Abstract
Transmissible spongiform encephalopathies (TSEs) are a group of progressive and ultimately fatal neurologic diseases of man and animals, all resulting from the propagated misfolding of the host’s normal cellular prion protein. These diseases can be spontaneous, heritable, anthropogenic/iatrogenic, or in some cases horizontally transmissible, and include such notable TSEs as bovine spongiform encephalopathy (BSE) of cattle and chronic wasting disease (CWD) of cervids. Although they are both unequivocally protein misfolding disorders, they differ markedly in their pathogenesis, transmissibility, and zoonotic potential. While the BSE epidemic has largely abated over the past three decades following global feed bans on ruminant meat and bone meal, CWD, which is readily transmitted through various forms of excreta, has rapidly expanded from its original endemic zone to encompass much of North America, along with recently identified foci in Scandinavia. Most importantly, although the classical form of BSE has proven transmissible to humans consuming contaminated beef or beef products, so far there have been no conclusive reports on the zoonotic transmission of CWD to humans. The underlying basis for these differences – whether host or agent directed – are not well understood, though may be due to inherent differences in the three-dimensional structure of the misfolded BSE or CWD prion proteins or the expression levels and tissue distribution of respective cellular prion proteins. With the uncontrolled geographic spread of CWD, it is imperative that we improve our understanding of the factors governing prion disease pathogenesis, transmission, and zoonotic potential.
Similar content being viewed by others
Introduction
The transmissible spongiform encephalopathies, or TSEs, are a group of infectious agents that are responsible for progressive, degenerative, and uniformly fatal central nervous system (CNS) disorders in their respective animal hosts, including humans (Collins et al. 2004). These diseases, including bovine spongiform encephalopathy (BSE) of cattle, chronic wasting disease (CWD) of deer and other cervids, and human Creutzfeldt-Jakob disease (CJD), tend to be highly species-specific and share similar patterns of clinical disease, neuropathology, and etiology. The agent at the heart of all TSEs is a misfolded isoform of the normal cellular prion protein, generally referred to as PrPSc for the various forms of disease-causing prions, is capable of forming a highly stable and neurotoxic amyloid that is devoid of nucleic acids and other familiar genetic building blocks found in bacteria, viruses, and other conventional pathogens (Prusiner 1982).
Transmissible spongiform encephalopathies may arise and spread through one of several different mechanisms. Some prion diseases, including CWD, are highly infectious between susceptible species, with horizontal (Williams 2005), vertical (Selariu et al. 2015; Nalls et al. 2021), and environmental transmission mechanisms reported (Mathiason et al. 2009; Miller et al. 2004). Its highly infectious nature has led to an incredible expansion of CWD across North America over the past several decades (Fig. 1). In contrast, others the classical form of BSE (c-BSE) are, in most cases reported so far, anthropogenic, or in some cases iatrogenic, with little evidence of animal-to-animal, person-to-person, or environmental transmission (Smith and Bradley 2003). Once the basis of c-BSE transmission was identified – the supplementation of cattle feed with rendered cattle meat and bone meal contaminated with BSE prions – the epidemic of the late 1980s and early 1990s was brought to a grinding halt (Narang 1996). Over the past two decades, most of the newly arising BSE cases identified worldwide have been atypical forms, spontaneous in nature, with case numbers significantly lower than those reported in the c-BSE epidemic of the late twentieth century (European Food Safety Authority 2021). Aside from infectious, anthropogenic/iatrogenic, and spontaneous forms of disease, a fourth mechanism of prion etiology, namely heritable forms, seems to be of relatively minor importance for either CWD or BSE, though is an important form of human TSEs (Appleby et al. 2022). It is not well understood why prion diseases like CWD are horizontally transmissible, while others like BSE are not. Some evidence points to host factors playing a key role in direct animal to animal transmission, while other experimental findings suggest the prion agent itself also modulates horizontal transmissibility. Ultimately, both host and agent likely contribute important pieces of the transmission puzzle.
Geographic extent of (A) classical and atypical BSE and (B) CWD. A States, provinces, and countries reporting cases of classical BSE (c-BSE) are shown in red. Note that the single case of c-BSE reported in Washington state in the U.S. was imported from Canada (United States Department of Agriculture 2004). Locations reporting cases of atypical BSE are shown in blue, while those reporting a mixture of both classical and atypical forms of BSE are shown in purple. In 2014, Romania reported two cases of BSE – one was confirmed as an atypical subtype, while the second was seemingly lost to follow up (European Food Safety Authority 2021; ProMED-Mail 2016). B States, provinces, and countries reporting cases of CWD in either farmed or free-ranging cervids are shown in green (Richards 2023)
Apart from transmission routes, there are other important distinctions between these two diseases, including pathogenesis, tissue distribution of the prion agent (Fig. 2), and the potential for distinct prion “strains.” (Greenlee and Greenlee 2015) Perhaps the most important distinction between the two is their zoonotic potential; whereas CWD has not demonstrably resulted in cases of human prion disease, upwards of 230 cases of variant Creutzfeldt-Jakob disease (vCJD) have been attributed to the consumption of BSE-contaminated beef or beef products (Houston and Andreoletti 2019). Some of the distinctions identified between the two diseases may ultimately be the root cause of their transmissibility differences, though it remains unknown whether there may be cases of CWD that are not transmissible, or whether a highly transmissible form of BSE may someday be identified.
Central and peripheral prion accumulation in different species infected with classical BSE or CWD. Generally, peripheral accumulation of either classical bovine spongiform encephalopathy (c-BSE) (Balkema-Buschmann et al. 2011; Franz et al. 2012; Ackermann et al. 2017; Ackermann et al. 2021; Iwata et al. 2006; Buschmann and Groschup 2005) or chronic wasting disease (CWD) (Hamir et al. 2007; Hamir et al. 2011b; Hamir et al. 2006c; Hamir et al. 2005; Haley et al. 2016c) prions is limited in cattle – with accumulation observed in the retina, tonsils, and mesenteric lymph nodes in animals inoculated with either c-BSE or CWD, along with the distal gastrointestinal tract of cattle infected with c-BSE. Sheep show a mixed distribution when infected with either c-BSE (Keulen et al. 2008; Lezmi et al. 2006; Jeffrey et al. 2001) or CWD (Cassmann et al. 2021a; Cassmann et al. 2021b; Hamir et al. 2006b), including deposits in tonsil, spleen, gastrointestinal tract, retina, and both retropharyngeal and mesenteric lymph nodes. Deer inoculated with BSE show a peripheral distribution similar to that of cattle with c-BSE, though lacking deposition in the tonsils and mesenteric lymph nodes occasionally seen in cattle with c-BSE (Dagleish et al. 2008; Martin et al. 2009). Most cervid species naturally infected with CWD have widespread peripheral prion accumulation across excretory organs, lymphoid tissues, as well as muscle and antler velvet (Sigurdson et al. 2001; Haley et al. 2011; Angers et al. 2009; Angers et al. 2006; Wild et al. 2002; Spraker et al. 2002a). Detection methods, including conventional western blotting or IHC, amplification techniques, or bioassay, varied across studies and are indicated for each assessment where appropriate
This review will focus on what is known about CWD and BSE (primarily the classic form, with atypical forms noted where appropriate) and the agents responsible for them – representing the prototype of either a horizontally transmissible or non-transmissible prion disorder, respectively. Along with clinical symptoms, diagnosis, and management, key differences in the pathogenesis, transmission, and both geographic and host range of CWD and BSE will be presented – including data from cross-species transmission studies (e.g., cattle inoculated with CWD and cervids inoculated with c-BSE) that may provide insight into the specific roles of the host and the agent in the disease process; importantly, these studies inform on the risk of the possibility for the development of a horizontally transmissible prion disease in human populations. Finally, we will present future research directions, noting additional studies that may shed further light on the nature of highly transmissible prion diseases.
Bovine spongiform encephalopathy
Bovine spongiform encephalopathy (BSE or “mad cow disease”) was the most economically important prion disease in veterinary medicine in the late 20th and early twenty-first centuries; in the 1990s, it was linked to a newly reported variant of Creutzfeldt-Jakob disease (vCJD) in humans (Collinge et al. 1996; Bruce et al. 1997; Ironside et al. 1996). Clinical symptoms of BSE are typical of those found in other prion diseases, including weight loss and behavioral abnormalities (apprehension, depression, etc.). Progressive neurologic dysfunction is also present in advanced cases, with additional symptoms including hyperesthesia, hyperreflexia, muscle tremors, ataxia, pruritis and reduced autonomic function (e.g., reduced rumination and bradycardia) (Wells et al. 1987). Incoordination and inability to rise are important discriminators that are often used to restrict cattle from conventional slaughterhouse processing. Both classical and atypical (spontaneous) subtypes of BSE have been identified, as noted above, and may be differentiated by western blotting analysis of molecular weight and glycosylation profiles (Fig. 3) as well as select amplification-based assays (Orru et al. 2015; Porcario et al. 2011).
Molecular characteristics of PrPres in different species infected with either BSE or CWD. Differentiation of the various forms of bovine spongiform encephalopathy (BSE) – including classical (Lane 1) and both L- and H-type atypical BSE (Lanes 2 and 3, respectively) – is readily accomplished by comparing the relative molecular weights, weight range, and ratios of the di-, mono-, and unglycosylated PrPres bands (Porcario et al. 2011). These profiles are distinct from BSE isolated in experimental studies of BSE in red deer (Lane 4) and sheep (Lane 5) (Martin et al. 2009). Isolates of chronic wasting disease (CWD) prions from experimentally infected sheep (lane 6) (Hamir et al. 2006b) and naturally infected mule deer from North America (NA, Lane 8) (Williams 2005) are quite similar, though distinct from isolates from both experimentally inoculated cattle (Lane 7) (Hamir et al. 2005) and a novel isolate from a naturally infected moose in Scandinavia (Sc, Lane 9) (Sun et al. 2023). Relative molecular weight and glycosylation profiles may vary subtly across brain regions and host Prnp genotypic background
Classical BSE first emerged as a newly recognized TSE in England in 1986, showing a rapid increase in incidence over the next few years (Smith and Bradley 2003; Wells et al. 1987). Soon after, novel TSE diseases were reported in captive zoo ungulates and felids, as well as domestic cats in the United Kingdom (Aldhous 1990; Kirkwood and Cunningham 1994). Cases of vCJD, “spillover events” arising from human consumption of BSE-contaminated beef, sausage, and other cattle byproducts, were first identified in 1996 and were distinguished from sporadic CJD cases based on age of onset and other clinical findings (Will et al. 1996).
Soon after the detection of c-BSE in the United Kingdom, reports of additional infected cattle began appearing in countries across Europe. These cases were ultimately linked to the export of infected animals, BSE-contaminated meat and bone meal (MBM), and possibly other contaminated animal products from the UK to the European continent. Since its initial descriptions, c-BSE has been reported in 26 countries, including cases in Europe, Israel, Japan, and North America, while atypical BSE cases have been reported in most European countries, North America, Brazil, and Japan (Fig. 1A) (European Food Safety Authority 2021).
Epidemiologic analyses strongly suggest that the primary mode of c-BSE transmission is through the ingestion of feed containing BSE-contaminated MBM (Smith and Bradley 2003). Since a nearly global ban on the use of MBM in ruminant feed, the incidence of the c-BSE has decreased sharply, with just a handful of cases reported over the past decade. Since 2013, the majority of the roughly 30 cases of BSE reported worldwide have been of the atypical subtype (European Food Safety Authority 2021). There has been no definitive evidence of horizontal transmission of either classical or atypical forms of BSE (Ferguson et al. 1997). Young cattle appear to be more susceptible to infection with the classical form than adults, and there is an increased risk of c-BSE in calves born to c-BSE affected cows (Wilesmith et al. 1997). The mechanism responsible for this increased risk in calves is unknown, however the possibility of factors such as milk replacer (Tsutsui et al. 2008), or less likely maternal transmission in utero or post-parturition (Hoinville et al. 1995), have not been completely ruled out. There is no strong evidence for environmental transmission of either subtype.
Wild ungulate and felid TSEs, as well as vCJD cases, suggest that c-BSE has an unusually wide susceptible host range, unlike other known TSEs. A handful of cases of c-BSE have also been reported in goats, likely through consumption of contaminated feed (Spiropoulos et al. 2011). Experimental infections with c-BSE have been reported in pigs, red deer, several non-human primates, and mice, although subsequent horizontal transmission between any of these species has not been demonstrated (Hedman et al. 2016; Dagleish et al. 2008; Piccardo et al. 2012; Herzog et al. 2004; Barlow and Middleton 1990). Studies of experimental c-BSE in sheep, described in detail below, have in contrast found some evidence of animal-to-animal transmission (Jeffrey et al. 2015). Because of its wide host range and particularly due to its association with vCJD, BSE has been considered a major threat to public health, forming the basis for national surveillance and eradication programs around the world.
Etiologic Agent
BSE, like other prion diseases, is caused by a misfolded protein, sometimes denoted as PrPBSE. The normal bovine prion protein is 264 amino acids in length, with an unstructured N-terminal domain and a highly structured C-terminal domain, typical of other mammalian prion proteins. The bovine prion protein shares a relatively high sequence homology (86%) with the 253 amino acid human prion protein, particularly in the structured C-terminal domain. Several different subtypes, including the classic form and two atypical forms – L-type (sometimes referred to as bovine amyloidotic spongiform encephalopathy or BASE) and H-type, have been described (Porcario et al. 2011). Each subtype can be distinguished from one another by determining the molecular mass and the degree of glycosylation of PrPres by western blot analysis (Fig. 3). Atypical L-type BSE is primarily characterized by a slightly lower molecular mass of the unglycosylated PrPres band, compared to that of c-BSE PrPres, while the H-type shows a higher molecular mass for the two glycosylated and single unglycosylated bands than those of c-BSE.
Most cases of atypical BSE have been detected through active national surveillance programs originally developed to detect cases of c-BSE, through targeted sampling of sick and downer cattle as recommended by World Organization for Animal Health (WOAH; formerly OIE) (World Organization for Animal Health (OIE) 2022). In general, these atypical BSE cases do not have distinct clinical signs as described for c-BSE. Most importantly, the majority of atypical BSE cases occur as single cases in a herd and are reported in cattle over 10 years of age. During active surveillance for BSE in France from 2001–2007, the estimated incidence of atypical BSE was 0.41 and 0.35 cases per million for H- and L-type forms, respectively (Biacabe et al. 2008). Case incidence in animals over 8 years of age was higher, with 1.9 and 1.7 cases per million for H- and L-type forms, respectively. This frequency is similar to that of sporadic CJD in humans, which has a yearly incidence of roughly 1 case per million people – typically appearing in those between the ages of 55 and 75; this supports the hypothesis that these atypical BSE cases are sporadic and spontaneous in nature (Parobkova et al. 2020).
Disease origins
The initial source of infectious material responsible for the emergence of c-BSE in the United Kingdom may never be known. Several theories have been provided to explain its emergence, including: the feeding of MBM containing (i) scrapie-contaminated sheep offal to cattle, either unchanged or structurally modified following changes made to traditional rendering processes (Taylor 1989; Huor et al. 2019; Brown and Bradley 1998); (ii) BSE prions from a single spontaneous or genetic case of BSE (Phillips 2000; Capobianco et al. 2007); or (iii) from animal feed imported from the Indian subcontinent that had been contaminated with the remains of humans suffering from one of the various human prion diseases (Colchester and Colchester 2005). A significant increase in sheep populations throughout the UK, and a subsequent increase in scrapie incidence prior to the emergence of c-BSE supports a possible link between the two diseases (Collee and Bradley 1997). Cross-species transmission studies of sheep scrapie into cattle, however, found that microscopic pathology and western blot profiles were distinct from both scrapie in sheep and c-BSE – hinting that it may be unlikely that the BSE epidemic had arisen directly from a crossover of scrapie into cattle (Konold et al. 2015; Cutlip et al. 1997; Cutlip et al. 1994). Regardless of the source, epidemiologic evidence suggests that a change in the rendering process in England in the late 1970s may have allowed for the increased stability of misfolded prion proteins in MBM, allowing for increasing levels of cattle exposure and ultimately an epidemic that would not be curtailed until the practice of feeding MBM was halted in the UK in 1988 (Woodgate and Wilkinson 2021).
Pathogenesis
Following oral exposure, c-BSE PrPSc is first detected in lymphoid follicles of the distal ileum by approximately 6 months post-inoculation (PI) (Balkema-Buschmann et al. 2011). The agent may occasionally be recovered from tonsilar by ~ 10 months PI (Wells et al. 2005). By most accounts, c-BSE pathogenesis bypasses further lymphoid accumulation in the periphery, including excretory tissues, and although PrPSc has been detected in several peripheral tissues using experimental amplification approaches (Franz et al. 2012; Ackermann et al. 2017; Ackermann et al. 2021), it has not been detected to any significant degree in retropharyngeal, mesenteric, popliteal lymph nodes, or the spleen of naturally infected cattle using conventional immunohistochemistry (IHC), western blotting, or transgenic mouse bioassay (Fig. 2) (Iwata et al. 2006; Buschmann and Groschup 2005). By 32 months PI, the agent appears in the CNS and dorsal root ganglia, followed by trigeminal ganglia at 36 months PI, likely transported via retrograde axonal transport in peripheral nerve endings innervating gastrointestinal targets. Once reaching the CNS, PrPSc progressively accumulates and is associated with degenerative CNS lesions that are generally similar to those reported in other prion diseases (Simmons et al. 2011; Okada et al. 2011). As with other TSEs, there is no specific immunologic response to the PrPSc agent (Aguzzi and Heikenwalder 2006).
Transmission
As noted above, the transmission of c-BSE is dependent on the consumption of BSE-contaminated feeds, e.g., rendered MBM derived from BSE-affected cattle. The lack of detectable PrPSc in broader peripheral lymphoid tissues and excretory organs likely correlates with the absence of horizontal c-BSE transmission, unlike what has been reported with CWD (Miller and Williams 2003). For that reason, a ban on the use of MBM in ruminant feed in the UK in 1988 essentially broke the transmission chain of c-BSE. A further ban on bovine offal in 1990, so called “specified risk material,” including skull, CNS, eyes, tonsils, and the distal ileum of the small intestine, from animal and human food chains further precluded the transmission of c-BSE to ruminants and other species (Heim and Kihm 2003). Despite these measures, evidence suggested that new feedborne cases continued in European cattle (Hazards EPanel oB et al. 2017); for additional food security, an earlier ban on cattle offal in animal feed was extended to a total ban on the inclusion of mammalian proteins in feed produced for any farm animals. Cases of c-BSE are now rare, outnumbered 5-to-1 by sporadic cases of atypical BSE over the past decade (European Food Safety Authority 2021).
Zoonotic potential
Zoonotic transmission of c-BSE to humans has been well documented, though has fortunately been a relatively rare occurrence, primarily due to the existence of a “transmission barrier” which limits the cross-species transmission of many TSEs (Houston and Andreoletti 2019; Manson and Diack 2016). This barrier is thought to be a result of differences in the primary structure between infectious source and host prion proteins as well as in the tertiary structure of the misfolded PrPSc protein and the host PrPC. Experiments have shown that the tertiary structure of the misfolded c-BSE prion in particular – or more appropriately its “cloud of conformations” as sometimes described (Collinge 2010), likely plays an important role in its ability to overcome transmission barriers in a wide range of species. Because of this transmission barrier, just 230 cases of vCJD have been reported worldwide so far – with the majority reported in UK residents with a history of consuming beef products – despite over 180,000 known cases of c-BSE reported in the UK alone (Alarcon et al. 2023). Variant CJD cases in humans peaked a decade after the BSE epidemic peak in the early 1990s, with an estimated incubation period of 15–20 years in most cases (Valleron et al. 2001). Interestingly, nearly all cases of vCJD in humans shared a common Prnp genotype – homozygosity for methionine at position 129 of the Prnp gene (M129). An alternate allele, carrying valine at position 129 (V129), was found to confer a very high level of protection against vCJD infection (Saba and Booth 2013).
Variant CJD prions have been found by various methods in a range of human peripheral tissues (Douet et al. 2017; Diack et al. 2017; Notari et al. 2010; Head et al. 2004), with minor overlap reported in distribution compared to the parent c-BSE strain (Franz et al. 2012). An early study using an enhanced immunoblot technique identified vCJD prions in the thymus, tonsil, spleen, adrenal gland, and rectum of several affected human patients (Wadsworth et al. 2001). A separate study employing serial protein misfolding cyclic amplification (sPMCA), an in vitro prion misfolding amplification assay, identified amplifiable prions in a number of additional peripheral tissues, including exocrine organs like the salivary gland and kidney (Douet et al. 2017). These findings contrast the general restriction of prions to the CNS as described in cases of sporadic and familial human prion diseases (Head et al. 2004), though more sensitive amplification studies have not yet been performed for the other forms of CJD. A small number of cases have also arisen through blood transfusions from vCJD-infected donors (Ironside 2006), with several additional studies finding amplifiable prions in blood components from both clinical and preclinical vCJD cases (Concha-Marambio et al. 2020). These findings suggest that the pathogenesis of vCJD differs from not just c-BSE, but other forms of CJD as well, suggesting that the agent itself may have an important role in shaping prion disease pathogenesis. Further understanding of the roles of the host and agent in this process requires additional research, outlined in later sections.
Prevention and management
The prevention and management of c-BSE relies entirely on eliminating MBM and other specified risk materials from cattle feed. While there have been no mutations within the cattle Prnp gene found to confer resistance to c-BSE, several insertion/deletion polymorphisms in the promoter region controlling Prnp expression levels have been associated with increased disease susceptibility and higher risk of atypical BSE (Clawson et al. 2008). Additionally, an E211K (glutamic acid, E, to lysine, K) polymorphism at position 211 within the bovine Prnp gene may be associated with H-type BSE, and may be the basis for heritable forms of BSE (Nicholson et al. 2008). This polymorphism is similar to an E200K polymorphism found in humans, which is thought to be associated with inherited CJD. Cattle that have had the Prnp gene “knocked-out” have been developed and shown completely resistant to c-BSE infection, though their utility, given the scarcity of c-BSE cases in the present day, is limited (Richt et al. 2007).
Chronic wasting disease
Chronic wasting disease was first identified in northern Colorado and southern Wyoming in the late 1960s and spread slowly and insidiously in this core area over several decades since its discovery (Williams and Young 1992). In the late 1990s and early 2000s, reports of CWD began appearing outside of its original core area, including cases in Wisconsin, Saskatchewan, and South Korea, in part through the movement of subclinically infected farmed deer and elk, and in part through natural wild cervid migration and the movement of infected carcasses (Haley and Hoover 2015). Over the past two decades, the endemic range of the disease has continued to expand across North America, with CWD having been reported in free-ranging or farmed deer in 31 U.S. states and four Canadian provinces (Richards 2023). In 2016, a novel CWD focus and strain was identified in reindeer in Norway, with additional cases and a second unique strain soon reported elsewhere in Scandinavia (Fig. 1B) (Tranulis et al. 2021). Absolute case numbers in North America are unknown, though likely extend well into the hundreds of thousands, while current reports in Scandinavia suggest a total of ~ 31 cases (Hazards et al. 2023).
Clinical symptoms of CWD are in line with those of other prion disorders in animals, with affected deer and elk showing behavioral changes including a reduced fear of humans or heightened aggression, along with variable neurologic defects, hair loss, and cachexia (Williams 2005). Increased salivation, bruxism, polydipsia, and polyuria are also common clinical findings in advanced cases. Clinical signs may never be apparent in free-ranging animals, as they are commonly removed from the herd in preclinical stages through predation, hunting, or vehicle collisions (Krumm et al. 2009; Krumm et al. 2005; Conner et al. 2000). In controlled settings, naturally and experimentally infected animals frequently die with signs of aspiration pneumonia, due to some combination of hypersalivation and dysphagia – a common cause of death in humans affected with various forms of CJD (Williams and Young 1992; Zerr et al. 2009). Incubation periods of CWD may range from 16 months to several years, and is strongly influenced by the Prnp genotype of the cervid host (Johnson et al. 2011; Hamir et al. 2006a).
A wide range of cervid species have been shown to be susceptible to CWD through oral transmission, including mule deer, white-tailed deer, North American elk, moose, caribou, red deer, sika deer, and muntjac. Non-cervid species have been found susceptible to CWD infection through experimental routes, e.g., intracranial inoculation, including some non-human primate species (Race et al. 2014), cattle (Hamir et al. 2007), swine (Moore et al. 2017), raccoon (Moore et al. 2019), domestic cats (Mathiason et al. 2013), ferrets (Bartz et al. 1998), and various rodent species (Heisey et al. 2010; Raymond et al. 2007). Fallow deer, interestingly, have been found to be resistant to natural routes of transmission, though are susceptible to intracranial inoculation (Hamir et al. 2011a). Collectively, the disease’s continued expansion across North America and now Scandinavia in both farmed and free-ranging cervids, as well the natural and experimental susceptibility of cervid and non-cervid species, makes CWD the most important prion disease at this time.
Etiologic agent
The prion agent causing CWD is sometimes referred to as PrPCWD. The normal prion protein in cervid species is 256 amino acids in length, with structural similarities to the bovine and human prion protein. The most common prion haplotype of white-tailed deer yields a protein that shares a 94% sequence homology with that of cattle, and an 89% sequence homology with the human prion protein, again primarily in the structured C-terminal end of the protein. While cases of CWD in North America are all considered infectious in origin and transmissible between susceptible cervid species, the appearance of CWD in Scandinavia – and the unique strains reported there – supports the potential for spontaneous origin of the disease (Pirisinu et al. 2018). There are thought to be a number of distinct CWD strains, based on differences in incubation periods and pathologic profiles in the natural host and laboratory species (Raymond et al. 2007; Perrott et al. 2012; Angers et al. 2010; Nonno et al. 2020; Sun et al. 2023; Otero et al. 2023). Based on western blotting profiles and studies in laboratory rodents, there is evidence that some isolates of CWD from Sweden and other parts of Scandinavia represent different strains than those present in North America (Fig. 3) (Pirisinu et al. 2018; Nonno et al. 2020; Bian et al. 2021). Apart from some Scandinavian isolates, differentiating CWD strains biochemically in the natural host has not yet been possible. There is very little epidemiologic information available on the North American CWD strains, with no data available on differences in geographic distribution, species susceptibility, or incubation periods in the natural host.
Disease origin
Chronic wasting disease shares much in common with sheep scrapie, one of the earliest known prion disorders. There is some speculation that CWD may have arisen through direct or indirect transmission of scrapie from sheep, though its true origins are unknown. Research has shown that scrapie can be efficiently transmitted by intracranial inoculation to elk (Hamir et al. 2004) and via intracranial and oral routes to white-tailed deer (Greenlee et al. 2022; Greenlee et al. 2011), and similarly, chronic wasting disease can be transmitted to sheep via intracranial and oral routes, however with relatively low attack rates (Cassmann et al. 2021a; Cassmann et al. 2021b; Hamir et al. 2006b). Lesion profiles and molecular characteristics between the two diseases, including in cross-species transmission studies, are quite similar and support the scrapie-origin hypothesis for CWD (Greenlee et al. 2022; Cassmann et al. 2021a). No firm evidence is available, however, to confirm an historical link between scrapie and CWD in either North American or Scandinavian cervids, and it seems equally plausible that CWD arose spontaneously in deer species.
Pathogenesis
For most reported isolates, CWD prions initially appear in gastrointestinal-associated lymphoid tissues (GALT), similar to c-BSE, with additional appearance in retropharyngeal lymph node (RPLN), tonsil, and mesenteric lymph nodes along the distal GI tract by 6 weeks PI (Sigurdson et al. 1999; Sigurdson et al. 2001; Sigurdson et al. 2002). It should be noted that a recently described strain of CWD in a moose from Finland, however, failed to show any evidence of lymphotropism (Sun et al. 2023). Because of the early appearance of PrPSc in the RPLN, it is one of the preferred tissues for diagnosing CWD in deer postmortem (United States Department of Agriculture 2020). Sympathetic connections associated with the germinal centers in these lymphoid tissues may serve as a conduit for PrPSc to reach the central nervous system, with early accumulation and corresponding spongiform degeneration appearing in the dorsal motor nucleus of the vagus (Sigurdson 2008; Williams and Miller 2002; Balkema-Buschmann et al. 2019). The agent continues its advance to higher brain centers, with widespread prion accumulation and neurodegeneration coinciding with the onset of clinical disease (Williams 2005).
An incomplete picture remains concerning the timing of the appearance of PrPSc in peripheral tissues (Fig. 2), integral to horizontal transmission as described below. It is likely that the appearance in excretory tissues occurs concurrent with CNS ingress, with progressive accumulation over time in salivary glands, kidneys, etc. (Haley et al. 2011), similar to what has been reported for vCJD. The effect of Prnp genetics on the kinetics of PrPSc accumulation in cervid excretory tissues is likely significant. While it is often argued that animals with more prolonged incubation periods may exhibit a greater duration of environmental shedding (Plummer et al. 2017), the approximate onset of shedding in cervids with specific Prnp polymorphisms, discussed in additional detail below, is unknown.
Transmission
Much work has been done over the past two decades to characterize the routes of CWD transmission, relying on studies in both the natural host and transgenic mice, as well as experimental protein misfolded amplification techniques. Several natural routes are likely to be important, including horizontal transmission through excreta, vertical transmission either in utero or post-parturition, and of course through environmental contamination. Work still remains, however on characterizing the onset of shedding in infected animals and the persistence of CWD prions in various environments.
Saliva from animals in the clinical and preclinical phases of infection has been shown to carry significant levels of infectivity, approaching those which may be found in CNS tissues (Henderson et al. 2013). Other excreta, including feces and urine, have lower yet demonstrable levels of infectivity and detectable PrPSc (Tamguney et al. 2012). Using amplification and bioassay approaches, chronic wasting disease prions also have been found in various blood fractions, as has been reported for vCJD, as well as antler velvet, muscle tissue, and fat of CWD infected deer and elk (Fig. 2) (Mathiason et al. 2010; Angers et al. 2009; Angers et al. 2006; Race et al. 2009). Transmission of CWD from mother to offspring in utero seems likely based on separate reports of amplifiable prions in tissues from elk and deer fetuses (Selariu et al. 2015; Nalls et al. 2021), though the frequency of its occurrence is unknown. Thus far, there have been no reports of infectivity in colostrum or milk, though it is certainly possible based on the current understanding of the disease and the potential transfer of scrapie and BSE via milk products (Tsutsui et al. 2008; Konold et al. 2013). There has been no evidence for the direct transmission of CWD through semen, however in vitro amplification approaches have identified low, potentially sub-infectious levels of CWD prions in semen from infected animals, and thus sexual transmission of CWD seems plausible as well (Kramm et al. 2019). Details on the timing of shedding in infected animals are not well understood, however infectious prions have been identified in various forms of excreta from preclinically infected deer and elk (Mathiason et al. 2009; Pulford et al. 2012). As noted above, it seems likely that Prnp genetic variations affect disease susceptibility and may shape the onset and duration of shedding in all forms of excreta and bodily fluids from affected cervids.
Apart from direct horizontal transmission, environmental contamination and transmission through infected carcasses and excreta is an equally important mechanism of disease spread and makes CWD incredibly difficult to manage – especially in free-ranging cervids (Miller et al. 2004). Using sensitive misfolded protein amplification techniques, CWD prions have been detected in water sources in endemic areas and from soil around mineral licks (Nichols et al. 2009; Plummer et al. 2018), and the agent has been shown to bind tightly to soil particles including clay and quartz – perhaps enhancing infectivity in the process (Johnson et al. 2007). CWD prions have even been experimentally recovered from plants cultivated in water containing CWD infected brain material and ticks collected from CWD-positive elk (Haley et al. 2021a; Pritzkow et al. 2015), although the precise role of plants and ticks in CWD transmission in nature is not yet known.
Zoonotic potential
To date, there have been no known cases of a human TSE linked to CWD exposure, despite the high sequence homology between cervid and human Prnp proteins. Several retrospective and prospective studies have been published without finding any evidence for zoonotic transmission, supporting the thought that the tertiary conformation of the infectious prions may be more influential than sequence homology for cross-species transmission (Olszowy et al. 2014; Belay et al. 2001). In vivo studies, using transgenic mice expressing various alleles of the human prion protein, and in vitro studies, examining amplification potential of CWD prions in human cellular prion substrate, have supported the hypothesis that, as it currently stands, the risk of zoonotic CWD transmission is negligible (Barria et al. 2018; Kong et al. 2005; Davenport et al. 2015; Hannaoui et al. 2022). It remains to be seen whether as-yet undiscovered CWD strains may have increased zoonotic risk.
Diagnosis
The diagnosis of CWD requires the examination of brainstem (at the level of the obex) and RPLN collected post-mortem (United States Department of Agriculture 2020). In white-tailed deer and mule deer, RPLN tissues have shown the greatest sensitivity, while in elk the obex is most often relied on for definitive diagnosis. Appropriate postmortem tissues in other cervids, including moose and reindeer, may vary, though generally both obex and RPLN are preferred (Benestad and Telling 2018). Samples are typically screened first via ELISA, with positive results subsequently confirmed by IHC (Hibler et al. 2003; Haley and Richt 2017). Because the sensitivity of both assays is imperfect, negative results are often simply reported as “not detected.”
Antemortem testing approaches, using recto-anal mucosa-associated lymphoid tissue (RAMALT) or tonsil biopsies for example, are well documented though to date have not been approved for regulatory testing (Haley et al. 2020; Wild et al. 2002). The prion load, and therefore diagnostic sensitivities, of these tissues are lower than those of obex and RPLN tissues collected postmortem, typically 70–90% (Thomsen et al. 2012; Haley et al. 2016a; Haley et al. 2016b). Interestingly, antemortem test sensitivity may be significantly affected by the animal’s Prnp genotype, with greater sensitivity reported in the highly susceptible genotypes described in the following section – most likely a result of the relatively rapid disease progression in these animals (Thomsen et al. 2012; Haley et al. 2016a; Haley et al. 2016b).
Experimental misfolded prion amplification techniques, including real time quaking-induced conversion (RT-QuIC) and sPMCA, have allowed for much greater sensitivity than conventional ELISA and IHC techniques in samples collected both antemortem and postmortem. They have additionally allowed for the evaluation of samples considered unsuitable using conventional methods, including saliva, nasal swabs, blood, urine, and feces (Henderson et al. 2013; Haley et al. 2016b; Henderson et al. 2017). Although these amplification assays have not yet been approved for regulatory testing, ongoing development and validation foreshadows their eventual approval for widescale use by regulatory agencies.
Prevention and management
Based on decades of research showing that selective breeding for scrapie resistant alleles in sheep has a significant impact in reducing scrapie prevalence (Hagenaars et al. 2010), an assumption might be made that a similar approach would prove useful for managing CWD – at least in farmed cervids. Although several different alleles for the Prnp gene have been reported in various cervid species, none have yet been found to provide complete resistance to experimental CWD infection (Johnson et al. 2011; Hamir et al. 2006a; Robinson et al. 2012). There are several notable polymorphisms that have been identified in white-tailed deer, mule deer, or elk that have been associated with a lowered risk of CWD infection at the herd level as well as protracted disease incubation periods in individual animals, indicating some level of resistance may be possible (Haley et al. 2021b). These include the polymorphisms Q95H (glutamine, Q to histidine, H at position 95) and G96S (glycine, G to serine, S at position 96) alleles in white-tailed deer, a S225F (serine to phenylalanine, F at position 225) allele in mule deer, and a M132L (methionine, M to leucine, L at position 132) allele in elk. Animals heterozygous or homozygous for these mutations are underrepresented in naturally occurring cases of CWD, and when found to be infected are often in less advanced stages of the disease (Thomsen et al. 2012; Haley et al. 2016b; Haley et al. 2019). When experimentally infected, these animals have been found to have significantly longer incubation periods (Johnson et al. 2011). Notably, these alleles exhibit an additive effect with regard to differential susceptibility, whereby prevalence rates may be lower and disease course further prolonged in homozygous animals compared to those that are heterozygous. While these polymorphisms, and others in related cervid species, have not been found to confer complete resistance to CWD, ongoing genome-wide association studies may identify additional genes that may contribute to CWD resistance, and could ultimately lead to the selective breeding of highly CWD-resistant deer and elk (Seabury et al. 2022; Seabury et al. 2020). Any newly identified resistance-associated genes may also prove influential in managing other related prion diseases or protein misfolding disorders in general.
Because our current understanding of genetic resistance in cervids does not allow for unassailably effective CWD prevention and management, disease control must rely on more traditional approaches. In both farmed and wild herds, active surveillance is extremely important in identifying cases early and minimalizing both horizontal transmission and environmental contamination. Quarantine, trace outs, and depopulation is the most common approach for managing CWD in farmed herds, while herd reduction and dispersal strategies are often relied upon when managing CWD in wild cervid populations (USDA 2019; Conner et al. 2007; Geremia et al. 2015). The continued expansion of CWD in both farmed and wild cervid populations suggest that the development of more effective management approaches will be critical for controlling disease spread in the near future.
Cross-species transmissibility and pathogenesis studies
After reflecting on the similarities and stark disparities between c-BSE and CWD, an appropriate question may be “What are the host- and agent-derived factors involved, and which are the most influential, in the pathogenesis, horizontal transmissibility, and zoonotic potential of prion disorders?” One important approach in understanding the respective roles of host and agent in prion disease pathogenesis is cross-species transmissibility, i.e., investigating the pathogenesis of experimental CWD infection in cattle and sheep, or experimental BSE in cervid species and sheep. These experiments, performed over the past several decades, have provided valuable insight into the role of host and agent in TSE pathogenesis – insight which may ultimately help answer the question of whether a horizontally-transmissible prion disease, like CWD in cervids, could arise in human populations.
CWD in cattle
In experiments intended to estimate the natural susceptibility of domestic cattle to CWD, cattle were inoculated intracranially with isolates of CWD prions from several cervid sources, including mule deer, white-tailed deer, and elk (Hamir et al. 2007; Greenlee et al. 2012; Hamir et al. 2011b; Hamir et al. 2006c; Hamir et al. 2005). Although a small number of the cattle developed clinical signs suggestive of a prion infection, typically within ~ 2 years of exposure, there was an unexpected absence of overt microscopic pathology in any symptomatic animal. Molecular evidence of infection, however, was identified through immunostaining and experimental prion amplification, though limited to the central nervous system and, rarely, peripheral lymphatic tissues (Fig. 2) (Haley et al. 2016c). CNS deposition patterns and western blotting profiles of PrPSc were distinct from those reported for BSE, and yet dissimilar from those reported in CWD-positive animals as well (Fig. 3 and Table 1). No evidence for prion deposition in excretory tissues was found in any of the affected cattle – even in animals inoculated with second passage mule deer CWD previously passaged through cattle, unlike what might be expected with CWD in the natural cervid host. Subsequent experiments have shown that cattle are not susceptible to primary CWD exposure through the oral route, even following prolonged incubation times of over a decade (Williams et al. 2018). Cross-species transmission of scrapie to cattle have yielded similar findings, with limited peripheral accumulation and microscopic/molecular pathology distinct from both BSE and scrapie (Konold et al. 2015; Cutlip et al. 1997; Cutlip et al. 1994; Konold et al. 2006). Taken together, these findings suggest that it is the bovine host that dictates the pathogenesis of experimental CWD infection, making it unlikely that a transmissible form of CWD might develop in cattle. Neuropathology and molecular features of the misfolded prion, in contrast, may be influenced by both the initiating prion agent and the host.
BSE in cervids
In converse experiments, intended to assess the susceptibility of cervids to BSE, red deer (Cervus elaphus) were inoculated either orally or intracranially with cattle-derived c-BSE (Dagleish et al. 2008; Martin et al. 2009). In these experiments, red deer were highly susceptible to intracranial inoculation, and marginally susceptible to oral exposure. Incubation periods in symptomatic animals ranged from 26–42 months for intracranially inoculated animals, with just one of six orally exposed red deer developing clinical signs 57 months. Deposition patterns of PrPSc in red deer were distinct from those of CWD and more closely resembled those of bovine c-BSE, i.e., readily distinguished from CWD (Table 1). Western blotting and lesion profiles were also distinct from both c-BSE and CWD (Fig. 3). As was described above for CWD in cattle, no evidence for peripheralization of BSE prions in red deer was identified – in either intracranially or orally inoculated animals (Fig. 2). Secondary passage experiments and prion amplification approaches for peripheral tissues were not performed and may have provided additional insight into BSE pathogenesis in deer species. When considering these experimental findings, one might conclude that the agent itself is the primary force driving disease pathogenesis and transmissibility. This is very different from the observations reported above for experimental CWD infection in cattle.
BSE in sheep
Several studies over the past two decades have sought to understand the susceptibility of sheep to BSE (Konold et al. 2006; Keulen et al. 2008; Ronzon et al. 2006; Lezmi et al. 2006; Jeffrey et al. 2001). These studies generally found attack rates and incubation periods that followed patterns of sheep susceptibility to classical scrapie across varied sheep Prnp genotypes. Both central and peripheral PrPSc accumulation, including lymphoid and muscular tissues, was similar to that reported for classical scrapie, albeit measurably lower based on ELISA testing (Fig. 2). Western blot profiles and lesion profiles of sheep BSE prions were similar to those of some strains of classical sheep scrapie (Fig. 3 and Table 1). These findings would suggest the potential for some level of horizontal transmission of BSE in sheep; interestingly, low rates of transmission, particularly vertical transmission, were in fact reported in an intensively managed flock of sheep with experimental BSE infections (Jeffrey et al. 2015). The authors of that study noted that transmission rates were low enough that it would be unlikely for sheep BSE to persist in the flock. These studies support the heightened role of the host in TSE pathogenesis and transmission.
CWD in sheep
Several studies have likewise been conducted to better understand the pathogenesis of CWD in sheep following either intracranial or oronasal inoculation (Cassmann et al. 2021a; Cassmann et al. 2021b; Hamir et al. 2006b; Hamir et al. 2006c). Although these studies did not thoroughly consider the peripheral distribution of prions, they do provide some insight into the susceptibility, pathogenesis, and molecular profile of sheep-passaged CWD. In an early study investigating the susceptibility of Suffolk sheep to intracranial inoculation with mule deer-origin CWD, a low attack rate was reported among sheep with mixed Prnp genetic backgrounds, with just 2 of 8 sheep developing either a clinical or pre-symptomatic infection with incubation periods ranging from 35–72 months (Cassmann et al. 2021a) Distribution of PrPSc in the CNS was similar to those reported in sheep scrapie, with one sheep showing additional prion accumulation in peripheral lymph nodes (Fig. 2 and Table 1). Western blot PrPres profiles were similar, but not identical to that of the original mule deer inoculum (Fig. 3). A follow-up study on secondary intracranial passage study in sheep was recently published, which found a 100% attack rate across varied Prnp genotypes, with all sheep having both central nervous system and peripheral accumulation of prions in both lymphoid and muscular tissues (Cassmann et al. 2021b). Disease progression across Prnp backgrounds was similar to, though not entirely consistent with those reported with sheep scrapie, which the authors note may have been a result of prion strain selection during primary passage. Finally, a more recent study examining the oronasal susceptibility of sheep to white-tailed deer derived CWD prions found a low attack rate, with just 1 of 7 sheep developing an asymptomatic infection after a 60-month incubation period (Greenlee et al. 2022). The lone TSE-positive animal did show peripheral lymphoid accumulation, and the authors noted that they could not rule out the potential for environmental shedding by this animal. In summary, these findings suggest that although the CWD and scrapie agents are distinct, both have the potential to disseminate to the periphery in a permissible sheep host – further implicating host factors as those most important in shaping prion disease pathogenesis and transmissibility.
Ultimately, the question of whether the host or the prion agent is more influential in prion pathogenesis and horizontal transmissibility remains incompletely answered. The preponderance of data from cross-species studies suggests that the host is the primary factor influencing pathogenesis and transmissibility, while both host and prion agent factors are capable of modulating lesion and western blotting profiles. Additional studies investigating c-BSE pathogenesis in species highly susceptible to CWD, e.g., white-tailed deer homozygous for the 96G Prnp allele, would allow a more complete understanding of the host’s role in TSE transmissibility. Studies thus far seem to suggest that c-BSE would, in fact, show at least some peripheralization in white-tailed deer – as it had in sheep (Jeffrey et al. 2015) – with similarly low levels of transmissibility. By extension, these findings suggest that, based on findings of vCJD prion peripheralization, there is the distinct possibility that a horizontally transmissible prion disease could arise in humans following transmission of different animal prion agents such as CWD. With the sharp decline in BSE cases worldwide, and so far little evidence that CWD has any zoonotic potential, the risk of such a scenario appears to be quite low, however scientific studies to identify and assess the transmissibility of novel CWD, BSE, CJD and other emerging prion strains (e.g., camel prion strains (Babelhadj et al. 2018)) are essential to protect animal and public health and need to continue.
Future directions
To improve our understanding of the pathogenesis and transmission of prion diseases, several important studies should be considered going forward. More thorough investigations into the onset, duration, and sites of shedding of CWD prions in cervid species – especially those with newly identified strains or rare and arguably less susceptible Prnp alleles – will provide important information on how and when deer and related cervid species begin shedding infectious prions, and whether alternate Prnp genotypes or strains have any effects on shedding kinetics. To better appreciate the respective roles of host and agent in TSE transmissibility, more in-depth studies of BSE transmission to cervids, including prion amplification-based evaluations of available tissues from past studies in red deer, and new studies examining the susceptibility and pathogenesis of BSE in white-tailed deer are necessary; prion amplification-based studies targeting peripheral tissues from patients with various forms of CJD would also shed more light on this subject. Lastly, a better understanding of the zoonotic transmissibility of novel prion strains – including newly identified strains in moose, those isolated from cervids with rare Prnp alleles, the recently described camel prion disease, or cross-species experiments, would inform health professionals on the ongoing risk associated with consumption of and contact with TSE-affected cervids and other species.
Conclusions
Although BSE and CWD are both prion diseases of ruminants, there are significant differences in their pathogenesis, transmission routes, and zoonotic potential. These inherent differences raise questions about how a misfolded protein can behave so differently in different mammalian hosts; questions that are partially explored in experimental cross-species transmission studies that have provided us with a glimpse of the roles of the host and the prion agent in prion pathogenesis and transmissibility. Future studies expanding on these cross-species experiments and focusing in more detail on human prion disorders and newly emerging prion strains will allow a better understanding of the host versus agent role and, perhaps more importantly, will be able to determine the risk for a horizontally transmissible prion disease to arise in human populations.
Availability of data and materials
Not applicable.
References
Ackermann, I., A. Balkema-Buschmann, R. Ulrich, K. Tauscher, J.C. Shawulu, M. Keller, O.I. Fatola, P. Brown, and M.H. Groschup. 2017. Detection of PrP(BSE) and prion infectivity in the ileal Peyer’s patch of young calves as early as 2 months after oral challenge with classical bovine spongiform encephalopathy. Veterinary Research 48: 88.
Ackermann I, Ulrich R, Tauscher K, Fatola OI, Keller M, Shawulu JC, Arnold M, Czub S, Groschup MH, Balkema-Buschmann A. 2021. Prion Infectivity and PrPBSE in the Peripheral and Central Nervous System of Cattle 8 Months Post Oral BSE Challenge. International Journal of Molecular Sciences 22, 11310. https://doi.org/10.3390/ijms222111310.
Agriculture USDo. 2004. Summary report: Epidemiological investigation of Washington State BSE case. https://www.aphis.usda.gov/animal_health/animal_diseases/bse/downloads/WashingtonState_epi_final3-04.pdf.
Aguzzi, A., and M. Heikenwalder. 2006. Pathogenesis of prion diseases: Current status and future outlook. Nature Reviews Microbiology 4: 765–775.
Alarcon, P., B. Wall, K. Barnes, M. Arnold, B. Rajanayagam, and J. Guitian. 2023. Classical BSE in Great Britain: Review of its epidemic, risk factors, policy and impact. Food Control 146: 109490.
Aldhous, P. 1990. BSE: Spongiform encephalopathy found in cat. Nature 345: 194.
Angers, R.C., S.R. Browning, T.S. Seward, C.J. Sigurdson, M.W. Miller, E.A. Hoover, and G.C. Telling. 2006. Prions in skeletal muscles of deer with chronic wasting disease. Science 311: 1117.
Angers, R.C., T.S. Seward, D. Napier, M. Green, E. Hoover, T. Spraker, K. O’Rourke, A. Balachandran, and G.C. Telling. 2009. Chronic wasting disease prions in elk antler velvet. Emerging Infectious Diseases 15: 696–703.
Angers, R.C., H.E. Kang, D. Napier, S. Browning, T. Seward, C. Mathiason, A. Balachandran, D. McKenzie, J. Castilla, C. Soto. et al. 2010. Prion strain mutation determined by prion protein conformational compatibility and primary structure. Science 328: 1154–1158.
Appleby, B.S., S. Shetty, and M. Elkasaby. 2022. Genetic aspects of human prion diseases. Frontiers in Neurology 13: 1003056.
Babelhadj, B., M.A. Di Bari, L. Pirisinu, B. Chiappini, S.B.S. Gaouar, G. Riccardi, S. Marcon, U. Agrimi, R. Nonno, and G. Vaccari. 2018. Prion disease in dromedary camels, Algeria. Emerging Infectious Diseases 24: 1029–1036.
Balkema-Buschmann, A., C. Fast, M. Kaatz, M. Eiden, U. Ziegler, L. McIntyre, M. Keller, B. Hills, and M.H. Groschup. 2011. Pathogenesis of classical and atypical BSE in cattle. Preventive Veterinary Medicine 102: 112–117.
Balkema-Buschmann, A., G. Priemer, R. Ulrich, R. Strobelt, B. Hills, and M.H. Groschup. 2019. Deciphering the BSE-type specific cell and tissue tropisms of atypical (H and L) and classical BSE. Prion 13: 160–172.
Barlow, R.M., and D.J. Middleton. 1990. Dietary transmission of bovine spongiform encephalopathy to mice. The Veterinary Record 126: 111–112. https://pubmed.ncbi.nlm.nih.gov/2309404/.
Barria, M.A., A. Libori, G. Mitchell, and M.W. Head. 2018. Susceptibility of human prion protein to conversion by chronic wasting disease prions. Emerging Infectious Diseases 24: 1482–1489.
Bartz, J.C., R.F. Marsh, D.I. McKenzie, and J.M. Aiken. 1998. The host range of chronic wasting disease is altered on passage in ferrets. Virology 251: 297–301.
Belay, E.D., P. Gambetti, L.B. Schonberger, P. Parchi, D.R. Lyon, S. Capellari, J.H. McQuiston, K. Bradley, G. Dowdle, J.M. Crutcher, and C.R. Nichols. 2001. Creutzfeldt-Jakob disease in unusually young patients who consumed venison. Archives of Neurology 58: 1673–1678.
Benestad, S.L., and G.C. Telling. 2018. Chronic wasting disease: An evolving prion disease of cervids. Handbook of Clinical Neurology 153: 135–151.
Biacabe, A.G., E. Morignat, J. Vulin, D. Calavas, and T.G. Baron. 2008. Atypical bovine spongiform encephalopathies, France, 2001–2007. Emerging Infectious Diseases 14: 298–300.
Bian, J., S. Kim, S.J. Kane, J. Crowell, J.L. Sun, J. Christiansen, E. Saijo, J.A. Moreno, J. DiLisio, E. Burnett. et al. 2021. Adaptive selection of a prion strain conformer corresponding to established North American CWD during propagation of novel emergent Norwegian strains in mice expressing elk or deer prion protein. PLOS Pathogens 17: e1009748.
Brown, P., and Y. Bradley. 1998. 1755 and all that: A historical primer of transmissible spongiform encephalopathy. BMJ 317: 1688–1692.
Bruce, M.E., R.G. Will, J.W. Ironside, I. McConnell, D. Drummond, A. Suttie, L. McCardle, A. Chree, J. Hope, C. Birkett, S. Cousens, H. Fraser, and C.J. Bostock. 1997. Transmissions to mice indicate that “new variant” CJD is caused by the BSE agent. Nature 389: 498–501.
Buschmann, A., and M.H. Groschup. 2005. Highly bovine spongiform encephalopathy-sensitive transgenic mice confirm the essential restriction of infectivity to the nervous system in clinically diseased cattle. Journal of Infectious Diseases 192: 934–942.
Capobianco, R., C. Casalone, S. Suardi, M. Mangieri, C. Miccolo, L. Limido, M. Catania, G. Rossi, G. Di Fede, G. Giaccone. et al. 2007. Conversion of the BASE prion strain into the BSE strain: The origin of BSE? PLoS Pathogens 3: e31.
Cassmann, E.D., S.J. Moore, and J.J. Greenlee. 2021a. Experimental oronasal transmission of chronic wasting disease agent from white-tailed deer to suffolk sheep. Emerging Infectious Diseases 27: 3156–3158.
Cassmann, E.D., R.D. Frese, and J.J. Greenlee. 2021b. Second passage of chronic wasting disease of mule deer to sheep by intracranial inoculation compared to classical scrapie. Journal of Veterinary Diagnostic Investigation 33: 711–720.
Clawson, M.L., J.A. Richt, T. Baron, A.-G. Biacabe, S. Czub, M.P. Heaton, T.P.L. Smith, and W.W. Laegreid. 2008. Association of a bovine prion gene haplotype with atypical BSE. PLoS One 3: e1830.
Colchester, A.C., and N.T. Colchester. 2005. The origin of bovine spongiform encephalopathy: The human prion disease hypothesis. Lancet 366: 856–861.
Collee, J.G., and R. Bradley. 1997. BSE: A decade on–Part I. Lancet 349: 636–641.
Collinge, J. 2010. Medicine. Prion Strain Mutation and Selection. Science 328: 1111–1112.
Collinge, J., K.C. Sidle, J. Meads, J. Ironside, and A.F. Hill. 1996. Molecular analysis of prion strain variation and the aetiology of “new variant” CJD. Nature 383: 685–690.
Collins, S.J., V.A. Lawson, and C.L. Masters. 2004. Transmissible spongiform encephalopathies. Lancet 363: 51–61.
Concha-Marambio, L., M.A. Chacon, and C. Soto. 2020. Preclinical detection of prions in blood of nonhuman primates infected with variant creutzfeldt-jakob disease. Emerging Infectious Diseases 26: 34–43.
Conner, M.M., C.W. McCarty, and M.W. Miller. 2000. Detection of bias in harvest-based estimates of chronic wasting disease prevalence in mule deer. Journal of Wildlife Diseases 36: 691–699.
Conner, M.M., M.W. Miller, M.R. Ebinger, and K.P. Burnham. 2007. A meta-BACI approach for evaluating management intervention on chronic wasting disease in mule deer. Ecological Applications 17: 140–153.
Cutlip, R.C., J.M. Miller, R.E. Race, A.L. Jenny, J.B. Katz, H.D. Lehmkuhl, B.M. DeBey, and M.M. Robinson. 1994. Intracerebral transmission of scrapie to cattle. Journal of Infectious Diseases 169: 814–820.
Cutlip, R.C., J.M. Miller, and H.D. Lehmkuhl. 1997. Second passage of a US scrapie agent in cattle. Journal of Comparative Pathology 117: 271–275.
Dagleish, M.P., S. Martin, P. Steele, J. Finlayson, S. Siso, S. Hamilton, F. Chianini, H.W. Reid, L. Gonzalez, and M. Jeffrey. 2008. Experimental transmission of bovine spongiform encephalopathy to European red deer (Cervus elaphus elaphus). BMC Veterinary Research 4: 17.
Davenport, K.A., D.M. Henderson, J. Bian, G.C. Telling, C.K. Mathiason, and E.A. Hoover. 2015. Insights into chronic wasting disease and bovine spongiform encephalopathy species barriers by use of real-time conversion. Journal of Virology 89: 9524–9531.
Diack, A.B., R.G. Will, and J.C. Manson. 2017. Public health risks from subclinical variant CJD. PLoS Pathogens 13: e1006642.
Douet, J.Y., C. Lacroux, N. Aron, M.W. Head, S. Lugan, C. Tillier, A. Huor, H. Cassard, M. Arnold, V. Beringue, J.W. Ironside, and O. Andreoletti. 2017. Distribution and Quantitative Estimates of Variant Creutzfeldt-Jakob Disease Prions in Tissues of Clinical and Asymptomatic Patients. Emerging Infectious Diseases 23: 946–956.
European Food Safety Authority. 2021. The European Union summary report on surveillance for the presence of transmissible spongiform encephalopathies (TSE) in 2020. EFSA Journal 19: e06934.
Ferguson, N.M., C.A. Donnelly, M.E. Woolhouse, and R.M. Anderson. 1997. The epidemiology of BSE in cattle herds in Great Britain. II. Model construction and analysis of transmission dynamics. Philosophical Transactions of the Royal Society of London. Series b, Biological Sciences 352: 803–838.
Franz, M., M. Eiden, A. Balkema-Buschmann, J. Greenlee, H. Schatzl, C. Fast, J. Richt, J.P. Hildebrandt, and M.H. Groschup. 2012. Detection of PrP(Sc) in peripheral tissues of clinically affected cattle after oral challenge with bovine spongiform encephalopathy. Journal of General Virology 93: 2740–2748.
Geremia, C., M.W. Miller, J.A. Hoeting, M.F. Antolin, and N.T. Hobbs. 2015. Bayesian modeling of prion disease dynamics in mule deer using population monitoring and capture-recapture data. PLoS One 10: e0140687.
Greenlee, J.J., and M.H. Greenlee. 2015. The transmissible spongiform encephalopathies of livestock. ILAR Journal 56: 7–25.
Greenlee, J.J., J.D. Smith, and R.A. Kunkle. 2011. White-tailed deer are susceptible to the agent of sheep scrapie by intracerebral inoculation. Veterinary Research 42: 107.
Greenlee, J.J., E.M. Nicholson, J.D. Smith, R.A. Kunkle, and A.N. Hamir. 2012. Susceptibility of cattle to the agent of chronic wasting disease from elk after intracranial inoculation. Journal of Veterinary Diagnostic Investigation 24: 1087–1093.
Greenlee, J.J., S.J. Moore, E.D. Cassmann, Z.J. Lambert, R.D. Kokemuller, J.D. Smith, R.A. Kunkle, Q. Kong, and M.H.W. Greenlee. 2022. White-tailed deer are susceptible to the agent of classical sheep scrapie after experimental oronasal exposure. Journal of Infectious Diseases. https://doi.org/10.1093/infdis/jiac443.
Hagenaars, T.J., M.B. Melchior, A. Bossers, A. Davidse, B. Engel, and F.G. van Zijderveld. 2010. Scrapie prevalence in sheep of susceptible genotype is declining in a population subject to breeding for resistance. BMC Veterinary Research 6: 25.
Haley, N.J., and E.A. Hoover. 2015. Chronic wasting disease of cervids: Current knowledge and future perspectives. Annu Rev Anim Biosci. https://doi.org/10.1146/annurev-animal-022114-111001.
Haley, N.J., C.K. Mathiason, S. Carver, M. Zabel, G.C. Telling, and E.A. Hoover. 2011. Detection of chronic wasting disease prions in salivary, urinary, and intestinal tissues of deer: Potential mechanisms of prion shedding and transmission. Journal of Virology 85: 6309–6318.
Haley, N.J., C. Siepker, L.L. Hoon-Hanks, G. Mitchell, W.D. Walter, M. Manca, R.J. Monello, J.G. Powers, M.A. Wild, E.A. Hoover, B. Caughey, and J.A. Richt. 2016a. 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. Journal of Clinical Microbiology 54: 1117–1126.
Haley, N.J., C. Siepker, W.D. Walter, B.V. Thomsen, J.J. Greenlee, A.D. Lehmkuhl, and J.A. Richt. 2016b. 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. Journal of Clinical Microbiology 54: 1108–1116.
Haley, N.J., C. Siepker, J.J. Greenlee, and J.A. Richt. 2016c. Limited amplification of chronic wasting disease prions in the peripheral tissues of intracerebrally inoculated cattle. Journal of General Virology 97: 1720–1724.
Haley, N.J., K. Merrett, A. Buros Stein, D. Simpson, A. Carlson, G. Mitchell, A. Staskevicius, T. Nichols, A.D. Lehmkuhl, and B.V. Thomsen. 2019. Estimating relative CWD susceptibility and disease progression in farmed white-tailed deer with rare PRNP alleles. PLoS ONE 14: e0224342.
Haley, N.J., R. Donner, D.M. Henderson, J. Tennant, E.A. Hoover, M. Manca, B. Caughey, N. Kondru, S. Manne, A. Kanthasamay. et al. 2020. Cross-validation of the RT-QuIC assay for the antemortem detection of chronic wasting disease in elk. Prion 14: 47–55.
Haley, N.J., D.M. Henderson, K. Senior, M. Miller, and R. Donner. 2021a. Evaluation of winter ticks (dermacentor albipictus) collected from North American Elk (Cervus canadensis) in an area of chronic wasting disease endemicity for evidence of PrP (CWD) amplification using real-time quaking-induced conversion assay. mSphere 6: e0051521.
Haley NJ, Richt JA. 2017. Evolution of Diagnostic Tests for Chronic Wasting Disease, a Naturally Occurring Prion Disease of Cervids. Pathogens 6:35. https://doi.org/10.3390/pathogens6030035.
Haley N, Donner R, Merrett K, Miller M, Senior K. 2021b. Selective breeding for disease-resistant PRNP variants to manage chronic wasting disease in farmed whitetail deer. Genes (Basel) 12.
Hamir, A.N., J.M. Miller, R.C. Cutlip, R.A. Kunkle, A.L. Jenny, M.J. Stack, M.J. Chaplin, and J.A. Richt. 2004. Transmission of sheep scrapie to elk (Cervus elaphus nelsoni) by intracerebral inoculation: Final outcome of the experiment. Journal of Veterinary Diagnostic Investigation 16: 316–321.
Hamir, A.N., R.A. Kunkle, R.C. Cutlip, J.M. Miller, K.I. O’Rourke, E.S. Williams, M.W. Miller, M.J. Stack, M.J. Chaplin, and J.A. Richt. 2005. Experimental transmission of chronic wasting disease agent from mule deer to cattle by the intracerebral route. Journal of Veterinary Diagnostic Investigation 17: 276–281.
Hamir, A.N., T. Gidlewski, T.R. Spraker, J.M. Miller, L. Creekmore, M. Crocheck, T. Cline, and K.I. O’Rourke. 2006a. Preliminary observations of genetic susceptibility of elk (Cervus elaphus nelsoni) to chronic wasting disease by experimental oral inoculation. Journal of Veterinary Diagnostic Investigation 18: 110–114.
Hamir, A.N., R.A. Kunkle, R.C. Cutlip, J.M. Miller, E.S. Williams, and J.A. Richt. 2006b. Transmission of chronic wasting disease of mule deer to Suffolk sheep following intracerebral inoculation. Journal of Veterinary Diagnostic Investigation 18: 558–565.
Hamir, A.N., R.A. Kunkle, J.M. Miller, J.J. Greenlee, and J.A. Richt. 2006c. Experimental second passage of chronic wasting disease (CWD(mule deer)) agent to cattle. Journal of Comparative Pathology 134: 63–69.
Hamir, A.N., J.M. Miller, R.A. Kunkle, S.M. Hall, and J.A. Richt. 2007. Susceptibility of cattle to first-passage intracerebral inoculation with chronic wasting disease agent from white-tailed deer. Veterinary Pathology 44: 487–493.
Hamir, A.N., J.J. Greenlee, E.M. Nicholson, R.A. Kunkle, J.A. Richt, J.M. Miller, and M. Hall. 2011a. Experimental transmission of chronic wasting disease (CWD) from elk and white-tailed deer to fallow deer by intracerebral route: Final report. Canadian Journal of Veterinary Research 75: 152–156.
Hamir, A.N., M.E. Kehrli Jr., R.A. Kunkle, J.J. Greenlee, E.M. Nicholson, J.A. Richt, J.M. Miller, and R.C. Cutlip. 2011b. Experimental interspecies transmission studies of the transmissible spongiform encephalopathies to cattle: Comparison to bovine spongiform encephalopathy in cattle. Journal of Veterinary Diagnostic Investigation 23: 407–420.
Hannaoui, S., I. Zemlyankina, S.C. Chang, M.I. Arifin, V. Béringue, D. McKenzie, H.M. Schatzl, and S. Gilch. 2022. Transmission of cervid prions to humanized mice demonstrates the zoonotic potential of CWD. Acta Neuropathologica 144: 767–784.
Hazards, EPo.B., K. Koutsoumanis, A. Allende, A. Alvarez-Ordoñez, D. Bolton, S. Bover-Cid, M. Chemaly, R. Davies, A. De Cesare, L. Herman. et al. 2023. Monitoring of chronic wasting disease (CWD) (IV). EFSA Journal 21: e07936.
Hazards EPanel oB, A. Ricci, A. Allende, D. Bolton, M. Chemaly, R. Davies, P.S. Fernández Escámez, R. Gironés, L. Herman, K. Koutsoumanis. et al. 2017. Bovine spongiform encephalopathy (BSE) cases born after the total feed ban. EFSA Journal 15: e04885.
Head, M.W., D. Ritchie, N. Smith, V. McLoughlin, W. Nailon, S. Samad, S. Masson, M. Bishop, L. McCardle, and J.W. Ironside. 2004. Peripheral tissue involvement in sporadic, iatrogenic, and variant Creutzfeldt-Jakob disease: An immunohistochemical, quantitative, and biochemical study. American Journal of Pathology 164: 143–153.
Hedman, C., R. Bolea, B. Marin, F. Cobriere, H. Filali, F. Vazquez, J.L. Pitarch, A. Vargas, C. Acin, B. Moreno, M. Pumarola, O. Andreoletti, and J.J. Badiola. 2016. Transmission of sheep-bovine spongiform encephalopathy to pigs. Veterinary Research 47: 14.
Heim, D., and U. Kihm. 2003. Risk management of transmissible spongiform encephalopathies in Europe. Revue Scientifique Et Technique 22: 179–199.
Heisey, D.M., N.A. Mickelsen, J.R. Schneider, C.J. Johnson, C.J. Johnson, J.A. Langenberg, P.N. Bochsler, D.P. Keane, and D.J. Barr. 2010. Chronic wasting disease (CWD) susceptibility of several North American rodents that are sympatric with cervid CWD epidemics. Journal of Virology 84: 210–215.
Henderson, D.M., M. Manca, N.J. Haley, N.D. Denkers, A.V. Nalls, C.K. Mathiason, B. Caughey, and E.A. Hoover. 2013. Rapid antemortem detection of CWD prions in deer saliva. PLoS One 8: e74377.
Henderson, D.M., J.M. Tennant, N.J. Haley, N.D. Denkers, C.K. Mathiason, and E.A. Hoover. 2017. Detection of chronic wasting disease prion seeding activity in deer and elk feces by real-time quaking-induced conversion. Journal of General Virology 98: 1953–1962.
Herzog, C., N. Sales, N. Etchegaray, A. Charbonnier, S. Freire, D. Dormont, J.P. Deslys, and C.I. Lasmezas. 2004. Tissue distribution of bovine spongiform encephalopathy agent in primates after intravenous or oral infection. Lancet 363: 422–428.
Hibler, C.P., K.L. Wilson, T.R. Spraker, M.W. Miller, R.R. Zink, L.L. DeBuse, E. Andersen, D. Schweitzer, J.A. Kennedy, L.A. Baeten. et al. 2003. Field validation and assessment of an enzyme-linked immunosorbent assay for detecting chronic wasting disease in mule deer (Odocoileus Hemionus), white-tailed deer (Odocoileus Virginianus), and rocky mountain elk (Cervus Elaphus Nelsoni). Journal of Veterinary Diagnostic Investigation 15: 311–319.
Hoinville, L.J., J.W. Wilesmith, and M.S. Richards. 1995. An investigation of risk factors for cases of bovine spongiform encephalopathy born after the introduction of the “feed ban.” The Veterinary Record 136: 312–318.
Houston, F., and O. Andreoletti. 2019. Animal prion diseases: The risks to human health. Brain Pathology 29: 248–262.
Huor, A., J.C. Espinosa, E. Vidal, H. Cassard, J.Y. Douet, S. Lugan, N. Aron, A. Marín-Moreno, P. Lorenzo, P. Aguilar-Calvo. et al. 2019. The emergence of classical BSE from atypical/Nor98 scrapie. Proc Natl Acad Sci U S A 116: 26853–26862.
Ironside, J.W. 2006. Variant Creutzfeldt-Jakob disease: risk of transmission by blood transfusion and blood therapies. Haemophilia 12 (Suppl 1): 8–15 (discussion 26-8).
Ironside, J.W., K. Sutherland, J.E. Bell, L. McCardle, C. Barrie, K. Estebeiro, M. Zeidler, and R.G. Will. 1996. A new variant of Creutzfeldt-Jakob disease: Neuropathological and clinical features. Cold Spring Harbor Symposia on Quantitative Biology 61: 523–530.
Iwata, N., Y. Sato, Y. Higuchi, K. Nohtomi, N. Nagata, H. Hasegawa, M. Tobiume, Y. Nakamura, K. Hagiwara, H. Furuoka, M. Horiuchi, Y. Yamakawa, and T. Sata. 2006. Distribution of PrP(Sc) in cattle with bovine spongiform encephalopathy slaughtered at abattoirs in Japan. Japanese Journal of Infectious Diseases 59: 100–107.
Jeffrey, M., S. Ryder, S. Martin, S.A. Hawkins, L. Terry, C. Berthelin-Baker, and S.J. Bellworthy. 2001. Oral inoculation of sheep with the agent of bovine spongiform encephalopathy (BSE). 1. Onset and distribution of disease-specific PrP accumulation in brain and viscera. Journal of Comparative Pathology 124: 280–289.
Jeffrey, M., J.P. Witz, S. Martin, S.A. Hawkins, S.J. Bellworthy, G.E. Dexter, L. Thurston, and L. Gonzalez. 2015. Dynamics of the natural transmission of bovine spongiform encephalopathy within an intensively managed sheep flock. Veterinary Research 46: 126.
Johnson, C.J., J.A. Pedersen, R.J. Chappell, D. McKenzie, and J.M. Aiken. 2007. Oral transmissibility of prion disease is enhanced by binding to soil particles. PLoS Pathogens 3: e93.
Johnson, C.J., A. Herbst, C. Duque-Velasquez, J.P. Vanderloo, P. Bochsler, R. Chappell, and D. McKenzie. 2011. Prion protein polymorphisms affect chronic wasting disease progression. PLoS One 6: e17450.
Kirkwood, J.K., and A.A. Cunningham. 1994. Epidemiological observations on spongiform encephalopathies in captive wild animals in the British Isles. The Veterinary Record 135: 296–303.
Kong, Q., S. Huang, W. Zou, D. Vanegas, M. Wang, D. Wu, J. Yuan, M. Zheng, H. Bai, H. Deng. et al. 2005. Chronic wasting disease of elk: Transmissibility to humans examined by transgenic mouse models. Journal of Neuroscience 25: 7944–7949.
Konold, T., Y.H. Lee, M.J. Stack, C. Horrocks, R.B. Green, M. Chaplin, M.M. Simmons, S.A. Hawkins, R. Lockey, J. Spiropoulos, J.W. Wilesmith, and G.A. Wells. 2006. Different prion disease phenotypes result from inoculation of cattle with two temporally separated sources of sheep scrapie from Great Britain. BMC Veterinary Research 2: 31.
Konold, T., S.J. Moore, S.J. Bellworthy, L.A. Terry, L. Thorne, A. Ramsay, F.J. Salguero, M.M. Simmons, and H.A. Simmons. 2013. Evidence of effective scrapie transmission via colostrum and milk in sheep. BMC Veterinary Research 9: 99.
Konold, T., R. Nonno, J. Spiropoulos, M.J. Chaplin, M.J. Stack, S.A. Hawkins, S. Cawthraw, J.W. Wilesmith, G.A. Wells, U. Agrimi. et al. 2015. Further characterisation of transmissible spongiform encephalopathy phenotypes after inoculation of cattle with two temporally separated sources of sheep scrapie from Great Britain. BMC Research Notes 8: 312.
Kramm, C., R. Gomez-Gutierrez, C. Soto, G. Telling, T. Nichols, and R. Morales. 2019. In Vitro detection of Chronic Wasting Disease (CWD) prions in semen and reproductive tissues of white tailed deer bucks (Odocoileus virginianus). PLoS ONE 14: e0226560.
Krumm, C.E., M.M. Conner, and M.W. Miller. 2005. Relative vulnerability of chronic wasting disease infected mule deer to vehicle collisions. Journal of Wildlife Diseases 41: 503–511.
Krumm, C.E., M.M. Conner, N.T. Hobbs, D.O. Hunter, and M.W. Miller. 2009. Mountain lions prey selectively on prion-infected mule deer. Biology Letters 6: 209–211.
Lezmi, S., F. Ronzon, A. Bencsik, A. Bedin, D. Calavas, Y. Richard, S. Simon, J. Grassi, and T. Baron. 2006. PrP(d) accumulation in organs of ARQ/ARQ sheep experimentally infected with BSE by peripheral routes. Acta Biochimica Polonica 53: 399–405.
Manson, J.C., and A.B. Diack. 2016. Evaluating the Species Barrier. Food Saf (tokyo) 4: 135–141.
Martin, S., M. Jeffrey, L. Gonzalez, S. Siso, H.W. Reid, P. Steele, M.P. Dagleish, M.J. Stack, M.J. Chaplin, and A. Balachandran. 2009. Immunohistochemical and biochemical characteristics of BSE and CWD in experimentally infected European red deer (Cervus elaphus elaphus). BMC Veterinary Research 5: 26.
Mathiason, C.K., S.A. Hays, J. Powers, J. Hayes-Klug, J. Langenberg, S.J. Dahmes, D.A. Osborn, K.V. Miller, R.J. Warren, G.L. Mason, and E.A. Hoover. 2009. Infectious prions in pre-clinical deer and transmission of chronic wasting disease solely by environmental exposure. PLoS ONE 4: e5916.
Mathiason, C.K., J. Hayes-Klug, S.A. Hays, J. Powers, D.A. Osborn, S.J. Dahmes, K.V. Miller, R.J. Warren, G.L. Mason, G.C. Telling, A.J. Young, and E.A. Hoover. 2010. B cells and platelets harbor prion infectivity in the blood of deer infected with chronic wasting disease. Journal of Virology 84: 5097–5107.
Mathiason, C.K., A.V. Nalls, D.M. Seelig, S.L. Kraft, K. Carnes, K.R. Anderson, J. Hayes-Klug, and E.A. Hoover. 2013. Susceptibility of domestic cats to chronic wasting disease. Journal of Virology 87: 1947–1956.
Miller, M.W., and E.S. Williams. 2003. Prion disease: Horizontal prion transmission in mule deer. Nature 425: 35–36.
Miller, M.W., E.S. Williams, N.T. Hobbs, and L.L. Wolfe. 2004. Environmental sources of prion transmission in mule deer. Emerging Infectious Diseases 10: 1003–1006.
Moore, S.J., J.D. Smith, J.A. Richt, and J.J. Greenlee. 2019. Raccoons accumulate PrP(Sc) after intracranial inoculation of the agents of chronic wasting disease or transmissible mink encephalopathy but not atypical scrapie. Journal of Veterinary Diagnostic Investigation 31: 200–209.
Moore SJ, West Greenlee MH, Kondru N, Manne S, Smith JD, Kunkle RA, Kanthasamy A, Greenlee JJ. 2017. Experimental transmission of the chronic wasting disease agent to swine after oral or intracranial inoculation. Journal of Virology 91:e00926-17. https://doi.org/10.1128/JVI.00926-17.
Nalls AV, McNulty EE, Mayfield A, Crum JM, Keel MK, Hoover EA, Ruder MG, Mathiason CK. 2021. Detection of Chronic Wasting Disease Prions in Fetal Tissues of Free-Ranging White-Tailed Deer. Viruses 13:2430.https://doi.org/10.3390/v13122430.
Narang, H. 1996. Origin and implications of bovine spongiform encephalopathy. Proceedings of the Society for Experimental Biology and Medicine 211: 306–322.
Nichols, T.A., B. Pulford, A.C. Wyckoff, C. Meyerett, B. Michel, K. Gertig, E.A. Hoover, J.E. Jewell, G.C. Telling, and M.D. Zabel. 2009. Detection of protease-resistant cervid prion protein in water from a CWD-endemic area. Prion 3: 171–183.
Nicholson, E.M., B.W. Brunelle, J.A. Richt, M.E. Kehrli Jr., and J.J. Greenlee. 2008. Identification of a heritable polymorphism in bovine PRNP associated with genetic transmissible spongiform encephalopathy: Evidence of heritable BSE. PLoS One 3: e2912.
Nonno, R., M.A. Di Bari, L. Pirisinu, C. D’Agostino, I. Vanni, B. Chiappini, S. Marcon, G. Riccardi, L. Tran, T. Vikøren. et al. 2020. Studies in bank voles reveal strain differences between chronic wasting disease prions from Norway and North America. Proc Natl Acad Sci U S A 117: 31417–31426.
Notari, S., F.J. Moleres, S.B. Hunter, E.D. Belay, L.B. Schonberger, I. Cali, P. Parchi, W.J. Shieh, P. Brown, S. Zaki, W.Q. Zou, and P. Gambetti. 2010. Multiorgan detection and characterization of protease-resistant prion protein in a case of variant CJD examined in the United States. PLoS ONE 5: e8765.
World Organization for Animal Health (OIE). 2022. Terrestrial animal health code. https://www.woah.org/en/what-we-do/standards/codes-and-manuals/terrestrial-code-online-access/. Accessed 20 April 2023.
Okada, H., Y. Iwamaru, M. Imamura, K. Masujin, Y. Matsuura, Y. Shimizu, K. Kasai, M. Takata, S. Fukuda, S. Nikaido. et al. 2011. Neuroanatomical distribution of disease-associated prion protein in cases of bovine spongiform encephalopathy detected by fallen stock surveillance in Japan. Journal of Veterinary Medical Science 73: 1465–1471.
Olszowy, K.M., J. Lavelle, K. Rachfal, S. Hempstead, K. Drouin, J.M. Darcy 2nd., C. Reiber, and R.M. Garruto. 2014. Six-year follow-up of a point-source exposure to CWD contaminated venison in an Upstate New York community: Risk behaviours and health outcomes 2005–2011. Public Health 128: 860–868.
Orru, C.D., A. Favole, C. Corona, M. Mazza, M. Manca, B.R. Groveman, A.G. Hughson, P.L. Acutis, M. Caramelli, G. Zanusso, C. Casalone, and B. Caughey. 2015. Detection and discrimination of classical and atypical L-type bovine spongiform encephalopathy by real-time quaking-induced conversion. Journal of Clinical Microbiology 53: 1115–1120.
Otero, A., C. Duque Velasquez, D. McKenzie, and J. Aiken. 2023. Emergence of CWD strains. Cell and Tissue Research 392: 135–148.
Parobkova, E., J. van der Zee, L. Dillen, C. Van Broeckhoven, R. Rusina, and R. Matej. 2020. Sporadic creutzfeldt-jakob disease and other proteinopathies in comorbidity. Frontiers in Neurology 11: 596108.
Perrott, M.R., C.J. Sigurdson, G.L. Mason, and E.A. Hoover. 2012. Evidence for distinct chronic wasting disease (CWD) strains in experimental CWD in ferrets. Journal of General Virology 93: 212–221.
Phillips LN. 2000. The BSE inquiry: return to an order of the Honourable the House of Commons dated October 2000 for the report, evidence and supporting papers of the inquiry into the emergence and identification of bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (vCJD) and the action taken in response to it up to 20 March 1996, vol 887. Stationery Office.
Piccardo, P., J. Cervenak, O. Yakovleva, L. Gregori, K. Pomeroy, A. Cook, F.S. Muhammad, T. Seuberlich, L. Cervenakova, and D.M. Asher. 2012. Squirrel monkeys (Saimiri sciureus) infected with the agent of bovine spongiform encephalopathy develop tau pathology. Journal of Comparative Pathology 147: 84–93.
Pirisinu, L., L. Tran, B. Chiappini, I. Vanni, M.A. Di Bari, G. Vaccari, T. Vikøren, K.I. Madslien, J. Våge. et al. 2018. Novel type of chronic wasting disease detected in Mmoose (Alces alces), Norway. Emerging Infectious Diseases 24: 2210–2218.
Plummer, I.H., S.D. Wright, C.J. Johnson, J.A. Pedersen, and M.D. Samuel. 2017. Temporal patterns of chronic wasting disease prion excretion in three cervid species. Journal of General Virology 98: 1932–1942.
Plummer, I.H., C.J. Johnson, A.R. Chesney, J.A. Pedersen, and M.D. Samuel. 2018. Mineral licks as environmental reservoirs of chronic wasting disease prions. PLoS One 13: e0196745.
Porcario, C., S.M. Hall, F. Martucci, C. Corona, B. Iulini, A.Z. Perazzini, P. Acutis, A.N. Hamir, C.M. Loiacono, J.J. Greenlee, J.A. Richt, M. Caramelli, and C. Casalone. 2011. Evaluation of two sets of immunohistochemical and Western blot confirmatory methods in the detection of typical and atypical BSE cases. BMC Research Notes 4: 376.
Pritzkow, S., R. Morales, F. Moda, U. Khan, G.C. Telling, E. Hoover, and C. Soto. 2015. Grass plants bind, retain, uptake, and transport infectious prions. Cell Reports 11: 1168–1175.
ProMED-Mail. 2016. BSE, bovine - Romania: (CJ) 2014, OIE, clarification, RFI, 3/9/2016 ed.
Prusiner, S.B. 1982. Novel proteinaceous infectious particles cause scrapie. Science 216: 136–144.
Pulford, B., T.R. Spraker, A.C. Wyckoff, C. Meyerett, H. Bender, A. Ferguson, B. Wyatt, K. Lockwood, J. Powers, G.C. Telling, M.A. Wild, and M.D. Zabel. 2012. Detection of PrPCWD in feces from naturally exposed Rocky Mountain elk (Cervus elaphus nelsoni) using protein misfolding cyclic amplification. Journal of Wildlife Diseases 48: 425–434.
Race, B., K. Meade-White, R. Race, and B. Chesebro. 2009. Prion infectivity in fat of deer with chronic wasting disease. Journal of Virology 83: 9608–9610.
Race, B., K.D. Meade-White, K. Phillips, J. Striebel, R. Race, and B. Chesebro. 2014. Chronic wasting disease agents in nonhuman primates. Emerging Infectious Diseases 20: 833–837.
Raymond, G.J., L.D. Raymond, K.D. Meade-White, A.G. Hughson, C. Favara, D. Gardner, E.S. Williams, M.W. Miller, R.E. Race, and B. Caughey. 2007. Transmission and adaptation of chronic wasting disease to hamsters and transgenic mice: Evidence for strains. Journal of Virology 81: 4305–4314.
Richards B. 2023. Expanding Distribution of Chronic Wasting Disease https://www.usgs.gov/centers/nwhc/science/expanding-distribution-chronic-wasting-disease. Accessed 18 July 2023.
Richt, J.A., P. Kasinathan, A.N. Hamir, J. Castilla, T. Sathiyaseelan, F. Vargas, J. Sathiyaseelan, H. Wu, H. Matsushita, J. Koster, S. Kato, I. Ishida, C. Soto, J.M. Robl, and Y. Kuroiwa. 2007. Production of cattle lacking prion protein. Nature Biotechnology 25: 132–138.
Robinson, S.J., M.D. Samuel, K.I. O’Rourke, and C.J. Johnson. 2012. The role of genetics in chronic wasting disease of North American cervids. Prion 6: 153–162.
Ronzon, F., A. Bencsik, S. Lezmi, J. Vulin, A. Kodjo, and T. Baron. 2006. BSE inoculation to prion diseases-resistant sheep reveals tricky silent carriers. Biochemical and Biophysical Research Communications 350: 872–877.
Saba, R., and S.A. Booth. 2013. The genetics of susceptibility to variant Creutzfeldt-Jakob disease. Public Health Genomics 16: 17–24.
Seabury, C.M., D.L. Oldeschulte, E.K. Bhattarai, D. Legare, P.J. Ferro, R.P. Metz, C.D. Johnson, M.A. Lockwood, and T.A. Nichols. 2020. Accurate genomic predictions for chronic wasting disease in U.S. white-tailed deer. G3 (Bethesda) 10: 1433–1441.
Seabury CM, Lockwood MA, Nichols TA. 2022. Genotype by environment interactions for chronic wasting disease in farmed US white-tailed deer. G3 (Bethesda) 12:12(7):jkac109. https://doi.org/10.1093/g3journal/jkac109.
Selariu, A., J.G. Powers, A. Nalls, M. Brandhuber, A. Mayfield, S. Fullaway, C.A. Wyckoff, W. Goldmann, M.M. Zabel, M.A. Wild, E.A. Hoover, and C.K. Mathiason. 2015. In utero transmission and tissue distribution of chronic wasting disease-associated prions in free-ranging Rocky Mountain elk. Journal of General Virology 96: 3444–3455.
Sigurdson, C.J. 2008. A prion disease of cervids: Chronic wasting disease. Veterinary Research 39: 41.
Sigurdson, C.J., E.S. Williams, M.W. Miller, T.R. Spraker, K.I. O’Rourke, and E.A. Hoover. 1999. Oral transmission and early lymphoid tropism of chronic wasting disease PrPres in mule deer fawns (Odocoileus hemionus). Journal of General Virology 80 (Pt 10): 2757–2764.
Sigurdson, C.J., T.R. Spraker, M.W. Miller, B. Oesch, and E.A. Hoover. 2001. PrP(CWD) in the myenteric plexus, vagosympathetic trunk and endocrine glands of deer with chronic wasting disease. Journal of General Virology 82: 2327–2334.
Sigurdson, C.J., C. Barillas-Mury, M.W. Miller, B. Oesch, L.J. van Keulen, J.P. Langeveld, and E.A. Hoover. 2002. PrP(CWD) lymphoid cell targets in early and advanced chronic wasting disease of mule deer. Journal of General Virology 83: 2617–2628.
Simmons, M.M., J. Spiropoulos, P.R. Webb, Y.I. Spencer, S. Czub, R. Mueller, A. Davis, M.E. Arnold, S. Marsh, S.A. Hawkins, J.A. Cooper, T. Konold, and G.A. Wells. 2011. Experimental classical bovine spongiform encephalopathy: Definition and progression of neural PrP immunolabeling in relation to diagnosis and disease controls. Veterinary Pathology 48: 948–963.
Smith, P.G., and R. Bradley. 2003. Bovine spongiform encephalopathy (BSE) and its epidemiology. British Medical Bulletin 66: 185–198.
Spiropoulos, J., R. Lockey, R.E. Sallis, L.A. Terry, L. Thorne, T.M. Holder, K.E. Beck, and M.M. Simmons. 2011. Isolation of prion with BSE properties from farmed goat. Emerging Infectious Diseases 17: 2253–2261.
Spraker, T.R., R.R. Zink, B.A. Cummings, C.J. Sigurdson, M.W. Miller, and K.I. O’Rourke. 2002a. Distribution of protease-resistant prion protein and spongiform encephalopathy in free-ranging mule deer (Odocoileus hemionus) with chronic wasting disease. Veterinary Pathology 39: 546–556.
Spraker, T.R., R.R. Zink, B.A. Cummings, M.A. Wild, M.W. Miller, and K.I. O’Rourke. 2002b. Comparison of histological lesions and immunohistochemical staining of proteinase-resistant prion protein in a naturally occurring spongiform encephalopathy of free-ranging mule deer (Odocoileus hemionus) with those of chronic wasting disease of captive mule deer. Veterinary Pathology 39: 110–119.
Sun, J.L., S. Kim, J. Crowell, B.K. Webster, E.K. Raisley, D.C. Lowe, J. Bian, S.L. Korpenfelt, S.L. Benestad, and G.C. Telling. 2023. Novel prion strain as cause of chronic wasting disease in a Mmoose, finland. Emerging Infectious Diseases 29: 323–332.
Tamguney, G., J.A. Richt, A.N. Hamir, J.J. Greenlee, M.W. Miller, L.L. Wolfe, T.M. Sirochman, A.J. Young, D.V. Glidden, N.L. Johnson, K. Giles, S.J. DeArmond, and S.B. Prusiner. 2012. Salivary prions in sheep and deer. Prion 6: 52–61.
Taylor, D.M. 1989. Scrapie agent decontamination: Implications for bovine spongiform encephalopathy. The Veterinary Record 124: 291–292.
Thomsen, B.V., D.A. Schneider, K.I. O’Rourke, T. Gidlewski, J. McLane, R.W. Allen, A.A. McIsaac, G.B. Mitchell, D.P. Keane, T.R. Spraker, and A. Balachandran. 2012. Diagnostic accuracy of rectal mucosa biopsy testing for chronic wasting disease within white-tailed deer (Odocoileus virginianus) herds in North America: Effects of age, sex, polymorphism at PRNP codon 96, and disease progression. Journal of Veterinary Diagnostic Investigation 24: 878–887.
Tranulis, M.A., D. Gavier-Widen, J. Vage, M. Noremark, S.L. Korpenfelt, M. Hautaniemi, L. Pirisinu, R. Nonno, and S.L. Benestad. 2021. Chronic wasting disease in Europe: New strains on the horizon. Acta Veterinaria Scandinavica 63: 48.
Tsutsui, T., T. Yamamoto, S. Hashimoto, T. Nonaka, A. Nishiguchi, and S. Kobayashi. 2008. Milk replacers and bovine spongiform encephalopathy in calves, Japan. Emerging Infectious Diseases 14: 525–526.
United States Department of Agriculture. Chronic wasting disease program – post mortem sample collection guidance procedure for removal of obex & medial retropharyngeal lymph nodes (MRPLN). https://www.aphis.usda.gov/animal_health/animal_diseases/cwd/downloads/cwd_sample_collection_guidance_card.pdf. Accessed 7 Feb 2020.
United States Department of Agriculture. 2019. Chronic wasting disease program standards. APHIS V, https://www.aphis.usda.gov/animal_health/animal_diseases/cwd/downloads/cwd-program-standards.pdf.
Valleron, A.-J., P.-Y. Boelle, R. Will, and J.-Y. Cesbron. 2001. Estimation of epidemic size and incubation time bBased on age characteristics of vCJD in the United Kingdom. Science 294: 1726–1728.
van Keulen, L.J., M.E. Vromans, C.H. Dolstra, A. Bossers, and F.G. van Zijderveld. 2008. Pathogenesis of bovine spongiform encephalopathy in sheep. Archives of Virology 153: 445–453.
Wadsworth, J.D., S. Joiner, A.F. Hill, T.A. Campbell, M. Desbruslais, P.J. Luthert, and J. Collinge. 2001. Tissue distribution of protease resistant prion protein in variant Creutzfeldt-Jakob disease using a highly sensitive immunoblotting assay. Lancet 358: 171–180.
Wells, G.A., A.C. Scott, C.T. Johnson, R.F. Gunning, R.D. Hancock, M. Jeffrey, M. Dawson, and R. Bradley. 1987. A novel progressive spongiform encephalopathy in cattle. The Veterinary Record 121: 419–420.
Wells, G.A., J. Spiropoulos, S.A. Hawkins, and S.J. Ryder. 2005. Pathogenesis of experimental bovine spongiform encephalopathy: Preclinical infectivity in tonsil and observations on the distribution of lingual tonsil in slaughtered cattle. The Veterinary Record 156: 401–407.
Wild, M.A., T.R. Spraker, C.J. Sigurdson, K.I. O’Rourke, and M.W. Miller. 2002. Preclinical diagnosis of chronic wasting disease in captive mule deer (Odocoileus hemionus) and white-tailed deer (Odocoileus virginianus) using tonsillar biopsy. Journal of General Virology 83: 2629–2634.
Wilesmith, J.W., G.A. Wells, J.B. Ryan, D. Gavier-Widen, and M.M. Simmons. 1997. A cohort study to examine maternally-associated risk factors for bovine spongiform encephalopathy. The Veterinary Record 141: 239–243.
Will, R.G., J.W. Ironside, M. Zeidler, S.N. Cousens, K. Estibeiro, A. Alperovitch, S. Poser, M. Pocchiari, A. Hofman, and P.G. Smith. 1996. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 347: 921–925.
Williams, E.S. 2005. Chronic wasting disease. Veterinary Pathology 42: 530–549.
Williams, E.S., and M.W. Miller. 2002. Chronic wasting disease in deer and elk in North America. Revue Scientifique Et Technique 21: 305–316.
Williams, E.S., and S. Young. 1992. Spongiform encephalopathies in Cervidae. Revue Scientifique Et Technique 11: 551–567.
Williams, E.S., D. O’Toole, M.W. Miller, T.J. Kreeger, and J.E. Jewell. 2018. Cattle ( Bos Taurus) resist chronic wasting disease following oral inoculation challenge or ten years’ natural exposure in contaminated environments. Journal of Wildlife Diseases 54: 460–470.
Woodgate, S.L., and R.G. Wilkinson. 2021. The role of rendering in relation to the bovine spongiform encephalopathy epidemic, the development of EU animal by-product legislation and the reintroduction of rendered products into animal feeds. Annals of Applied Biology 178: 430–441.
Zerr, I., K. Kallenberg, D.M. Summers, C. Romero, A. Taratuto, U. Heinemann, M. Breithaupt, D. Varges, B. Meissner, A. Ladogana. et al. 2009. Updated clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease. Brain 132: 2659–2668.
Acknowledgements
Not applicable.
Funding
This work is funded in part by the Center on Emerging and Zoonotic Infectious Diseases (CEZID) of the National Institutes of General Medical Sciences under award number P20GM130448.
Author information
Authors and Affiliations
Contributions
NJH and JAR contributed equally to the writing of this manuscript.
Corresponding author
Ethics declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Haley, N.J., Richt, J.A. Classical bovine spongiform encephalopathy and chronic wasting disease: two sides of the prion coin. Animal Diseases 3, 24 (2023). https://doi.org/10.1186/s44149-023-00087-7
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s44149-023-00087-7