Mucosal transmission and pathogenesis of chronic wasting disease in ferrets

Abstract

Chronic wasting disease (CWD) of cervids is almost certainly transmitted by mucosal contact with the causative prion, whether by direct (animal-to-animal) or indirect (environmental) means. Yet the sites and mechanisms of prion entry remain to be further understood. This study sought to extend this understanding by demonstrating that ferrets exposed to CWD via several mucosal routes developed infection, CWD prion protein (PrP CWD ) amplification in lymphoid tissues, neural invasion and florid transmissible spongiform encephalopathy lesions resembling those in native cervid hosts. The ferrets developed extensive PrP CWD accumulation in the nervous system, retina and olfactory epithelium, with lesser deposition in tongue, muscle, salivary gland and the vomeronasal organ. PrP CWD accumulation in mucosal sites, including upper respiratory tract epithelium, olfactory epithelium and intestinal Peyer's patches, make the shedding of prions by infected ferrets plausible. It was also observed that regionally targeted exposure of the nasopharyngeal mucosa resulted in an increased attack rate when compared with oral exposure. The latter finding suggests that nasal exposure enhances permissiveness to CWD infection. The ferret model has further potential for investigation of portals for initiation of CWD infection.

The ecology of chronic wasting disease in wildlife

“…Beyond elk, deer (red, mule, white-tailed, black-tailed), and moose populations, the role of other species in CWD maintenance has not been explored extensively. Experimental data, generally using intra-cranial inoculation (Hamir et al, 2008), reveal that rodents (voles, mice, hamsters) (Bartz et al, 1998;Raymond et al, 2007;Heisey et al, 2010;Watts et al, 2014;Orrú et al, 2015), mesocarnivores (ferrets, mink, cats) (Bartz et al, 1998;Sigurdson et al, 2008;Perrott et al, 2013), livestock (cattle, sheep, pigs) (Hamir et al, 2001(Hamir et al, , 2005(Hamir et al, , 2006Madsen-Bouterse et al, 2016;Moore et al, 2017), and other deer species (Reeve's muntjac, Muntiacus reevesi and fallow deer, Dama dama) (Hamir et al, 2011;Nalls et al, 2013) are susceptible to infectious CWD prions. In vitro and in vivo models have produced mixed results regarding the ability of CWD to cross the species barrier into humans and livestock.…”

Evolution of Diagnostic Tests for Chronic Wasting Disease, a Naturally Occurring Prion Disease of Cervids

“…As with other TSEs, including scrapie of sheep, bovine spongiform encephalopathy (BSE), and human variant and sporadic Creutzfeldt-Jakob disease (CJD), CWD is characterized by central nervous system pathology mediated by an abnormally folded isoform of the normal cellular prion protein (PrP res when referring to the misfolded variant or PrP Sc when referring to the infectious isoform specifically, and PrP C , respectively). The primary structure of PrP C , dictated by the host’s prion protein gene ( PRNP ), plays a vital role in intra- and inter-species susceptibility, reducing susceptibility in animals with specific alleles and serving as the basis for the “species barrier”, limiting the disease almost exclusively to cervids [ 4 , 5 , 6 , 7 , 8 , 9 ]. The molecular pathogenesis of prion diseases like CWD shares many common traits with other protein misfolding disorders, including Alzheimer’s disease and Parkinson’s disease, and while most prion diseases are decreasing or stable in prevalence, the ever-expanding range of CWD makes it a tempting model system for the broad development of novel diagnostic approaches for these proteinopathies.…”

Seeded Amplification of Chronic Wasting Disease Prions in Nasal Brushings and Recto-anal Mucosa-Associated Lymphoid Tissues from Elk by Real-Time Quaking-Induced Conversion

“…For this reason, major efforts have been undertaken to identify peripheral lymphoid tissues for antemortem collection and diagnosis which may exhibit sensitivities comparable to those of the brainstem/RLN, including third-eyelid, tonsil, and recto-anal mucosa-associated lymphoid tissue (RAMALT) samples (27,(32)(33)(34)(35)(36)(37). Previous studies have additionally demonstrated high levels of PrP res in olfactory epithelium and nasal secretions in several prion diseases (38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48), though this prospect has not been assessed with CWD. Both RA-MALT biopsy specimens and nasal brush samples collected from the olfactory epithelium are easily and efficiently collected and processed, making these tissues promising additions in the area of antemortem detection of prion diseases and the samples of choice for our study.…”