Chronic wasting disease in bank voles: characterisation of the shortest incubation time model for prion diseases.

Michele Angelo Di Bari,Romolo Nonno,Umberto Agrimi,Jan Langeveld,Robert Kunkle,Juergen Richt,Geraldina Riccardi,Claudia D'Agostino,Laura Pirisinu,Michela Conte,Gabriele Vaccari,Joaquín Castilla

doi:10.1371/journal.ppat.1003219

Abstract

In order to assess the susceptibility of bank voles to chronic wasting disease (CWD), we inoculated voles carrying isoleucine or methionine at codon 109 (Bv109I and Bv109M, respectively) with CWD isolates from elk, mule deer and white-tailed deer. Efficient transmission rate (100%) was observed with mean survival times ranging from 156 to 281 days post inoculation. Subsequent passages in Bv109I allowed us to isolate from all CWD sources the same vole-adapted CWD strain (Bv109ICWD), typified by unprecedented short incubation times of 25–28 days and survival times of ∼35 days. Neuropathological and molecular characterisation of Bv109ICWD showed that the classical features of mammalian prion diseases were all recapitulated in less than one month after intracerebral inoculation. Bv109ICWD was characterised by a mild and discrete distribution of spongiosis and relatively low levels of protease-resistant PrPSc (PrPres) in the same brain regions. Despite the low PrPres levels and the short time lapse available for its accumulation, end-point titration revealed that brains from terminally-ill voles contained up to 108,4 i.c. ID50 infectious units per gram. Bv109ICWD was efficiently replicated by protein misfolding cyclic amplification (PMCA) and the infectivity faithfully generated in vitro, as demonstrated by the preservation of the peculiar Bv109ICWD strain features on re-isolation in Bv109I. Overall, we provide evidence that the same CWD strain was isolated in Bv109I from the three-cervid species. Bv109ICWD showed unique characteristics of “virulence”, low PrPres accumulation and high infectivity, thus providing exceptional opportunities to improve basic knowledge of the relationship between PrPSc, neurodegeneration and infectivity.

Highlights

Chronic wasting disease (CWD) of cervids belongs to the family of transmissible spongiform encephalopathies (TSE) or prion diseases, a group of fatal neurodegenerative pathologies affecting animals and humans
SS7B, a scrapie isolate previously shown to replicate efficiently in Bv109M [19], showed a 60 days longer median survival time in Bv109I. These data demonstrate that the 109 methionine/isoleucine variation influences the susceptibility of voles in a strain dependent fashion and that Bv109I is a fast model for CWD replication
In the present study we investigated the susceptibility of Bv109I and Bv109M to seven CWD isolates from three deer species and found that these animal models are highly permissive to CWD, showing 100% attack rate and mean survival times between 156 and 281 d.p.i

Summary

Introduction

Chronic wasting disease (CWD) of cervids belongs to the family of transmissible spongiform encephalopathies (TSE) or prion diseases, a group of fatal neurodegenerative pathologies affecting animals and humans. They are characterised by spongiform changes, gliosis and the deposition in the brain of a posttranslational misfolded isoform (PrPSc) of the host-encoded cellular prion protein (PrPc). CWD is the only prion disease known to affect free-ranging wild animals. It was first described in the United States in the late 1960s [1]. The disease has been documented in Rocky Mountain elk (Cervus elaphus nelsoni), mule deer (Odocoileus hemionus), white-tailed deer (Odocoileus virginianus) and moose (Alces alces) [4]

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