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. Here we sought to extend this understanding by demonstrating that ferrets exposed to CWD via several mucosal routes develop infection, PrPCWD amplification in lymphoid tissues, neural invasion, and florid TSE lesions resembling those in native cervid hosts. Ferrets developed extensive PrPCWD accumulation in the nervous system, retina, and olfactory epithelium, with lesser deposition in tongue, muscle, salivary gland and the vomero-nasal organ. PrPCWD accumulation in mucosal sites, including the upper respiratory tract epithelium, olfactory epithelium and intestinal Peyer's patches make the shedding of prions by infected ferrets plausible. We 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.
[Show abstract][Hide abstract] ABSTRACT: The transmission of infectious prions into different host species requires compatible prion protein (PrP) primary structures,
and even one heterologous residue at a pivotal position can block prion infection. Mapping the key amino acid positions that
govern cross-species prion conversion has not yet been possible, although certain residue positions have been identified as
restrictive, including residues in the β2-α2 loop region of PrP. To further define how β2-α2 residues impact conversion, we investigated residue substitutions in PrPC using an in vitro prion conversion assay. Within the β2-α2 loop, a tyrosine residue at position 169 is strictly conserved among mammals, and transgenic mice expressing mouse PrP having
the Y169G, S170N, and N174T substitutions resist prion infection. To better understand the structural requirements of specific
residues for conversion initiated by mouse prions, we substituted a diverse array of amino acids at position 169 of PrP. We
found that the substitution of glycine, leucine, or glutamine at position 169 reduced conversion by ∼75%. In contrast, replacing
tyrosine 169 with either of the bulky, aromatic residues, phenylalanine or tryptophan, supported efficient prion conversion.
We propose a model based on a requirement for tightly interdigitating complementary amino acid side chains within specific
domains of adjacent PrP molecules, known as “steric zippers,” to explain these results. Collectively, these studies suggest
that an aromatic residue at position 169 supports efficient prion conversion.
[Show abstract][Hide abstract] ABSTRACT: A naturally occurring transmissible spongiform encephalopathy (TSE) of mule deer was first reported in Colorado and Wyoming in 1967 and has since spread to other members of the cervid family in 22 states, 2 Canadian provinces, and the Republic of Korea. Chronic wasting disease (CWD), caused by exposure to an abnormally folded isoform of the cellular prion protein, is characterized by progressive neurological disease in susceptible natural and experimental hosts and is ultimately fatal.CWDis thought to be transmitted horizontally in excreta and through contaminated environments, features common to scrapie of sheep, though rare among TSEs. Evolving detection methods have revealed multiple strains of CWD and with continued development may lead to an effective antemortem test. Managing the spread of CWD, through the development of a vaccine or environmental cleanup strategies, is an active area of interest. As such, CWD represents a unique challenge in the study of prion diseases. Expected final online publication date for the Annual Review of Animal Biosciences Volume 3 is February 15, 2015. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
[Show abstract][Hide abstract] ABSTRACT: Prions are amyloid-forming proteins that cause transmissible spongiform encephalopathies through a process involving the templated conversion of the normal cellular prion protein (PrPC) to a pathogenic misfolded conformation. Templated conversion has been modeled in several in vitro assays, including serial protein misfolding amplification (sPMCA), amyloid seeding, and real time quaking induced conversion (RT-QuIC). Because RT-QuIC measures formation of amyloid fibrils in real time, it can be used to estimate the rate of seeded conversion. Here we use samples from deer infected with chronic wasting disease (CWD) in RT-QuIC to show that serial dilution of prion seed is linearly related to the rate of amyloid formation over a range of 10-3 to 10-8 µg. We then used an amyloid formation rate standard curve derived from a bioassayed reference sample (CWD+ brain homogenate) to estimate the prion seed concentration and infectivity in tissues, body fluids and excreta. Using these methods we estimate that urine and saliva from CWD-infected deer contain between 1 and 5 LD50 per 10 ml, respectively. Thus, over the 1 to 2 year course of infection, a substantial environmental reservoir of CWD prion contamination accumulates.
Journal of General Virology 10/2014; 96(Pt_1). DOI:10.1099/vir.0.069906-0 · 3.18 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.