The elk PRNP codon 132 polymorphism controls cervid and scrapie prion propagation

• Published in: Journal of general virology Vol. 89; no. 2; pp. 598 - 608
• Main Authors: Green, Kristi M, Browning, Shawn R, Seward, Tanya S, Jewell, Jean E, Ross, Dana L, Green, Michael A, Williams, Elizabeth S, Hoover, Edward A, Telling, Glenn C
• Format: Journal Article
• Language: English
• Published: Reading Soc General Microbiol 01.02.2008; Society for General Microbiology
• Subjects: Animals; Biological and medical sciences; Cervidae; Codon; Deer; Disease Models, Animal; Disease Susceptibility; Fundamental and applied biological sciences. Psychology; Mice; Mice, Transgenic; Microbiology; Miscellaneous; Polymorphism, Genetic; Prion Diseases - transmission; Prions - metabolism; PrPC Proteins - genetics; PrPC Proteins - isolation & purification; Scrapie; Virology; Wasting Disease, Chronic - genetics; Wasting Disease, Chronic - transmission; Prion disease; Nervous system diseases; Microbiology; Scrapie; Cerebral disorder; Infection; Vertebrata; Mammalia; Codon; Central nervous system disease; Sheep; Degenerative disease; Prion; Artiodactyla; Spongiform encephalopathy; Veterinary; Ungulata; Polymorphism
• ISSN: 0022-1317; 1465-2099
• DOI: 10.1099/vir.0.83168-0

1 Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, KY, USA 2 Sanders Brown Center on Aging, University of Kentucky, Lexington, KY, USA 3 Department of Veterinary Sciences, University of Wyoming, Laramie, WY, USA 4 Transgenic Facility, University of Kentucky, Lexington, KY, USA 5 Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO, USA 6 Department of Neurology, University of Kentucky, Lexington, KY, USA Correspondence Glenn C. Telling gtell2{at}uky.edu The elk prion protein gene ( PRNP ) encodes either methionine (M) or leucine (L) at codon 132, the L132 allele apparently affording protection against chronic wasting disease (CWD). The corresponding human codon 129 polymorphism influences the host range of bovine spongiform encephalopathy (BSE) prions. To fully address the influence of this cervid polymorphism on CWD pathogenesis, we created transgenic (Tg) mice expressing cervid PrP C with L at residue 132, referred to as CerPrP C -L132, and compared the transmissibility of CWD prions from elk of defined PRNP genotypes, namely homozygous M/M or L/L or heterozygous M/L, in these Tg mice with previously described Tg mice expressing CerPrP C -M132, referred to as Tg(CerPrP) mice. While Tg(CerPrP) mice were consistently susceptible to CWD prions from elk of all three genotypes, Tg(CerPrP-L132) mice uniformly failed to develop disease following challenge with CWD prions. In contrast, SSBP/1 sheep scrapie prions transmitted efficiently to both Tg(CerPrP) and Tg(CerPrP-L132) mice. Our findings suggest that the elk 132 polymorphism controls prion susceptibility at the level of prion strain selection and that cervid PrP L132 severely restricts propagation of CWD prions. We speculate that the L132 polymorphism results in less efficient conversion of CerPrP C -L132 by CWD prions, an effect that is overcome by the SSBP/1 strain. Our studies show the accumulation of subclinical levels of CerPrP Sc in aged asymptomatic CWD-inoculated Tg(CerPrP-L132) mice and also suggests the establishment of a latent infection state in apparently healthy elk expressing this seemingly protective allele. Present address: Department of Infectology, Scripps Research Institute, 5353 Parkside Drive, RF-2, Jupiter, FL 33458, USA. Supplementary material is available with the online version of this paper.