Transmission of Chronic Wasting Disease Identifies a Prion Strain Causing Cachexia and Heart Infection in Hamsters

Abstract

Chronic wasting disease (CWD) is an emerging prion disease of free-ranging and captive cervids in North America. In this study we established a rodent model for CWD in Syrian golden hamsters that resemble key features of the disease in cervids including cachexia and infection of cardiac muscle. Following one to three serial passages of CWD from white-tailed deer into transgenic mice expressing the hamster prion protein gene, CWD was subsequently passaged into Syrian golden hamsters. In one passage line there were preclinical changes in locomotor activity and a loss of body mass prior to onset of subtle neurological symptoms around 340 days. The clinical symptoms included a prominent wasting disease, similar to cachexia, with a prolonged duration. Other features of CWD in hamsters that were similar to cervid CWD included the brain distribution of the disease-specific isoform of the prion protein, PrPSc, prion infection of the central and peripheral neuroendocrine system, and PrPSc deposition in cardiac muscle. There was also prominent PrPSc deposition in the nasal mucosa on the edge of the olfactory sensory epithelium with the lumen of the nasal airway that could have implications for CWD shedding into nasal secretions and disease transmission. Since the mechanism of wasting disease in prion diseases is unknown this hamster CWD model could provide a means to investigate the physiological basis of cachexia, which we propose is due to a prion-induced endocrinopathy. This prion disease phenotype has not been described in hamsters and we designate it as the ‘wasting’ or WST strain of hamster CWD.

Host Determinants of Prion Strain Diversity Independent of Prion Protein Genotype

“…Table 1 summarizes the transmission studies of CWD into HPrP7752KO mice and SGH. A portion of this table appeared in a previous publication and is included here in order to present the transmission history of the wasted (WST) strain of CWD (previously called CWD line A) and CWD line B, now identified as the cheeky (CKY) strain of CWD (40). The new animal transmission data includes second and third serial passages of CKY CWD and WST CWD in SGH, respectively, and serial backpassage of each into HPrP7752KO mice.…”

“…For biochemical tissue analysis, tissues were collected, immediately frozen over dry ice, and stored at Ϫ80°C until use. For collection of tissues for immunohistochemistry, hamsters were intracardially perfused with periodatelysine-paraformaldehyde fixative, and tissues were dissected and processed for embedding in paraffin wax as previously described (39)(40)(41).…”

“…PrP Sc immunohistochemistry (IHC) was performed on paraffin embedded tissue as previously described (39)(40)(41). Tissue sections were subjected to antigen retrieval by treatment with 99% (wt/vol) formic acid for 30 min and successively incubated with anti-PrP monoclonal 3F4 antibody overnight at 4°C, horse anti-mouse IgG biotinylated antibody (1:400; Vector Laboratories, Burlingame, CA) at room temperature for 30 min, and streptavidin-horseradish peroxidase (HRP) at room temperature for 20 min.…”

Lack of Prion Infectivity in Fixed Heart Tissue from Patients with Creutzfeldt-Jakob Disease or Amyloid Heart Disease

“…These data raised the possibility not only that PrP Sc might be deposited in the heart of individuals with prion disease but also that abnormal forms of PrP could be an unrecognized component of amyloid heart disease in humans (19). Consistent with this possibility, PrP Sc has been reported in the heart of one sCJD patient (20), in muscle tissue (including heart) of BSEinfected nonhuman primates (21), in a BSE-infected macaque with a prion-amyloid cardiomyopathy (22), and in several chronic wasting disease models (23,24). In contrast, several studies have failed to detect PrP Sc in either sCJD heart tissue (9,12,19) or human amyloid hearts (19), and heart tissue from several sCJD patients did not transmit disease to nonhuman primates (25).…”

Strain Characterization of the Korean CWD Cases in 2001 and 2004

“…Recently, using a model of transgenic mice overexpressing mule deer prion, the possibility of at least two CWD strains existing in North American cervids was raised [1]. More evidence on the two distinct CWD strains that originated from the mule deer was suggested using the ferret model [9] and from Syrian hamster model studies, and the emergence of a new "wasting strain" (WST) would appear to have occurred in white-tailed deer [2]. Epidemiological investigations showed that CWD was introduced to the Korean peninsula via importation of infected elk from Canada in 1994, 1995 and 1997 [7].…”