scholarly journals Exposure Risk of Chronic Wasting Disease in Humans

Viruses ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1454
Author(s):  
Satish K. Nemani ◽  
Jennifer L. Myskiw ◽  
Lise Lamoureux ◽  
Stephanie A. Booth ◽  
Valerie L. Sim
Keyword(s):  
Chronic Wasting Disease ◽  
Prion Diseases ◽  
Causal Link ◽  
In Vivo Studies ◽  
Spongiform Encephalopathy ◽  
Strain Typing ◽  
Species Barrier ◽  
Wasting Disease

The majority of human prion diseases are sporadic, but acquired disease can occur, as seen with variant Creutzfeldt–Jakob disease (vCJD) following consumption of bovine spongiform encephalopathy (BSE). With increasing rates of cervid chronic wasting disease (CWD), there is concern that a new form of human prion disease may arise. Currently, there is no evidence of transmission of CWD to humans, suggesting the presence of a strong species barrier; however, in vitro and in vivo studies on the zoonotic potential of CWD have yielded mixed results. The emergence of different CWD strains is also concerning, as different strains can have different abilities to cross species barriers. Given that venison consumption is common in areas where CWD rates are on the rise, increased rates of human exposure are inevitable. If CWD was to infect humans, it is unclear how it would present clinically; in vCJD, it was strain-typing of vCJD prions that proved the causal link to BSE. Therefore, the best way to screen for CWD in humans is to have thorough strain-typing of harvested cervids and human CJD cases so that we will be in a position to detect atypical strains or strain shifts within the human CJD population.

scholarly journals Cervid Prion Protein Polymorphisms: Role in Chronic Wasting Disease Pathogenesis

2021 ◽  
Vol 22 (5) ◽  
pp. 2271
Author(s):  
Maria Immaculata Arifin ◽  
Samia Hannaoui ◽  
Sheng Chun Chang ◽  
Simrika Thapa ◽  
Hermann M. Schatzl ◽  
...  
Keyword(s):  
Prion Protein ◽  
Chronic Wasting Disease ◽  
In Vivo Studies ◽  
Wasting Disease ◽  
Endogenous Factors ◽  
Prion Strains ◽  
Free Ranging

Chronic wasting disease (CWD) is a prion disease found in both free-ranging and farmed cervids. Susceptibility of these animals to CWD is governed by various exogenous and endogenous factors. Past studies have demonstrated that polymorphisms within the prion protein (PrP) sequence itself affect an animal’s susceptibility to CWD. PrP polymorphisms can modulate CWD pathogenesis in two ways: the ability of the endogenous prion protein (PrPC) to convert into infectious prions (PrPSc) or it can give rise to novel prion strains. In vivo studies in susceptible cervids, complemented by studies in transgenic mice expressing the corresponding cervid PrP sequence, show that each polymorphism has distinct effects on both PrPC and PrPSc. It is not entirely clear how these polymorphisms are responsible for these effects, but in vitro studies suggest they play a role in modifying PrP epitopes crucial for PrPC to PrPSc conversion and determining PrPC stability. PrP polymorphisms are unique to one or two cervid species and most confer a certain degree of reduced susceptibility to CWD. However, to date, there are no reports of polymorphic cervid PrP alleles providing absolute resistance to CWD. Studies on polymorphisms have focused on those found in CWD-endemic areas, with the hope that understanding the role of an animal’s genetics in CWD can help to predict, contain, or prevent transmission of CWD.

scholarly journals Generation of human chronic wasting disease in transgenic mice

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Zerui Wang ◽  
Kefeng Qin ◽  
Manuel V. Camacho ◽  
Ignazio Cali ◽  
Jue Yuan ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Prion Disease ◽  
Protein Misfolding ◽  
Chronic Wasting Disease ◽  
Cellular Prion Protein ◽  
Spongiform Encephalopathy ◽  
Species Barrier ◽  
Wasting Disease ◽  
Bona Fide

AbstractChronic wasting disease (CWD) is a cervid prion disease caused by the accumulation of an infectious misfolded conformer (PrPSc) of cellular prion protein (PrPC). It has been spreading rapidly in North America and also found in Asia and Europe. Although bovine spongiform encephalopathy (i.e. mad cow disease) is the only animal prion disease known to be zoonotic, the transmissibility of CWD to humans remains uncertain. Here we report the generation of the first CWD-derived infectious human PrPSc by elk CWD PrPSc-seeded conversion of PrPC in normal human brain homogenates using in vitro protein misfolding cyclic amplification (PMCA). Western blotting with human PrP selective antibody confirmed that the PMCA-generated protease-resistant PrPSc was derived from the human PrPC substrate. Two lines of humanized transgenic mice expressing human PrP with either Val or Met at the polymorphic codon 129 developed clinical prion disease following intracerebral inoculation with the PMCA-generated CWD-derived human PrPSc. Diseased mice exhibited distinct PrPSc patterns and neuropathological changes in the brain. Our study, using PMCA and animal bioassays, provides the first evidence that CWD PrPSc can cross the species barrier to convert human PrPC into infectious PrPSc that can produce bona fide prion disease when inoculated into humanized transgenic mice.

scholarly journals PrP P102L and Nearby Lysine Mutations Promote Spontaneous In Vitro Formation of Transmissible Prions

2017 ◽  
Vol 91 (21) ◽  
Author(s):  
Allison Kraus ◽  
Gregory J. Raymond ◽  
Brent Race ◽  
Katrina J. Campbell ◽  
Andrew G. Hughson ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Diseases ◽  
Transmissible Spongiform Encephalopathy ◽  
Clinical Signs ◽  
Protein Aggregates ◽  
Structural Features ◽  
Spongiform Encephalopathy ◽  
Specific Sequence

ABSTRACT Accumulation of fibrillar protein aggregates is a hallmark of many diseases. While numerous proteins form fibrils by prion-like seeded polymerization in vitro, only some are transmissible and pathogenic in vivo. To probe the structural features that confer transmissibility to prion protein (PrP) fibrils, we have analyzed synthetic PrP amyloids with or without the human prion disease-associated P102L mutation. The formation of infectious prions from PrP molecules in vitro has required cofactors and/or unphysiological denaturing conditions. Here, we demonstrate that, under physiologically compatible conditions without cofactors, the P102L mutation in recombinant hamster PrP promoted prion formation when seeded by minute amounts of scrapie prions in vitro. Surprisingly, combination of the P102L mutation with charge-neutralizing substitutions of four nearby lysines promoted spontaneous prion formation. When inoculated into hamsters, both of these types of synthetic prions initiated substantial accumulation of prion seeding activity and protease-resistant PrP without transmissible spongiform encephalopathy (TSE) clinical signs or notable glial activation. Our evidence suggests that PrP's centrally located proline and lysine residues act as conformational switches in the in vitro formation of transmissible PrP amyloids. IMPORTANCE Many diseases involve the damaging accumulation of specific misfolded proteins in thread-like aggregates. These threads (fibrils) are capable of growing on the ends by seeding the refolding and incorporation of the normal form of the given protein. In many cases such aggregates can be infectious and propagate like prions when transmitted from one individual host to another. Some transmitted aggregates can cause fatal disease, as with human iatrogenic prion diseases, while other aggregates appear to be relatively innocuous. The factors that distinguish infectious and pathogenic protein aggregates from more innocuous ones are poorly understood. Here we have compared the combined effects of prion seeding and mutations of prion protein (PrP) on the structure and transmission properties of synthetic PrP aggregates. Our results highlight the influence of specific sequence features in the normally unstructured region of PrP that influence the infectious and neuropathogenic properties of PrP-derived aggregates.

scholarly journals Experimental Transmission of the Chronic Wasting Disease Agent to Swine after Oral or Intracranial Inoculation

2017 ◽  
Vol 91 (19) ◽  
Author(s):  
S. Jo Moore ◽  
M. Heather West Greenlee ◽  
Naveen Kondru ◽  
Sireesha Manne ◽  
Jodi D. Smith ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Chronic Wasting Disease ◽  
Mouse Bioassay ◽  
Lymphoid Tissues ◽  
Species Barrier ◽  
Wasting Disease ◽  
Disease Agent ◽  
Domestic Swine

ABSTRACT Chronic wasting disease (CWD) is a naturally occurring, fatal neurodegenerative disease of cervids. The potential for swine to serve as hosts for the agent of CWD is unknown. The purpose of this study was to investigate the susceptibility of swine to the CWD agent following experimental oral or intracranial inoculation. Crossbred piglets were assigned to three groups, intracranially inoculated (n = 20), orally inoculated (n = 19), and noninoculated (n = 9). At approximately the age at which commercial pigs reach market weight, half of the pigs in each group were culled (“market weight” groups). The remaining pigs (“aged” groups) were allowed to incubate for up to 73 months postinoculation (mpi). Tissues collected at necropsy were examined for disease-associated prion protein (PrPSc) by Western blotting (WB), antigen capture enzyme immunoassay (EIA), immunohistochemistry (IHC), and in vitro real-time quaking-induced conversion (RT-QuIC). Brain samples from selected pigs were also bioassayed in mice expressing porcine prion protein. Four intracranially inoculated aged pigs and one orally inoculated aged pig were positive by EIA, IHC, and/or WB. By RT-QuIC, PrPSc was detected in lymphoid and/or brain tissue from one or more pigs in each inoculated group. The bioassay was positive in four out of five pigs assayed. This study demonstrates that pigs can support low-level amplification of CWD prions, although the species barrier to CWD infection is relatively high. However, detection of infectivity in orally inoculated pigs with a mouse bioassay raises the possibility that naturally exposed pigs could act as a reservoir of CWD infectivity. IMPORTANCE We challenged domestic swine with the chronic wasting disease agent by inoculation directly into the brain (intracranially) or by oral gavage (orally). Disease-associated prion protein (PrPSc) was detected in brain and lymphoid tissues from intracranially and orally inoculated pigs as early as 8 months of age (6 months postinoculation). Only one pig developed clinical neurologic signs suggestive of prion disease. The amount of PrPSc in the brains and lymphoid tissues of positive pigs was small, especially in orally inoculated pigs. Regardless, positive results obtained with orally inoculated pigs suggest that it may be possible for swine to serve as a reservoir for prion disease under natural conditions.

scholarly journals Inhibition of Protease-Resistant Prion Protein Formation in a Transformed Deer Cell Line Infected with Chronic Wasting Disease

2006 ◽  
Vol 80 (2) ◽  
pp. 596-604 ◽  
Author(s):  
Gregory J. Raymond ◽  
Emily A. Olsen ◽  
Kil Sun Lee ◽  
Lynne D. Raymond ◽  
P. Kruger Bryant ◽  
...  
Keyword(s):  
Cell Line ◽  
Prion Protein ◽  
Chronic Wasting Disease ◽  
Transmissible Spongiform Encephalopathy ◽  
Mule Deer ◽  
Simian Virus 40 ◽  
Spongiform Encephalopathy ◽  
Wasting Disease ◽  
Neuronal Marker

ABSTRACT Chronic wasting disease (CWD) is an emerging transmissible spongiform encephalopathy (prion disease) of North American cervids, i.e., mule deer, white-tailed deer, and elk (wapiti). To facilitate in vitro studies of CWD, we have developed a transformed deer cell line that is persistently infected with CWD. Primary cultures derived from uninfected mule deer brain tissue were transformed by transfection with a plasmid containing the simian virus 40 genome. A transformed cell line (MDB) was exposed to microsomes prepared from the brainstem of a CWD-affected mule deer. CWD-associated, protease-resistant prion protein (PrPCWD) was used as an indicator of CWD infection. Although no PrPCWD was detected in any of these cultures after two passes, dilution cloning of cells yielded one PrPCWD-positive clone out of 51. This clone, designated MDBCWD, has maintained stable PrPCWD production through 32 serial passes thus far. A second round of dilution cloning yielded 20 PrPCWD-positive subclones out of 30, one of which was designated MDBCWD2. The MDBCWD2 cell line was positive for fibronectin and negative for microtubule-associated protein 2 (a neuronal marker) and glial fibrillary acidic protein (an activated astrocyte marker), consistent with derivation from brain fibroblasts (e.g., meningeal fibroblasts). Two inhibitors of rodent scrapie protease-resistant PrP accumulation, pentosan polysulfate and a porphyrin compound, indium (III) meso-tetra(4-sulfonatophenyl)porphine chloride, potently blocked PrPCWD accumulation in MDBCWD cells. This demonstrates the utility of these cells in a rapid in vitro screening assay for PrPCWD inhibitors and suggests that these compounds have potential to be active against CWD in vivo.

scholarly journals Antemortem Detection of Chronic Wasting Disease Prions in Nasal Brush Collections and Rectal Biopsy Specimens from White-Tailed Deer by Real-Time Quaking-Induced Conversion

2016 ◽  
Vol 54 (4) ◽  
pp. 1108-1116 ◽  
Author(s):  
Nicholas J. Haley ◽  
Chris Siepker ◽  
W. David Walter ◽  
Bruce V. Thomsen ◽  
Justin J. Greenlee ◽  
...  
Keyword(s):  
Real Time ◽  
Large Scale ◽  
Chronic Wasting Disease ◽  
Transmissible Spongiform Encephalopathy ◽  
Rectal Biopsy ◽  
Spongiform Encephalopathy ◽  
Wasting Disease ◽  
Experimental Conditions ◽  
Biopsy Specimens

Chronic wasting disease (CWD), a transmissible spongiform encephalopathy of cervids, was first documented nearly 50 years ago in Colorado and Wyoming and has since spread to cervids in 23 states, two Canadian provinces, and the Republic of Korea. The expansion of this disease makes the development of sensitive diagnostic assays and antemortem sampling techniques crucial for the mitigation of its spread; this is especially true in cases of relocation/reintroduction of farmed or free-ranging deer and elk or surveillance studies of private or protected herds, where depopulation is contraindicated. This study sought to evaluate the sensitivity of the real-time quaking-induced conversion (RT-QuIC) assay by using recto-anal mucosa-associated lymphoid tissue (RAMALT) biopsy specimens and nasal brush samples collected antemortem from farmed white-tailed deer (n= 409). Antemortem findings were then compared to results from ante- and postmortem samples (RAMALT, brainstem, and medial retropharyngeal lymph nodes) evaluated by using the current gold standardin vitroassay, immunohistochemistry (IHC) analysis. We hypothesized that the sensitivity of RT-QuIC would be comparable to IHC analysis in antemortem tissues and would correlate with both the genotype and the stage of clinical disease. Our results showed that RAMALT testing by RT-QuIC assay had the highest sensitivity (69.8%) compared to that of postmortem testing, with a specificity of >93.9%. These data suggest that RT-QuIC, like IHC analysis, is an effective assay for detection of PrPCWDin rectal biopsy specimens and other antemortem samples and, with further research to identify more sensitive tissues, bodily fluids, or experimental conditions, has potential for large-scale and rapid automated testing for CWD diagnosis.

scholarly journals Molecular Profiling of Ovine Prion Diseases by Using Thermolysin-Resistant PrPSc and Endogenous C2 PrP Fragments

2007 ◽  
Vol 81 (19) ◽  
pp. 10532-10539 ◽  
Author(s):  
Jonathan P. Owen ◽  
Helen C. Rees ◽  
Ben C. Maddison ◽  
Linda A. Terry ◽  
Leigh Thorne ◽  
...  
Keyword(s):  
Prion Diseases ◽  
Transmissible Spongiform Encephalopathy ◽  
Spongiform Encephalopathy ◽  
Western Blots ◽  
Sheep Population ◽  
Natural Scrapie ◽  
Caudal Medulla ◽  
Scrapie Strains

ABSTRACT Disease-associated PrP fragments produced upon in vitro or in vivo proteolysis can provide significant insight into the causal strain of prion disease. Here we describe a novel molecular strain typing assay that used thermolysin digestion of caudal medulla samples to produce PrPres signatures on Western blots that readily distinguished experimental sheep bovine spongiform encephalopathy (BSE) from classical scrapie. Furthermore, the accumulation of such PrPres species within the cerebellum also appeared to be dependent upon the transmissible spongiform encephalopathy (TSE) strain, allowing discrimination between two experimental strains of scrapie and grouping of natural scrapie isolates into two profiles. The occurrence of endogenously produced PrP fragments, namely, glycosylated and unglycosylated C2, within different central nervous system (CNS) regions is also described; this is the first detailed description of such scrapie-associated fragments within a natural host. The advent of C2 fragments within defined CNS regions, compared between BSE and scrapie cases and also between two experimental scrapie strains, appeared to be largely dependent upon the TSE strain. The combined analyses of C2 fragments and thermolysin-resistant PrP species within caudal medulla, cerebellum, and spinal cord samples allowed natural scrapie isolates to be separated into four distinct molecular profiles: most isolates produced C2 and PrPres in all CNS regions, a second group lacked detectable cerebellar C2 fragments, one isolate lacked both cerebellar PrPres and C2, and a further isolate lacked detectable C2 within all three CNS regions and also lacked cerebellar PrPres. This CNS region-specific deposition of disease-associated PrP species may reflect the natural heterogeneity of scrapie strains in the sheep population in the United Kingdom.

scholarly journals Susceptibility of Cattle to First-passage Intracerebral Inoculation with Chronic Wasting Disease Agent from White-tailed Deer

2007 ◽  
Vol 44 (4) ◽  
pp. 487-493 ◽  
Author(s):  
A. N. Hamir ◽  
J. M. Miller ◽  
R. A. Kunkle ◽  
S. M. Hall ◽  
J. A. Richt
Keyword(s):  
Chronic Wasting Disease ◽  
Prion Diseases ◽  
Clinical Signs ◽  
Diagnostic Techniques ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Wasting Disease ◽  
Spongiform Encephalopathies ◽  
Disease Agent ◽  
Sheep Scrapie

Fourteen, 3-month-old calves were intracerebrally inoculated with the agent of chronic wasting disease (CWD) from white-tailed deer (CWDwtd) to compare the clinical signs and neuropathologic findings with those of certain other transmissible spongiform encephalopathies (TSE, prion diseases) that have been shown to be experimentally transmissible to cattle (sheep scrapie, CWD of mule deer [CWDmd], bovine spongiform encephalopathy [BSE], and transmissible mink encephalopathy). Two uninoculated calves served as controls. Within 26 months postinoculation (MPI), 12 inoculated calves had lost considerable weight and eventually became recumbent. Of the 12 inoculated calves, 11 (92%) developed clinical signs. Although spongiform encephalopathy (SE) was not observed, abnormal prion protein (PrPd) was detected by immunohistochemistry (IHC) and Western blot (WB) in central nervous system tissues. The absence of SE with presence of PrPd has also been observed when other TSE agents (scrapie and CWDmd) were similarly inoculated into cattle. The IHC and WB findings suggest that the diagnostic techniques currently used to confirm BSE would detect CWDwtd in cattle, should it occur naturally. Also, the absence of SE and a distinctive IHC pattern of CWDwtd and CWDmd in cattle suggests that it should be possible to distinguish these conditions from other TSEs that have been experimentally transmitted to cattle.

Zombie deer and the species barrier. Should humans worry about it?

2020 ◽  
Keyword(s):  
Chronic Disease ◽  
Bovine Spongiform Encephalopathy ◽  
Chronic Wasting Disease ◽  
Spongiform Encephalopathy ◽  
Species Barrier ◽  
Wasting Disease ◽  
Prion Infection ◽  
The Moment

This commentary reports of a deer chronic disease (chronic wasting disease - CWD), which might be transmitted to humans. It is due to a prion infection, similar to the bovine spongiform encephalopathy (BSE). At the moment, it is not known if the disease may be transmitted to humans. That is why all of us should be aware of the disease, and more careful while consuming deer meat.

scholarly journals Longitudinal Detection of Prion Shedding in Saliva and Urine by Chronic Wasting Disease-Infected Deer by Real-Time Quaking-Induced Conversion

2015 ◽  
Vol 89 (18) ◽  
pp. 9338-9347 ◽  
Author(s):  
Davin M. Henderson ◽  
Nathaniel D. Denkers ◽  
Clare E. Hoover ◽  
Nina Garbino ◽  
Candace K. Mathiason ◽  
...  
Keyword(s):  
Prion Disease ◽  
Chronic Wasting Disease ◽  
Prion Diseases ◽  
Lethal Dose ◽  
Disease Course ◽  
Wasting Disease ◽  
Daily Production ◽  
Canadian Provinces ◽  
Free Ranging

ABSTRACTChronic wasting disease (CWD) is an emergent, rapidly spreading prion disease of cervids. Shedding of infectious prions in saliva and urine is thought to be an important factor in CWD transmission. To help to elucidate this issue, we applied anin vitroamplification assay to determine the onset, duration, and magnitude of prion shedding in longitudinally collected saliva and urine samples from CWD-exposed white-tailed deer. We detected prion shedding as early as 3 months after CWD exposure and sustained shedding throughout the disease course. We estimated that the 50% lethal dose (LD50) for cervidized transgenic mice would be contained in 1 ml of infected deer saliva or 10 ml of urine. Given the average course of infection and daily production of these body fluids, an infected deer would shed thousands of prion infectious doses over the course of CWD infection. The direct and indirect environmental impacts of this magnitude of prion shedding on cervid and noncervid species are surely significant.IMPORTANCEChronic wasting disease (CWD) is an emerging and uniformly fatal prion disease affecting free-ranging deer and elk and is now recognized in 22 U.S. states and 2 Canadian provinces. It is unique among prion diseases in that it is transmitted naturally through wild populations. A major hypothesis to explain CWD's florid spread is that prions are shed in excreta and transmitted via direct or indirect environmental contact. Here we use a rapidin vitroassay to show that infectious doses of CWD prions are in fact shed throughout the multiyear disease course in deer. This finding is an important advance in assessing the risks posed by shed CWD prions to animals as well as humans.

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