Humanized Transgenic Mice Are Resistant to Chronic Wasting Disease Prions From Norwegian Reindeer and Moose

Wadsworth, Jonathan D. F.; Joiner, Susan; Linehan, Jacqueline M.; Jack, Kezia; Al-Doujaily, Huda; Costa, Helena; Ingold, Thea; Taema, Maged M.; Zhang, Fuquan; Sandberg, Malin; Brandner, Sebastian; Tran, Linh; Vikøren, Turid; Våge, Jørn; Madslien, Knut; Ytrehus, Bjørnar; Benestad, Sylvie L.; Asante, Emmanuel A.; Collinge, John

doi:10.1093/infdis/jiab033

Cited by 30 publications

(32 citation statements)

References 15 publications

(37 reference statements)

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“…Primary passage of transmission experiments into humanized mice (transgenic mice expressing the human PRNP gene) with isolates from three of the Norwegian cases (one moose, one reindeer, and one red deer) were reassuringly negative, suggesting a strong transmission barrier to humans, as previously reported for North American CWD [ 104 ]. However, further investigations are ongoing, with several Norwegian CWD isolates and different lines of humanized mice.…”

Section: Cwd In Norwegian Reindeermentioning

confidence: 58%

Chronic wasting disease in Europe: new strains on the horizon

et al. 2021

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Prion diseases are fatal neurodegenerative disorders with known natural occurrence in humans and a few other mammalian species. The diseases are experimentally transmissible, and the agent is derived from the host-encoded cellular prion protein (PrPC), which is misfolded into a pathogenic conformer, designated PrPSc (scrapie). Aggregates of PrPSc molecules, constitute proteinaceous infectious particles, known as prions. Classical scrapie in sheep and goats and chronic wasting disease (CWD) in cervids are known to be infectious under natural conditions. In CWD, infected animals can shed prions via bodily excretions, allowing direct host-to-host transmission or indirectly via prion-contaminated environments. The robustness of prions means that transmission via the latter route can be highly successful and has meant that limiting the spread of CWD has proven difficult. In 2016, CWD was diagnosed for the first time in Europe, in reindeer (Rangifer tarandus) and European moose (Alces alces). Both were diagnosed in Norway, and, subsequently, more cases were detected in a semi-isolated wild reindeer population in the Nordfjella area, in which the first case was identified. This population was culled, and all reindeer (approximately 2400) were tested for CWD; 18 positive animals, in addition to the first diagnosed case, were found. After two years and around 25,900 negative tests from reindeer (about 6500 from wild and 19,400 from semi-domesticated) in Norway, a new case was diagnosed in a wild reindeer buck on Hardangervidda, south of the Nordfjella area, in 2020. Further cases of CWD were also identified in moose, with a total of eight in Norway, four in Sweden, and two cases in Finland. The mean age of these cases is 14.7 years, and the pathological features are different from North American CWD and from the Norwegian reindeer cases, resembling atypical prion diseases such as Nor98/atypical scrapie and H- and L-forms of BSE. In this review, these moose cases are referred to as atypical CWD. In addition, two cases were diagnosed in red deer (Cervus elaphus) in Norway. The emergence of CWD in Europe is a threat to European cervid populations, and, potentially, a food-safety challenge, calling for a swift, evidence-based response. Here, we review data on surveillance, epidemiology, and disease characteristics, including prion strain features of the newly identified European CWD agents.

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Section: Cwd In Norwegian Reindeermentioning

confidence: 58%

Chronic wasting disease in Europe: new strains on the horizon

et al. 2021

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“…The highly efficient peripheralization of CWD in NA deer and elk and resultant prion infectivity in skeletal muscle and other materials destined for consumption by humans [ 9 , 35 ], their ability to template in vitro conversion of human PrP [ 68 , 69 ], and the emerging results of transmission studies in non-human primates [ 70 – 72 ] elicit additional concern. As alluded to above, our findings in GtE226 and GtQ226 mice detailing the importance of peripheral PrP expression force us to reconsider the precision of Tg mice expressing human PrP for assessing zoonotic transmission of CWD [ 73 – 76 ] and suggest that Gt models provide an improved platform for making this determination. Unfortunately, previously generated knock-in mice designed to be susceptible to human prions had long incubation times and incomplete attack rates; similarly constructed knock-in mice designed to be susceptible to BSE were paradoxically less responsive to this strain than their wild type mouse counterparts [ 77 , 78 ].…”

Section: Discussionmentioning

confidence: 99%

Adaptive selection of a prion strain conformer corresponding to established North American CWD during propagation of novel emergent Norwegian strains in mice expressing elk or deer prion protein

et al. 2021

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Prions are infectious proteins causing fatal, transmissible neurodegenerative diseases of animals and humans. Replication involves template-directed refolding of host encoded prion protein, PrPC, by its infectious conformation, PrPSc. Following its discovery in captive Colorado deer in 1967, uncontrollable contagious transmission of chronic wasting disease (CWD) led to an expanded geographic range in increasing numbers of free-ranging and captive North American (NA) cervids. Some five decades later, detection of PrPSc in free-ranging Norwegian (NO) reindeer and moose marked the first indication of CWD in Europe. To assess the properties of these emergent NO prions and compare them with NA CWD we used transgenic (Tg) and gene targeted (Gt) mice expressing PrP with glutamine (Q) or glutamate (E) at residue 226, a variation in wild type cervid PrP which influences prion strain selection in NA deer and elk. Transmissions of NO moose and reindeer prions to Tg and Gt mice recapitulated the characteristic features of CWD in natural hosts, revealing novel prion strains with disease kinetics, neuropathological profiles, and capacities to infect lymphoid tissues and cultured cells that were distinct from those causing NA CWD. In support of strain variation, PrPSc conformers comprising emergent NO moose and reindeer CWD were subject to selective effects imposed by variation at residue 226 that were different from those controlling established NA CWD. Transmission of particular NO moose CWD prions in mice expressing E at 226 resulted in selection of a kinetically optimized conformer, subsequent transmission of which revealed properties consistent with NA CWD. These findings illustrate the potential for adaptive selection of strain conformers with improved fitness during propagation of unstable NO prions. Their potential for contagious transmission has implications for risk analyses and management of emergent European CWD. Finally, we found that Gt mice expressing physiologically controlled PrP levels recapitulated the lymphotropic properties of naturally occurring CWD strains resulting in improved susceptibilities to emergent NO reindeer prions compared with over-expressing Tg counterparts. These findings underscore the refined advantages of Gt models for exploring the mechanisms and impacts of strain selection in peripheral compartments during natural prion transmission.

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“…Due to their recent identification, many studies are still ongoing and needed to assess the zoonotic risks associated with the Scandinavian CWD strains and help determining strategies to limit their impact on the wild and farm-populations. Recently, it was shown that humanized mice resisted infection with these agents (primary passage negative) [80]. A larger set of experiments, including (i) transgenic models in which peripheral replication can be addressed because prion zoonosis can be tissue specific [67], (ii) a larger panel of CWD isolates from different species because it can impact the transmission properties as exemplified with sheep-passaged BSE [81], are necessary to conclude on the zoonotic potential of CWD prions.…”

Section: Interspecies Transmission Of Cwdmentioning

confidence: 99%

Review on PRNP genetics and susceptibility to chronic wasting disease of Cervidae

Moazami‐Goudarzi

Andréoletti

Vilotte

et al. 2021

Vet Res

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To date, chronic wasting disease (CWD) is the most infectious form of prion disease affecting several captive, free ranging and wild cervid species. Responsible for marked population declines in North America, its geographical spread is now becoming a major concern in Europe. Polymorphisms in the prion protein gene (PRNP) are an important factor influencing the susceptibility to prions and their rate of propagation. All reported cervid PRNP genotypes are affected by CWD. However, in each species, some polymorphisms are associated with lower attack rates and slower progression of the disease. This has potential consequences in terms of genetic selection, CWD diffusion and strain evolution. CWD also presents a zoonotic risk due to prions capacity to cross species barriers. This review summarizes our current understanding of CWD control, focusing on PRNP genetic, strain diversity and capacity to infect other animal species, including humans.

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Humanized Transgenic Mice Are Resistant to Chronic Wasting Disease Prions From Norwegian Reindeer and Moose

Cited by 30 publications

References 15 publications

Chronic wasting disease in Europe: new strains on the horizon

Chronic wasting disease in Europe: new strains on the horizon

Adaptive selection of a prion strain conformer corresponding to established North American CWD during propagation of novel emergent Norwegian strains in mice expressing elk or deer prion protein

Review on PRNP genetics and susceptibility to chronic wasting disease of Cervidae

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