Location: Virus and Prion ResearchTitle: Chronic wasting disease in bank voles: characterisation of the shortest incubation time model for prion diseases Author
|Di Bari, Michele|
Submitted to: PLoS Pathogens
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/14/2013
Publication Date: 3/7/2013
Publication URL: http://handle.nal.usda.gov/10113/55901
Citation: Di Bari, M.A., Nonno, R., Castilla, J., D'Agostino, C., Pirisinu, L., Riccardi, G., Conte, M., Richt, J., Kunkle, R., Langeveld, J., Vaccari, G., Agrimi, U. 2013. Chronic wasting disease in bank voles: characterisation of the shortest incubation time model for prion diseases. PLoS Pathogens. 9(3):e1003219. Interpretive Summary: Chronic wasting disease (CWD) is a prion disease that affects free-ranging and captive cervids and is slowly spreading in certain regions of the United States and Canada. Animal models are of key importance in the study of prion diseases but their development for CWD has long been hampered by its very inefficient transmission to wild-type mice traditionally used in research. Significant progress was made following genetic manipulation of laboratory mice making them transgenic (mice that over-express the cervid prion genes instead of mouse prion genes). Studies reported here show that the bank vole (Myodes glareolus), a wild rodent species that has been demonstrated to be susceptible to many animal and human prion diseases, is also unique in its susceptibility to CWD from elk, mule deer and white-tailed deer. Moreover, experimental studies reported here found passage of CWD to bank voles led to the isolation of a prion strain with peculiar characteristics; most notable are the unprecedented short incubation and survival times, respectively of 25-28 and ~35 days. Development of a rapid animal model for prion diseases that leads to disease in less than one month represents a significant tool for investigating, neurodegenerative diseases (like prion diseases) where no known treatments or cures exist.
Technical 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 (Bv**I/ICWD), typified by unprecedented short incubation times of 25-28 days and survival times of ~35 days. Neuropathological and molecular characterisation of Bv**I/ICWD showed that the classical features of mammalian prion diseases were all recapitulated in less than one month after intracerebral inoculation. Bv**I/ICWD was characterised by a mild and discrete distribution of spongiosis and relatively low levels of protease-resistant PrP**Sc (PrP**res) in the same brain regions. Despite the low PrP**res 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. Bv**I/ICWD was efficiently replicated by protein misfolding cyclic amplification (PMCA) and the infectivity faithfully generated in vitro, as demonstrated by the preservation of the peculiar Bv**I/ICWD 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. Bv**I/ICWD showed unique characteristics of "'virulence"', low PrP**res accumulation and high infectivity, thus providing exceptional opportunities to improve basic knowledge of the relationship between PrP**Sc, neurodegeneration and infectivity.