Lack of prion accumulation in lymphoid tissues of PRNP ARQ/ARR sheep intracranially inoculated with the agent of scrapie.

Justin J Greenlee,Amir N Hamir,Jürgen A Richt,Robert A Kunkle,Eric M Nicholson,Jason Bartz

doi:10.1371/journal.pone.0108029

Abstract

Sheep scrapie is a transmissible spongiform encephalopathy that can be transmitted horizontally. The prion protein gene (PRNP) profoundly influences the susceptibility of sheep to the scrapie agent and the tissue levels and distribution of PrPSc in affected sheep. The purpose of this study was to compare the survival time and PrPSc tissue distribution in sheep with highly resistant and highly susceptible PRNP genotypes after intracranial inoculation of the agent of scrapie. Five sheep each of genotype VRQ/VRQ, VRQ/ARR or ARQ/ARR were inoculated. Sheep were euthanized when clinical signs of scrapie became severe. Clinical signs, microscopic lesions, and western blot profiles were uniform across genotypes and consistent with manifestations of classical scrapie. Mean survival time differences were associated with the 171 polymorphic site with VRQ/VRQ sheep surviving 18 months, whereas VRQ/ARR and ARQ/ARR sheep survived 60 and 56 months, respectively. Labeling of PrPSc by immunohistochemistry revealed similar accumulations in central nervous system tissues regardless of host genotype. Immunoreactivity for PrPSc in lymphoid tissue was consistently abundant in VRQ/VRQ, present but confined to tonsil or retropharyngeal lymph node in 4/5 VRQ/ARR, and totally absent in ARQ/ARR sheep. The results of this study demonstrate the susceptibility of sheep with the ARQ/ARR genotype to scrapie by the intracranial inoculation route with PrPSc accumulation in CNS tissues, but prolonged incubation times and lack of PrPSc in lymphoid tissue.

Highlights

Scrapie is a horizontally transmitted, uniformly fatal neurodegenerative disease of sheep and goats
Our results demonstrate that ARQ/ ARR sheep are susceptible to scrapie following IC inoculation, but with extended survival times and absence of immunohistochemical evidence of PrPSc distribution within lymphoid tissues
Resistant ARQ/ARR sheep had a mean incubation period of 56 months. This was markedly longer than the mean incubation of 18 months for genetically highly susceptible VRQ/VRQ sheep

Summary

Introduction

Scrapie is a horizontally transmitted, uniformly fatal neurodegenerative disease of sheep and goats. Definitive diagnosis is typically defined by postmortem pathology and detection of the disease-specific prion protein, called PrPSc, in affected tissues. Exposure to the scrapie agent initiates an autocatalytic, templated conversion of the highly conserved, host-encoded, membraneanchored glycoprotein PrPC to the abnormally folded PrPSc. The clinical and pathological hallmarks of scrapie develop as PrPSc gradually accumulates in the central nervous system (CNS) months or years after initial exposure. Lymphoid tissues can accumulate PrPSc in scrapie-affected sheep, and immunohistochemical (IHC) detection of PrPSc in palatine tonsil, [2] third eyelid, [3] or gutassociated lymphatic tissue of the rectal mucosa [4] of sheep has been used for the diagnosis of scrapie at either the preclinical or clinical stage of disease

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