Transmissible spongiform encephalopathies: Prion genetics, transmission barriers, and disease control

Robert Dylan Harrington

doi:10.7273/000006148

Transmissible Spongiform Encephalopathies (TSE) are invariably fatal neurodegenerative diseases associated with misfolded prion protein. Host prion gene (PRNP) variation affects TSE transmission barriers within and between species, and forms the basis of disease control strategies. Reported herein are aspects of PRNP genetics related to prion transmission, species barriers, and management. A TSE species barrier in ruminant to carnivore transmission was investigated by the hypothesis that primary oral challenge with chronic wasting disease (CWD) causes a prion disease in mink. It was found that while CWD can cause a prion disease when given intracerebrally to mink, such disease is not characteristic of Transmissible Mink Encephalopathy (TME) and oral challenge does not result in disease. A novel PRNP variant at codon 27 variant may affect TSE transmission, possibly by altered membrane localization of normal prion protein. This study shows that CWD is poorly transmissible to non-cervid hosts, CWD is an unlikely cause of TME, and mink are an unlikely to be involved in natural CWD transmission. Thus, Bovine Spongiform Encephalopathy is the only ruminant TSE orally transmissible to mink suggesting that a previously unrecognized prion-like disease was a cause of some cases of TME. The effect of PRNP promoter regions upon TSE transmission was examined by the hypothesis that transgenic incorporation of the cervid PRNP putative promoter (PP) region and open reading frame (ORF) renders transgenic mice susceptible to CWD administered by intracerebral, intraperitoneal, and oral routes. Transgenic insertion of a mule deer PRNP PP and ORF transgene resulted in stable transcription and translation in mice without developmental, anatomical, or behavioral abnormalities. Transgenic mice accumulated disease associated prion protein following challenge with CWD, thus providing an alternative system for study of peripheral exposure routes in CWD pathogenesis. To determine adverse affects of PRNP selection for scrapie control a hypothesis that the sheep PRNP 171 arginine (R) allele is associated with higher prevalence of ovine progressive pneumonia virus (OPPV) and higher OPPV provirus levels was tested. Results showed that OPPV presence and provirus levels are independent of the PRNP 171R allele indicating that PRNP selection will not adversely affect OPPV within a flock.

Transmissible spongiform encephalopathies: Prion genetics, transmission barriers, and disease control

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