Tuesday, October 15, 2013

AD.47: Polymorphic variations in cervid prion protein affect CWD agent properties

AD.47: Polymorphic variations in cervid prion protein affect CWD agent properties


Camilo Duque-Velasquez,1 Allen Herbst1 Chiye Kim,1 Chad Johnson,2 Judd Aiken1 and Debbie McKenzie1 'Centre for Prions and Protein Folding Diseases; University of Alberta; Edmonton, AB Canada; 2Soil Sciences Department; University of Wisconsin; Madison, WI USA


Chronic wasting disease (CWD) is a prion disease of free ranging and farmed cervids of North America. Similar to other prion diseases, such as sheep Scrapie and bovine spongiform encephalopathy, it appears there are isolates of CWD with distinct biological properties (i.e., strains).


Experimental evidence has confirmed the link between variations in the primary structure of the prion protein, PrPres properties and differential susceptibility to prion infection.


Given the variability of the amino acid sequence of the prion protein in cervids and the contagious nature of the disease, there is a likelihood of continuous agent adaptation. As a result, CWD strains circulating within heterogeneous cervid populations might be subjected to structural variations, when replicating in polymorphic PRNP genotypes, affecting strain-specific biological and physico-chemical properties.


We have previously shown that PRNP polymorphisms Q95G96 (wt), H95G96 (H95) and Q95S96 (S96) influence susceptibility to CWD in free-ranging white-railed deer.'


Oral infection of white-tailed deer of known PRNP genotypes (with inoculum from CWD-positive wt/wt deer) confirmed the link between prion protein primary sequence, disease progression and PrPCWD properties.2 Deer homozygous for wt alleles had the shortest incubation period, while heterogeneity of the PRNP alleles resulted in differential extension of the incubation period: wt/S96 > wt/H95 > H95/S96. Interestingly, biochemical and structural properties of the proteinase K-res PrPCWD of wt/H95 and wt/S96 isolates resemble the wt/wt profile. CWD from deer heterozygous for H95/S96 exhibited distinct properties, suggesting that this isolate might be a unique CWD strain.


Inoculation of transgenic (tg) mice expressing wt and S96 alleles with CWD isolates of defined PRNP genotype resulted in 100% attack rates for tg mice expressing the wt allele. S96 tg mice succumbed with CWD only when inoculated with isolates from wt/H95 and H95/S96 deer. Since infection of these transgenic lines with CWD isolates from Colorado/Wyoming suggested that S96 polymorphism conferred resistance to develop CWD infection3 our data further suggests that CWD prions containing H95 PrP, expand their tropism to infect resistant genotypes while maintaining tropism for the original host genotype. Given that CWD endemic zones are geographical areas where different cervids species might overlap their niches, some PRNP alleles might facilitate inter-and intra-species CWD transmission.




1. Johnson C. Johnson J. Vanderloo JP, Keane D, Aiken JM, McKenzie D. Prion protein polymorphisms in white-tailed deer influence susceptibility to chronic wasting disease. J Gen Virol 2006; 87:2109-14: PMID:16760415; http://dx.doi.org/10.1099/vir.0.81615-0


2. Johnson CJ, Herbst A. Duque-Velasquez C, Vanderloo JP. Bochsler P. Chappell R, et al. Prion protein polymorphisms affect chronic wasting disease progression. PLoS One 2011; 6:e17450; PMID:21445256: http://dx.doi.org/10.1371/journal.pone.0017450


3. Meade-White K, Race B, Trifilo M, Bossers A, Favara C. Lacasse R. et al. Resistance to chronic wasting disease in transgenic mice expressing a naturally occurring allelic variant of deer prion protein. J Virol 2007; 81 :4533-9; PMID: 17314157; http://dx.doi.org/10.1128/JVI.02762-06
















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