) PrPC

Abstract

Chronic wasting disease (CWD) of elk (Cervus elaphus nelsoni) and mule deer (Odocoileus hemionus) is one of three naturally occurring forms of prion disease, the others being Creutzfeldt-Jakob disease in humans and scrapie in sheep. In the last few decades, CWD has spread among captive and free-ranging cervids in 13 US states, two Canadian provinces and recently in Korea. The origin of the CWD agent(s) in cervids is not known. This study describes the development of a transgenic mouse line (TgElk) homozygous for a transgene array encoding the elk prion protein (PrP C ) and its use in propagating and simulating CWD in mice. Intracerebral injection of one mule deer and three elk CWD isolates into TgElk mice led to disease with incubation periods of 127 and 95 days, respectively. Upon secondary passage, the incubation time was reduced to 108 and 90 days, respectively. Upon passage into TgElk mice, CWD prions (PrP Sc ) maintained the characteristic Western blot profiles seen in CWD-affected mule deer and elk and produced histopathological modifications consistent with those observed in the natural disease. The short incubation time observed on passage from cervid to mouse with both mule deer and elk CWD brain homogenates and the demonstrated capacity of the animals to propagate (mouse to mouse) CWD agents make the TgElk line a valuable model to study CWD agents in cervid populations. In addition, these results with this new transgenic line suggest the intriguing hypothesis that there could be more than one strain of CWD agent in cervids.

A prion disease of cervids: Chronic wasting disease

“…Here, mice developed different PrP Sc aggregate morphologies in brain, either dense, congophilic plaques or fine, diffuse aggregates which could be selectively passaged [78]. LaFauci et al have reported that elk PrP expressing transgenic mice developed phenotypically divergent diseases when inoculated with either mule deer or elk CWD, which was suggestive of different strains among cervids [44]. In some of these studies, it is not clear whether mule deer and elk possess heterogeneous PrP aggregates (strain mixture), or whether the strains may have developed in the new host.…”

“…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.…”

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].…”