Protective Effect of Val129-PrP against Bovine Spongiform Encephalopathy but not Variant Creutzfeldt-Jakob Disease.

Natalia Fernández-Borges,Emmanuel A Asante,Tetsuyuki Kitamoto,Olivier Andréoletti,Juan Carlos Espinosa,Juan María Torres,Shirou Mohri,Alba Marín-Moreno,Patricia Aguilar-Calvo

doi:10.3201/eid2309.161948

Abstract

Bovine spongiform encephalopathy (BSE) is the only known zoonotic prion that causes variant Creutzfeldt-Jakob disease (vCJD) in humans. The major risk determinant for this disease is the polymorphic codon 129 of the human prion protein (Hu-PrP), where either methionine (Met129) or valine (Val129) can be encoded. To date, all clinical and neuropathologically confirmed vCJD cases have been Met129 homozygous, with the exception of 1 recently reported Met/Val heterozygous case. Here, we found that transgenic mice homozygous for Val129 Hu-PrP show severely restricted propagation of the BSE prion strain, but this constraint can be partially overcome by adaptation of the BSE agent to the Met129 Hu-PrP. In addition, the transmission of vCJD to transgenic mice homozygous for Val129 Hu-PrP resulted in a prion with distinct strain features. These observations may indicate increased risk for vCJD secondary transmission in Val129 Hu-PrP–positive humans with the emergence of new strain features.

Highlights

The presence of variant Creutzfeldt-Jakob disease is considered by strong epidemiologic, pathologic, and molecular evidence to be a likely consequence of human dietary exposure to the bovine spongiform encephalopathy (BSE) agent [1,2,3]
Bovine spongiform encephalopathy (BSE) Resistance in TgVal129 Mice To evaluate the relative susceptibility of the 3 human PRNP codon 129 genotypes to BSE, we performed serial transmission studies in 3 transgenic mouse lines expressing human prion protein (PrP)
We observed no clinical signs of prion disease or proteinase K (PK)–resistant PrP (PrPres) accumulation in control mice inoculated with transmissible spongiform encephalopathies (TSEs)-free control brain homogenate

Summary

Introduction

The presence of variant Creutzfeldt-Jakob disease (vCJD) is considered by strong epidemiologic, pathologic, and molecular evidence to be a likely consequence of human dietary exposure to the bovine spongiform encephalopathy (BSE) agent [1,2,3]. Retrospective studies of the prevalence of subclinical vCJD infection using appendectomy and tonsillectomy specimens in the United Kingdom described 6 appendixes that were positive for disease-associated prion protein in Val/Val129 persons [23,24,25]. All of these human studies, in addition to the extremely prolonged and variable incubation periods seen in prion transmission experiments when crossing a species barrier, suggest that persons encoding any of the 3 human PrP codon 129 genotypes may be susceptible to vCJD, including secondary vCJD transmitted through blood transfusion, blood products, tissue and organ transplantation, and other iatrogenic routes. Mice with the Val/Val129 genotype were more susceptible to vCJD infection than expected but lack the neuropathological characteristics observed with Met/Met129 [2,26,27,28]

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Conclusion