Transmission of Elk and Deer Prions to Transgenic Mice

Abstract

Chronic wasting disease (CWD) is a fatal prion disease in deer and elk. Unique among the prion diseases, it is transmitted among captive and free-ranging animals. To facilitate studies of the biology of CWD prions, we generated five lines of transgenic (Tg) mice expressing prion protein (PrP) from Rocky Mountain elk (Cervus elaphus nelsoni), denoted Tg(ElkPrP), and two lines of Tg mice expressing PrP common to white-tailed deer (Odocoileus virginianus) and mule deer (Odocoileus hemionus), denoted Tg(DePrP). None of the Tg(ElkPrP) or Tg(DePrP) mice exhibited spontaneous neurologic dysfunction at more than 600 days of age. Brain samples from CWD-positive elk, white-tailed deer, and mule deer produced disease in Tg(ElkPrP) mice between 180 and 200 days after inoculation and in Tg(DePrP) mice between 300 and 400 days. One of eight cervid brain inocula transmitted disease to Tg(MoPrP)4053 mice overexpressing wild-type mouse PrP-A in ϳ540 days. Neuropathologic analysis revealed abundant PrP amyloid plaques in the brains of ill mice. Brain homogenates from symptomatic Tg(ElkPrP) mice produced disease in 120 to 190 days in Tg(ElkPrP) mice. In contrast to the Tg(ElkPrP) and Tg(DePrP) mice, Tg mice overexpressing human, bovine, or ovine PrP did not develop prion disease after inoculation with CWD prions from among nine different isolates after >500 days. These findings suggest that CWD prions from elk, mule deer, and white-tailed deer can be readily transmitted among these three cervid species.

A prion disease of cervids: Chronic wasting disease

“…Whereas the elk PrP expressing mice developed disease after only 118-142 days post-inoculation, human PrP expressing mice (129M) did not develop any features of TSE after more than 657 or more than 756 days [41]. In accordance with these results, Tamgüney et al also reported that human PrP overexpressing mice were not susceptible to nine CWD isolates from mule deer, white-tailed deer, and elk [84]. However, mice have a limited lifespan and further passages may be necessary to detect low levels of prion pinfectivity that may be present subclinically.…”

“…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].…”