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1.  Insights into the Management of Emerging Infections: Regulating Variant Creutzfeldt-Jakob Disease Transfusion Risk in the UK and the US 
PLoS Medicine  2006;3(10):e342.
Background
Variant Creutzfeldt-Jakob disease (vCJD) is a human prion disease caused by infection with the agent of bovine spongiform encephalopathy. After the recognition of vCJD in the UK in 1996, many nations implemented policies intended to reduce the hypothetical risk of transfusion transmission of vCJD. This was despite the fact that no cases of transfusion transmission had yet been identified. In December 2003, however, the first case of vCJD in a recipient of blood from a vCJD-infected donor was announced. The aim of this study is to ascertain and compare the factors that influenced the motivation for and the design of regulations to prevent transfusion transmission of vCJD in the UK and US prior to the recognition of this case.
Methods and Findings
A document search was conducted to identify US and UK governmental policy statements and guidance, transcripts (or minutes when transcripts were not available) of scientific advisory committee meetings, research articles, and editorials published in medical and scientific journals on the topic of vCJD and blood transfusion transmission between March 1996 and December 2003. In addition, 40 interviews were conducted with individuals familiar with the decision-making process and/or the science involved. All documents and transcripts were coded and analyzed according to the methods and principles of grounded theory. Data showed that while resulting policies were based on the available science, social and historical factors played a major role in the motivation for and the design of regulations to protect against transfusion transmission of vCJD. First, recent experience with and collective guilt resulting from the transfusion-transmitted epidemics of HIV/AIDS in both countries served as a major, historically specific impetus for such policies. This history was brought to bear both by hemophilia activists and those charged with regulating blood products in the US and UK. Second, local specificities, such as the recall of blood products for possible vCJD contamination in the UK, contributed to a greater sense of urgency and a speedier implementation of regulations in that country. Third, while the results of scientific studies played a prominent role in the construction of regulations in both nations, this role was shaped by existing social and professional networks. In the UK, early focus on a European study implicating B-lymphocytes as the carrier of prion infectivity in blood led to the introduction of a policy that requires universal leukoreduction of blood components. In the US, early focus on an American study highlighting the ability of plasma to serve as a reservoir of prion infectivity led the FDA and its advisory panel to eschew similar measures.
Conclusions
The results of this study yield three important theoretical insights that pertain to the global management of emerging infectious diseases. First, because the perception and management of disease may be shaped by previous experience with disease, especially catastrophic experience, there is always the possibility for over-management of some possible routes of transmission and relative neglect of others. Second, local specificities within a given nation may influence the temporality of decision making, which in turn may influence the choice of disease management policies. Third, a preference for science-based risk management among nations will not necessarily lead to homogeneous policies. This is because the exposure to and interpretation of scientific results depends on the existing social and professional networks within a given nation. Together, these theoretical insights provide a framework for analyzing and anticipating potential conflicts in the international management of emerging infectious diseases. In addition, this study illustrates the utility of qualitative methods in investigating research questions that are difficult to assess through quantitative means.
A qualitative study of US and UK governmental policy statements on the topic of vCJD and blood transfusion transmission identified factors responsible for differences in the policies adopted.
Editors' Summary
Background.
In 1996 in the UK, a new type of human prion disease was seen for the first time. This is now known as variant Creutzfeldt-Jakob disease (vCJD). Prion diseases are rare brain diseases passed from individual to individual (or between animals) by a particular type of wrongly folded protein, and they are fatal. It was suspected that vCJD had passed to humans from cattle, and that the agent causing vCJD was the same as that causing bovine spongiform encephalopathy (or “mad cow disease”). Shortly after vCJD was recognized, authorities in many countries became concerned about the possibility that it could be transmitted from one person to another through contaminated blood supplies used for transfusion in hospitals. Even though there wasn't any evidence of actual transmission of the disease through blood before December 2003, authorities in the UK, US, and elsewhere set up regulations designed to reduce the chance of that happening. At this early stage in the epidemic, there was little in the way of scientific information about the transmission properties of the disease. Both the UK and US, however, sought to make decisions in a scientific manner. They made use of evidence as it was being produced, often before it had been published. Despite this, the UK and US decided on very different changes to their respective regulations on blood donation. Both countries chose to prevent certain people (who they thought would be at greater risk of having vCJD) from donating blood. In the UK, however, the decision was made to remove white blood cells from donated blood to reduce the risk of transmitting vCJD, while the US decided that such a step was not merited by the evidence.
Why Was This Study Done?
This researcher wanted to understand more clearly why the UK and US ended up with different policies: what role was played by science, and what role was played by non-scientific factors? She hoped that insights from this investigation would also be relevant to similar challenges in the future—for example, as many countries try to work out how to control the threat of avian flu.
What Did the Researcher Do and Find?
The researcher searched for all relevant official government documents from the US and UK, as well as scientific papers, published between the time vCJD was first identified (March 1996) and the first instance of vCJD carried through blood (December 2003). She also interviewed people who knew about vCJD management in the US and UK—for example, members of government agencies and the relevant advisory committees. From the documents and interviews, the researcher picked out and grouped shared ideas. Although these documents and interviews suggested that policy making was rooted in scientific evidence, many non-scientific factors were also important. The researcher found substantial uncertainty in the scientific evidence available at the time. The document search and interviews showed that policy makers felt guilty about a previous experience in which people had become infected with HIV/AIDS through contaminated blood and were concerned about repeating this experience. Finally, in the UK, the possibility of blood contamination was seen as a much more urgent problem than in the US, because BSE and vCJD were found there first and there were far more cases. This meant that when the UK made its decision about whether to remove white blood cells from donated blood, there was less scientific evidence available. In fact, the main study that was relied on at the time would later be questioned.
What Do These Findings Mean?
These findings show that for this particular case, science was not the only factor affecting government policies. Historical and social factors such as previous experience, sense of urgency, public pressure, and the relative importance of different scientific networks were also very important. The study predicts that in the future, infectious disease–related policy decisions are unlikely to be the same across different countries because the interpretation of scientific evidence depends, to a large extent, on social factors.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030342.
National Creutzfeldt-Jakob Disease Surveillance Unit, Edinburgh, UK
US Centers for Disease Control and Prevention pages about prion diseases
World Health Organization variant Creutzfeldt-Jakob disease fact sheet
US National Institute of Neurological Disorders and Stroke information about prion diseases
doi:10.1371/journal.pmed.0030342
PMCID: PMC1621089  PMID: 17076547
2.  Preclinical Detection of Variant CJD and BSE Prions in Blood 
PLoS Pathogens  2014;10(6):e1004202.
The emergence of variant Creutzfeldt Jakob Disease (vCJD) is considered a likely consequence of human dietary exposure to Bovine Spongiform Encephalopathy (BSE) agent. More recently, secondary vCJD cases were identified in patients transfused with blood products prepared from apparently healthy donors who later went on to develop the disease. As there is no validated assay for detection of vCJD/BSE infected individuals the prevalence of the disease in the population remains uncertain. In that context, the risk of vCJD blood borne transmission is considered as a serious concern by health authorities. In this study, appropriate conditions and substrates for highly efficient and specific in vitro amplification of vCJD/BSE agent using Protein Misfolding Cyclic Amplification (PMCA) were first identified. This showed that whatever the origin (species) of the vCJD/BSE agent, the ovine Q171 PrP substrates provided the best amplification performances. These results indicate that the homology of PrP amino-acid sequence between the seed and the substrate is not the crucial determinant of the vCJD agent propagation in vitro. The ability of this method to detect endogenous vCJD/BSE agent in the blood was then defined. In both sheep and primate models of the disease, the assay enabled the identification of infected individuals in the early preclinical stage of the incubation period. Finally, sample panels that included buffy coat from vCJD affected patients and healthy controls were tested blind. The assay identified three out of the four tested vCJD affected patients and no false positive was observed in 141 healthy controls. The negative results observed in one of the tested vCJD cases concurs with results reported by others using a different vCJD agent blood detection assay and raises the question of the potential absence of prionemia in certain patients.
Author Summary
Variant Creutzfeldt Jakob Disease (vCJD) cases were identified in patients who received blood products that had been prepared from donors who later developed the disease. The blood borne transmission of vCJD is a major concern for blood transfusion banks, plasma derived products manufacturers and public health authorities. A vCJD blood screening test would represent an ideal solution for identifying donors/blood donations that might be at risk. In this study, we describe a blood assay which is based on the in vitro amplification of vCJD agent by Protein Misfolding Cyclic Amplification (PMCA). In vCJD animal models (sheep and primate), the assay enabled the identification of infected individuals in a very early stage of the asymptomatic incubation phase. We also provide evidence of the high specificity and the high analytical sensitivity of this assay using blood samples from vCJD affected and healthy patients.
doi:10.1371/journal.ppat.1004202
PMCID: PMC4055790  PMID: 24945656
3.  Beyond PrPres Type 1/Type 2 Dichotomy in Creutzfeldt-Jakob Disease 
PLoS Pathogens  2008;4(3):e1000029.
Sporadic Creutzfeldt-Jakob disease (sCJD) cases are currently subclassified according to the methionine/valine polymorphism at codon 129 of the PRNP gene and the proteinase K (PK) digested abnormal prion protein (PrPres) identified on Western blotting (type 1 or type 2). These biochemically distinct PrPres types have been considered to represent potential distinct prion strains. However, since cases of CJD show co-occurrence of type 1 and type 2 PrPres in the brain, the basis of this classification system and its relationship to agent strain are under discussion. Different brain areas from 41 sCJD and 12 iatrogenic CJD (iCJD) cases were investigated, using Western blotting for PrPres and two other biochemical assays reflecting the behaviour of the disease-associated form of the prion protein (PrPSc) under variable PK digestion conditions. In 30% of cases, both type 1 and type 2 PrPres were identified. Despite this, the other two biochemical assays found that PrPSc from an individual patient demonstrated uniform biochemical properties. Moreover, in sCJD, four distinct biochemical PrPSc subgroups were identified that correlated with the current sCJD clinico-pathological classification. In iCJD, four similar biochemical clusters were observed, but these did not correlate to any particular PRNP 129 polymorphism or western blot PrPres pattern. The identification of four different PrPSc biochemical subgroups in sCJD and iCJD, irrespective of the PRNP polymorphism at codon 129 and the PrPres isoform provides an alternative biochemical definition of PrPSc diversity and new insight in the perception of Human TSE agents variability.
Author Summary
Prion diseases are transmissible neurodegenerative disorders characterized by accumulation of an abnormal isoform (PrPSc) of a host-encoded protein (PrPC) in affected tissues. According to the prion hypothesis, PrPSc alone constitutes the infectious agent. Sporadic Creutzfeldt-Jakob disease (sCJD) is the commonest human prion disease. Although considered as a spontaneous disorder, the clinicopathological phenotype of sCJD is variable and substantially influenced by the methionine/valine polymorphism at codon 129 of the prion protein gene (PRNP). Based on these clinicopathological and genetic criteria, a subclassification of sCJD has been proposed. Here, we used two new biochemical assays that identified four distinct biochemical PrPSc subgroups in a cohort of 41 sCJD cases. These subgroups correlate with the current sCJD subclassification and could therefore represent distinct prion strains. Iatrogenic CJD (iCJD) occurs following presumed accidental human-to-human sCJD transmission. Our biochemical investigations on 12 iCJD cases from different countries found the same four subgroups as in sCJD. However, in contrast to the sCJD cases, no particular correlation between the PRNP codon 129 polymorphism and biochemical PrPSc phenotype could be established in iCJD cases. This study provides an alternative biochemical definition of PrPSc diversity in human prion diseases and new insights into the perception of agent variability.
doi:10.1371/journal.ppat.1000029
PMCID: PMC2279301  PMID: 18389084
4.  Distinct origins of dura mater graft-associated Creutzfeldt-Jakob disease: past and future problems 
Dura mater graft-associated Creutzfeldt-Jakob disease (dCJD) can be divided into two subgroups that exhibit distinct clinical and neuropathological features, with the majority represented by a non-plaque-type of dCJD (np-dCJD) and the minority by a plaque-type of dCJD (p-dCJD). The two distinct phenotypes of dCJD had been considered to be unrelated to the genotype (methionine, M or valine, V) at polymorphic codon 129 of the PRNP gene or type (type 1 or type 2) of abnormal isoform of prion protein (PrPSc) in the brain, while these are major determinants of clinicopathological phenotypes of sporadic CJD (sCJD). The reason for the existence of two distinct subgroups in dCJD had remained elusive. Recent progress in research of the pathogenesis of dCJD has revealed that two distinct subgroups of dCJD are caused by infection with different PrPSc strains from sCJD, i.e., np-dCJD caused by infection with sCJD-MM1/MV1, and p-dCJD caused by infection with sCJD-VV2 or -MV2. These studies have also revealed previously unrecognized problems as follows: (i) the numbers of p-dCJD patients may increase in the future, (ii) the potential risks of secondary infection from dCJD, particularly from p-dCJD, may be considerable, and (iii) the effectiveness of the current PrPSc decontamination procedures against the PrPSc from p-dCJD is uncertain. To prevent secondary infection from p-dCJD, the establishment of effective decontamination procedures is an urgent issue. In this review, we summarize the past and future problems surrounding dCJD.
doi:10.1186/2051-5960-2-32
PMCID: PMC3976164  PMID: 24685293
Creutzfeldt-Jakob disease; Prion protein; Dura mater grafts; Humanized knock-in mouse
5.  Human Prion Diseases in The Netherlands (1998–2009): Clinical, Genetic and Molecular Aspects 
PLoS ONE  2012;7(4):e36333.
Prion diseases are rare and fatal neurodegenerative disorders that can be sporadic, inherited or acquired by infection. Based on a national surveillance program in the Netherlands we describe here the clinical, neuropathological, genetic and molecular characteristics of 162 patients with neuropathologically confirmed prion disease over a 12-year period (1998–2009). Since 1998, there has been a relatively stable mortality of Creutzfeldt-Jakob disease (CJD) in the Netherlands, ranging from 0.63 to 1.53 per million inhabitants per annum. Genetic analysis of the codon 129 methionine/valine (M/V) polymorphism in all patients with sporadic CJD (sCJD) showed a trend for under-representation of VV cases (7.0%), compared with sCJD cohorts in other Western countries, whereas the MV genotype was relatively over-represented (22,4%). Combined PrPSc and histopathological typing identified all sCJD subtypes known to date, except for the VV1 subtype. In particular, a “pure" phenotype was demonstrated in 60.1% of patients, whereas a mixed phenotype was detected in 39.9% of all sCJD cases. The relative excess of MV cases was largely accounted for by a relatively high incidence of the MV 2K subtype. Genetic analysis of the prion protein gene (PRNP) was performed in 161 patients and showed a mutation in 9 of them (5.6%), including one FFI and four GSS cases. Iatrogenic CJD was a rare phenomenon (3.1%), mainly associated with dura mater grafts. Three patients were diagnosed with new variant CJD (1.9%) and one with variably protease-sensitive prionopathy (VPSPr). Post-mortem examination revealed an alternative diagnosis in 156 patients, most commonly Alzheimer's disease (21.2%) or vascular causes of dementia (19.9%). The mortality rates of sCJD in the Netherlands are similar to those in other European countries, whereas iatrogenic and genetic cases are relatively rare. The unusual incidence of the VV2 sCJD subtype compared to that reported to date in other Western countries deserves further investigation.
doi:10.1371/journal.pone.0036333
PMCID: PMC3340342  PMID: 22558438
6.  Application of Atomic Dielectric Resonance Spectroscopy for the screening of blood samples from patients with clinical variant and sporadic CJD 
Background
Sub-clinical variant Creutzfeldt-Jakob disease (vCJD) infection and reports of vCJD transmission through blood transfusion emphasise the need for blood screening assays to ensure the safety of blood and transplanted tissues. Most assays aim to detect abnormal prion protein (PrPSc), although achieving required sensitivity is a challenge.
Methods
We have used innovative Atomic Dielectric Resonance Spectroscopy (ADRS), which determines dielectric properties of materials which are established by reflectivity and penetration of radio/micro waves, to analyse blood samples from patients and controls to identify characteristic ADR signatures unique to blood from vCJD and to sCJD patients. Initial sets of blood samples from vCJD, sCJD, non-CJD neurological diseases and normal healthy adults (blood donors) were screened as training samples to determine group-specific ADR characteristics, and provided a basis for classification of blinded sets of samples.
Results
Blood sample groups from vCJD, sCJD, non-CJD neurological diseases and normal healthy adults (blood donors) screened by ADRS were classified with 100% specificity and sensitivity, discriminating these by a co-variance expert analysis system.
Conclusion
ADRS appears capable of recognising and discriminating serum samples from vCJD, sCJD, non-CJD neurological diseases, and normal healthy adults, and might be developed to provide a system for primary screening or confirmatory assay complementary to other screening systems.
doi:10.1186/1479-5876-5-41
PMCID: PMC2008164  PMID: 17760958
7.  PrPTSE Distribution in a Primate Model of Variant, Sporadic, and Iatrogenic Creutzfeldt-Jakob Disease 
Journal of Virology  2005;79(22):14339-14345.
Human prion diseases, such as Creutzfeldt-Jakob disease (CJD), are neurodegenerative and fatal. Sporadic CJD (sCJD) can be transmitted between humans through medical procedures involving highly infected organs, such as the central nervous system. However, in variant CJD (vCJD), which is due to human contamination with the bovine spongiform encephalopathy (BSE) agent, lymphoreticular tissue also harbors the transmissible spongiform encephalopathy-associated prion protein (PrPTSE), which poses a particularly acute risk for iatrogenic transmission. Two blood transfusion-related cases are already documented. In addition, the recent observation of PrPTSE in spleen and muscle in sCJD raised the possibility that peripheral PrPTSE is not limited to vCJD cases. We aimed to clarify the peripheral pathogenesis of human TSEs by using a nonhuman primate model which mimics human diseases. A highly sensitive enzyme-linked immunosorbent assay was adapted to the detection of extraneural PrPTSE. We show that affected organs can be divided into two groups. The first is peripheral organs accumulating large amounts of PrPTSE, which represent a high risk of iatrogenic transmission. This category comprises only lymphoreticular organs in the vCJD/BSE model. The second is organs with small amounts of PrPTSE associated with nervous structures. These are the muscles, adrenal glands, and enteric nervous system in the sporadic, iatrogenic, and variant CJD models. In contrast to the first set of organs, this low level of tissue contamination is not strain restricted and seems to be linked to secondary centrifugal spread of the agent through nerves. It might represent a risk for iatrogenic transmission, formerly underestimated despite previous reports of low rates of transmission from peripheral organs of humans to nonhuman primates (5, 10). This study provides an additional experimental basis for the classification of human organs into different risk categories and a rational re-evaluation of current risk management measures.
doi:10.1128/JVI.79.22.14339-14345.2005
PMCID: PMC1280201  PMID: 16254368
8.  Prion Diseases as Transmissible Zoonotic Diseases 
Prion diseases, also called transmissible spongiform encephalopathies (TSEs), lead to neurological dysfunction in animals and are fatal. Infectious prion proteins are causative agents of many mammalian TSEs, including scrapie (in sheep), chronic wasting disease (in deer and elk), bovine spongiform encephalopathy (BSE; in cattle), and Creutzfeldt–Jakob disease (CJD; in humans). BSE, better known as mad cow disease, is among the many recently discovered zoonotic diseases. BSE cases were first reported in the United Kingdom in 1986. Variant CJD (vCJD) is a disease that was first detected in 1996, which affects humans and is linked to the BSE epidemic in cattle. vCJD is presumed to be caused by consumption of contaminated meat and other food products derived from affected cattle. The BSE epidemic peaked in 1992 and decreased thereafter; this decline is continuing sharply owing to intensive surveillance and screening programs in the Western world. However, there are still new outbreaks and/or progression of prion diseases, including atypical BSE, and iatrogenic CJD and vCJD via organ transplantation and blood transfusion. This paper summarizes studies on prions, particularly on prion molecular mechanisms, BSE, vCJD, and diagnostic procedures. Risk perception and communication policies of the European Union for the prevention of prion diseases are also addressed to provide recommendations for appropriate government policies in Korea.
doi:10.1016/j.phrp.2012.12.008
PMCID: PMC3747681  PMID: 24159531
prion; risk perception; surveillance; transmissible spongiform encephalopathy; variant Creutzfeldt–Jakob disease
9.  Alzheimer‐type neuropathology in a 28 year old patient with iatrogenic Creutzfeldt‐Jakob disease after dural grafting 
We report the case of a 28 year old man who had received a cadaverous dura mater graft after a traumatic open skull fracture with tearing of the dura at the age of 5 years. A clinical suspicion of Creutzfeldt‐Jakob disease (CJD) was confirmed by a brain biopsy 5 months prior to death and by autopsy, thus warranting the diagnosis of iatrogenic CJD (iCJD) according to WHO criteria. Immunohistochemistry showed widespread cortical depositions of disease associated prion protein (PrPsc) in a synaptic pattern, and western blot analysis identified PrPsc of type 2A according to Parchi et al. Surprisingly, we found Alzheimer‐type senile plaques and cerebral amyloid angiopathy in widespread areas of the brain. Plaque‐type and vascular amyloid was immunohistochemically identified as deposits of beta‐A4 peptide. CERAD criteria for diagnosis of definite Alzheimer's disease (AD) were met in the absence of neurofibrillar tangles or alpha‐synuclein immunoreactive inclusions. There was no family history of AD, CJD, or any other neurological disease, and genetic analysis showed no disease specific mutations of the prion protein, presenilin 1 and 2, or amyloid precursor protein genes. This case represents (a) the iCJD case with the longest incubation time after dural grafting reported so far, (b) the youngest documented patient with concomitant CJD and Alzheimer‐type neuropathology to date, (c) the first description of Alzheimer‐type changes in iCJD, and (d) the second case of iCJD in Austria. Despite the young patient age, the Alzheimer‐type changes may be an incidental finding, possibly related to the childhood trauma.
doi:10.1136/jnnp.2005.070805
PMCID: PMC2077694  PMID: 16484658
Alzheimers disease; trauma; iatrogenic Creutzfeldt‐Jakob disease
10.  The Impact of Creutzfeldt–Jakob Disease on Surgical Practice 
Creutzfeldt–Jakob disease (CJD) is characterised by abnormal prion protein that can replicate and replace nervous tissue, with rapid lethal neurodegenerative consequences. The transmissible nature of CJD has been known for half a century and transmission has occurred through neurosurgical procedures. Variant Creutzfeldt–Jakob disease (vCJD) emerged in 1996, and the presence of abnormal prion in lymphatic tissue extended the number of surgical specialties dealing with infected material; transmission through blood transfusion raised the possibilities of a large carrier pool and spread of epidemic proportion.
The abnormal prion is difficult to remove and this could influence future decontamination programmes. Contaminated instruments must be withdrawn from surgical practice, and this can interfere with the efficient running of a surgical unit and optimal patient care.
There is an urgent need for reliable methods for the detection of abnormal prion, within and outside the body. These will help to clarify the epidemiology of CJD, and to reduce its transmission via blood and tissue. They will also allow determination of the efficacy of new decontamination products in surgical practice, and the value of any treatment of sufferers and carriers of CJD. In the meantime, continued vigilance and informed regulation of all aspects of CJD must remain.
doi:10.1308/003588408X261726
PMCID: PMC2443292  PMID: 18325202
CJD; BSE; Surgical practice
11.  Accelerated, Spleen-Based Titration of Variant Creutzfeldt-Jakob Disease Infectivity in Transgenic Mice Expressing Human Prion Protein with Sensitivity Comparable to That of Survival Time Bioassay 
Journal of Virology  2014;88(15):8678-8686.
ABSTRACT
The dietary exposure of the human population to the prions responsible for the bovine spongiform encephalopathy (BSE) epizooty has led to the emergence of variant Creutzfeldt-Jakob disease (vCJD). This fatal, untreatable neurodegenerative disorder is a growing public health concern because the prevalence of the infection seems much greater than the disease incidence and because secondary transmission of vCJD by blood transfusion or use of blood products has occurred. A current limitation in variant CJD risk assessment is the lack of quantitative information on the infectivity of contaminated tissues. To address this limitation, we tested the potential of a transgenic mouse line overexpressing human prion protein (PrP), which was previously reported to propagate vCJD prions. Endpoint titration of vCJD infectivity in different tissues was evaluated by two different methods: (i) the “classical” bioassay, based on the appearance of clinical symptoms and the detection of pathological prion protein in tissues of the inoculated mouse, and (ii) a shortened bioassay based on the detection of the protein in the mouse spleen at defined time points. The two methods proved equally sensitive in quantifying infectivity, even after very-low-dose inoculation of infected material, but the time schedule was shortened from ∼2.5 years to ∼1 year with the spleen bioassay. Compared to the “gold-standard” RIII model routinely used for endpoint titration of vCJD/BSE prions, either method improved the sensitivity by >2 orders of magnitude and allowed reevaluating the infectious titer of spleen from a vCJD individual at disease end stage to >1,000-fold-higher values.
IMPORTANCE Here, we provide key reevaluation of the infectious titer of variant CJD brain and spleen tissues. The highly sensitive, accelerated spleen-based assay should thus constitute a key advance for variant CJD epidemiological and risk assessment purposes and should greatly facilitate future titration studies, including, for example, those aimed at validating decontamination procedures. The overlooked notion that the lymphoid tissue exhibits a higher capacity than the brain to replicate prions even after low-dose infection raises new questions about the molecular and/or cellular determinant(s) involved, a key issue regarding potent silent carriers of variant CJD in the lymphoid tissue.
doi:10.1128/JVI.01118-14
PMCID: PMC4135959  PMID: 24850746
12.  Multiorgan Detection and Characterization of Protease-Resistant Prion Protein in a Case of Variant CJD Examined in the United States 
PLoS ONE  2010;5(1):e8765.
Background
Variant Creutzfeldt–Jakob disease (vCJD) is a prion disease thought to be acquired by the consumption of prion-contaminated beef products. To date, over 200 cases have been identified around the world, but mainly in the United Kingdom. Three cases have been identified in the United States; however, these subjects were likely exposed to prion infection elsewhere. Here we report on the first of these subjects.
Methodology/Principal Findings
Neuropathological and genetic examinations were carried out using standard procedures. We assessed the presence and characteristics of protease-resistant prion protein (PrPres) in brain and 23 other organs and tissues using immunoblots performed directly on total homogenate or following sodium phosphotungstate precipitation to increase PrPres detectability. The brain showed a lack of typical spongiform degeneration and had large plaques, likely stemming from the extensive neuronal loss caused by the long duration (32 months) of the disease. The PrPres found in the brain had the typical characteristics of the PrPres present in vCJD. In addition to the brain and other organs known to be prion positive in vCJD, such as the lymphoreticular system, pituitary and adrenal glands, and gastrointestinal tract, PrPres was also detected for the first time in the dura mater, liver, pancreas, kidney, ovary, uterus, and skin.
Conclusions/Significance
Our results indicate that the number of organs affected in vCJD is greater than previously realized and further underscore the risk of iatrogenic transmission in vCJD.
doi:10.1371/journal.pone.0008765
PMCID: PMC2808239  PMID: 20098730
13.  Detection of Prion Protein in Urine-Derived Injectable Fertility Products by a Targeted Proteomic Approach 
PLoS ONE  2011;6(3):e17815.
Background
Iatrogenic transmission of human prion disease can occur through medical or surgical procedures, including injection of hormones such as gonadotropins extracted from cadaver pituitaries. Annually, more than 300,000 women in the United States and Canada are prescribed urine-derived gonadotropins for infertility. Although menopausal urine donors are screened for symptomatic neurological disease, incubation of Creutzfeldt-Jakob disease (CJD) is impossible to exclude by non-invasive testing. Risk of carrier status of variant CJD (vCJD), a disease associated with decades-long peripheral incubation, is estimated to be on the order of 100 per million population in the United Kingdom. Studies showing infectious prions in the urine of experimental animals with and without renal disease suggest that prions could be present in asymptomatic urine donors. Several human fertility products are derived from donated urine; recently prion protein has been detected in preparations of human menopausal gonadotropin (hMG).
Methodology/Principal Findings
Using a classical proteomic approach, 33 and 34 non-gonadotropin proteins were identified in urinary human chorionic gonadotropin (u-hCG) and highly-purified urinary human menopausal gonadotropin (hMG-HP) products, respectively. Prion protein was identified as a major contaminant in u-hCG preparations for the first time. An advanced prion protein targeted proteomic approach was subsequently used to conduct a survey of gonadotropin products; this approach detected human prion protein peptides in urine-derived injectable fertility products containing hCG, hMG and hMG-HP, but not in recombinant products.
Conclusions/Significance
The presence of protease-sensitive prion protein in urinary-derived injectable fertility products containing hCG, hMG, and hMG-HP suggests that prions may co-purify in these products. Intramuscular injection is a relatively efficient route of transmission of human prion disease, and young women exposed to prions can be expected to survive an incubation period associated with a minimal inoculum. The risks of urine-derived fertility products could now outweigh their benefits, particularly considering the availability of recombinant products.
doi:10.1371/journal.pone.0017815
PMCID: PMC3063168  PMID: 21448279
14.  Prominent and Persistent Extraneural Infection in Human PrP Transgenic Mice Infected with Variant CJD 
PLoS ONE  2008;3(1):e1419.
Background
The evolution of the variant Creutzfeldt-Jakob disease (vCJD) epidemic is hazardous to predict due to uncertainty in ascertaining the prevalence of infection and because the disease might remain asymptomatic or produce an alternate, sporadic-like phenotype.
Methodology/Principal Findings
Transgenic mice were produced that overexpress human prion protein with methionine at codon 129, the only allele found so far in vCJD-affected patients. These mice were infected with prions derived from variant and sporadic CJD (sCJD) cases by intracerebral or intraperitoneal route, and transmission efficiency and strain phenotype were analyzed in brain and spleen. We showed that i) the main features of vCJD infection in humans, including a prominent involvement of the lymphoid tissues compared to that in sCJD infection were faithfully reproduced in such mice; ii) transmission of vCJD agent by intracerebral route could lead to the propagation of either vCJD or sCJD-like prion in the brain, whereas vCJD prion was invariably propagated in the spleen, iii) after peripheral exposure, inefficient neuroinvasion was observed, resulting in an asymptomatic infection with life-long persistence of vCJD prion in the spleen at stable and elevated levels.
Conclusion/Significance
Our findings emphasize the possibility that human-to-human transmission of vCJD might produce alternative neuropathogical phenotypes and that lymphoid tissue examination of CJD cases classified as sporadic might reveal an infection by vCJD-type prions. They also provide evidence for the strong propensity of this agent to establish long-lasting, subclinical vCJD infection of lymphoreticular tissues, thus amplifying the risk for iatrogenic transmission.
doi:10.1371/journal.pone.0001419
PMCID: PMC2171367  PMID: 18183299
15.  Population Screening for Variant Creutzfeldt-Jakob Disease Using a Novel Blood Test 
JAMA neurology  2014;71(4):421-428.
IMPORTANCE
Our study indicates a prototype blood-based variant Creutzfeldt-Jakob disease (vCJD) assay has sufficient sensitivity and specificity to justify a large study comparing vCJD prevalence in the United Kingdom with a bovine spongiform encephalopathy–unexposed population. In a clinical diagnostic capacity, the assay’s likelihood ratios dramatically change an individual’s pretest disease odds to posttest probabilities and can confirm vCJD infection.
OBJECTIVES
To determine the diagnostic accuracy of a prototype blood test for vCJD and hence its suitability for clinical use and for screening prion-exposed populations.
DESIGN, SETTING, AND PARTICIPANTS
Retrospective, cross-sectional diagnostic study of blood samples from national blood collection and prion disease centers in the United States and United Kingdom. Anonymized samples were representative of the US blood donor population (n = 5000), healthy UK donors (n = 200), patients with nonprion neurodegenerative diseases (n = 352), patients in whom a prion disease diagnosis was likely (n = 105), and patients with confirmed vCJD (n = 10).
MAIN OUTCOME AND MEASURE
Presence of vCJD infection determined by a prototype test (now in clinical diagnostic use) that captures, enriches, and detects disease-associated prion protein from whole blood using stainless steel powder.
RESULTS
The assay’s specificity among the presumed negative American donor samples was 100% (95% CI, 99.93%-100%) and was confirmed in a healthy UK cohort (100% specificity; 95% CI, 98.2%-100%). Of potentially cross-reactive blood samples from patients with nonprion neurodegenerative diseases, no samples tested positive (100% specificity; 95% CI, 98.9%-100%). Among National Prion Clinic referrals in whom a prion disease diagnosis was likely, 2 patients with sporadic CJD tested positive (98.1% specificity; 95% CI, 93.3%-99.8%). Finally, we reconfirmed but could not refine our previous sensitivity estimate in a small blind panel of samples from unaffected individuals and patients with vCJD (70% sensitivity; 95% CI, 34.8%-93.3%).
CONCLUSIONS AND RELEVANCE
In conjunction with the assay’s established high sensitivity (71.4%; 95% CI, 47.8%-88.7%), the extremely high specificity supports using the assay to screen for vCJD infection in prion-exposed populations. Additionally, the lack of cross-reactivity and false positives in a range of nonprion neurodegenerative diseases supports the use of the assay in patient diagnosis.
doi:10.1001/jamaneurol.2013.6001
PMCID: PMC4158718  PMID: 24590363
16.  Variant Creutzfeldt-Jakob disease: prion protein genotype analysis of positive appendix tissue samples from a retrospective prevalence study 
BMJ : British Medical Journal  2006;332(7551):1186-1188.
Objective To perform prion protein gene (PRNP) codon 129 analysis in DNA extracted from appendix tissue samples that had tested positive for disease associated prion protein.
Design Reanalysis of positive cases identified in a retrospective anonymised unlinked prevalence study of variant Creutzfeldt-Jakob disease (vCJD) in the United Kingdom.
Study samples Three positive appendix tissue samples out of 12 674 samples of appendix and tonsil tested for disease associated prion protein. The patients from whom these samples were obtained were aged 20-29 years at the time of surgery, which took place in 1996-9.
Setting Pathology departments in two tertiary centres in England and Scotland.
Results Adequate DNA was available for analysis in two of the three specimens, both of which were homozygous for valine at codon 129 in the PRNP.
Conclusions This is the first indication that the valine homozygous subgroup at codon 129 in the PRNP is susceptible to vCJD infection. All tested clinical cases of vCJD have so far occurred in the methionine homozygous subgroup, and a single case of probable iatrogenic vCJD infection has been identified in one patient who was a methionine/valine heterozygote at this genetic locus. People infected with vCJD with a valine homozygous codon 129 PRNP genotype may have a prolonged incubation period, during which horizontal spread of the infection could occur either from blood donations or from contaminated surgical instruments used on these individuals during the asymptomatic phase of the illness.
doi:10.1136/bmj.38804.511644.55
PMCID: PMC1463905  PMID: 16606639
17.  Re-Assessment of PrPSc Distribution in Sporadic and Variant CJD 
PLoS ONE  2013;8(7):e66352.
Human prion diseases are fatal neurodegenerative disorders associated with an accumulation of PrPSc in the central nervous system (CNS). Of the human prion diseases, sporadic Creutzfeldt-Jakob disease (sCJD), which has no known origin, is the most common form while variant CJD (vCJD) is an acquired human prion disease reported to differ from other human prion diseases in its neurological, neuropathological, and biochemical phenotype. Peripheral tissue involvement in prion disease, as judged by PrPSc accumulation in the tonsil, spleen, and lymph node has been reported in vCJD as well as several animal models of prion diseases. However, this distribution of PrPSc has not been consistently reported for sCJD. We reexamined CNS and non-CNS tissue distribution and levels of PrPSc in both sCJD and vCJD. Using a sensitive immunoassay, termed SOFIA, we also assessed PrPSc levels in human body fluids from sCJD as well as in vCJD-infected humanized transgenic mice (Tg666). Unexpectedly, the levels of PrPSc in non-CNS human tissues (spleens, lymph nodes, tonsils) from both sCJD and vCJD did not differ significantly and, as expected, were several logs lower than in the brain. Using protein misfolding cyclic amplification (PMCA) followed by SOFIA, PrPSc was detected in cerebrospinal fluid (CSF), but not in urine or blood, in sCJD patients. In addition, using PMCA and SOFIA, we demonstrated that blood from vCJD-infected Tg666 mice showing clinical disease contained prion disease-associated seeding activity although the data was not statistically significant likely due to the limited number of samples examined. These studies provide a comparison of PrPSc in sCJD vs. vCJD as well as analysis of body fluids. Further, these studies also provide circumstantial evidence that in human prion diseases, as in the animal prion diseases, a direct comparison and intraspecies correlation cannot be made between the levels of PrPSc and infectivity.
doi:10.1371/journal.pone.0066352
PMCID: PMC3700981  PMID: 23843953
18.  Medical Procedures and Risk for Sporadic Creutzfeldt-Jakob Disease, Japan, 1999–2008 
Emerging Infectious Diseases  2009;15(2):265-271.
Surgery or blood transfusion had little effect on the incidence of sCJD.
To elucidate the association between medical procedures and sporadic Creutzfeldt-Jakob disease (sCJD), we analyzed medical procedures (any surgical procedure, neurosurgery, ophthalmic surgery, and blood transfusion) for patients registered by the CJD Surveillance Committee in Japan during 1999–2008. We conducted an age-stratified case–control study with 753 sCJD patients and 210 controls and a study of patients who underwent neurosurgical or ophthalmic surgical procedures at the same hospital. Although the control group was relatively small, no evidence was found that prion disease was transmitted through the investigated medical procedures before onset of sCJD. After onset of sCJD, 4.5% of the sCJD patients underwent operations, including neurosurgical for 0.8% and ophthalmic for 1.9%; no special precautions against transmission of prion diseases were taken. Fortunately, we have not identified patients with prion disease attributed to these operations. Our findings indicate that surgical procedures or blood transfusion had little effect on the incidence of sCJD.
doi:10.3201/eid1502.080749
PMCID: PMC2657619  PMID: 19193271
Prion; Creutzfeldt-Jakob disease; medical procedure; surgery; neurosurgery; ophthalmic surgery; blood transfusion; Japan; research
19.  Graft-related disease progression in dura mater graft-associated Creutzfeldt-Jakob disease: a cross-sectional study 
BMJ Open  2013;3(8):e003400.
Objectives
Details of abnormal prion protein (PrPSc) propagation in the human central nervous system (CNS) are unclear. To assess the spread of PrPSc through the human CNS, we evaluated dura mater graft-associated Creutzfeldt-Jakob disease (dCJD) cases focusing on sites of grafting and dCJD pathological subtypes.
Design
A cross-sectional study.
Setting
nationwide surveillance data of human prion diseases in Japan over the past 12 years were applied for the study.
Participants
Clinical data were obtained from 84 dCJD patients.
Outcome measures
The clinical courses in cases of dCJD were analysed according to the grafting sites (supratentorial and infratentorial groups) and the pathological subtypes (non-plaque and plaque types).
Results
Of the 84 cases of dCJD in this study, 36 (43%) were included in the supratentorial group and 39 (46%) were included in the infratentorial group. As initial manifestations, vertigo (p=0.007) and diplopia (p=0.041) were significantly more frequent in the infratentorial group than in the supratentorial group. During their clinical course, cerebellar signs appeared more frequently in the infratentorial group than in the supratentorial group (p=0.024). In the non-plaque type cases (n=53), the infratentorial group developed vertigo more frequently than the supratentorial group (p=0.017); moreover, cerebellar signs appeared more frequently in the infratentorial group (p=0.014). However, there was no significant difference between groups in the plaque type (n=18).
Conclusions
The high frequency of clinical manifestations related to brain stem and cerebellar dysfunction in the non-plaque type dCJD with infratentorial grafting suggests that PrPSc commonly shows direct propagation into the CNS from contaminated dura mater grafts.
doi:10.1136/bmjopen-2013-003400
PMCID: PMC3753481  PMID: 23975105
Infectious Diseases
20.  No Major Change in vCJD Agent Strain after Secondary Transmission via Blood Transfusion 
PLoS ONE  2008;3(8):e2878.
Background
The identification of transmission of variant Creutzfeldt-Jakob disease (vCJD) by blood transfusion has prompted investigation to establish whether there has been any alteration in the vCJD agent following this route of secondary transmission. Any increase in virulence or host adaptation would require a reassessment of the risk analyses relating to the possibility of a significant secondary outbreak of vCJD. Since there are likely to be carriers of the vCJD agent in the general population, there is a potential for further infection by routes such as blood transfusion or contaminated surgical instruments.
Methodology
We inoculated both wild-type and transgenic mice with material from the first case of transfusion associated vCJD infection.
Principal Findings
The strain transmission properties of blood transfusion associated vCJD infection show remarkable similarities to the strain of vCJD associated with transmission from bovine spongiform encephalopathy (BSE).
Conclusions
Although it has been hypothesized that adaptation of the BSE agent through secondary passage in humans may result in a greater risk of onward transmission due to an increased virulence of the agent for humans, our data presented here in two murine models suggest no significant alterations to transmission efficiency of the agent following human-to-human transmission of vCJD.
doi:10.1371/journal.pone.0002878
PMCID: PMC2478718  PMID: 18682737
21.  PRNP variation in UK sporadic and variant Creutzfeldt Jakob disease highlights genetic risk factors and a novel non-synonymous polymorphism 
BMC Medical Genetics  2009;10:146.
Background
Genetic analysis of the human prion protein gene (PRNP) in suspect cases of Creutzfeldt-Jakob disease (CJD) is necessary for accurate diagnosis and case classification. Previous publications on the genetic variation at the PRNP locus have highlighted the presence of numerous polymorphisms, in addition to the well recognised one at codon 129, with significant variability between geographically distinct populations. It is therefore of interest to consider their influence on susceptibility or the clinico-pathological disease phenotype. This study aimed to characterise the frequency and effect of PRNP open reading frame polymorphisms other than codon 129 in both disease and control samples sourced from the United Kingdom population.
Methods
DNA was extracted from blood samples and genetic data obtained by full sequence analysis of the prion protein gene or by restriction fragment length polymorphism analysis using restriction enzymes specific to the gene polymorphism under investigation.
Results
147 of 166 confirmed cases of variant CJD (vCJD) in the UK have had PRNP codon 129 genotyping and all are methionine homozygous at codon 129; 118 have had full PRNP gene sequencing. Of the latter, 5 cases have shown other polymorphic loci: at codon 219 (2, 1.69%), at codon 202 (2, 1.69%), and a 24 bp deletion in the octapeptide repeat region (1, 0.85%). E219K and D202D were not found in sporadic CJD (sCJD) cases and therefore may represent genetic risk factors for vCJD.
Genetic analysis of 309 confirmed UK sCJD patients showed codon 129 genotype frequencies of MM: 59.5% (n = 184), MV: 21.4% (n = 66), and VV: 19.1% (n = 59). Thirteen (4.2%) had the A117A polymorphism, one of which also had the P68P polymorphism, four (1.3%) had a 24 bp deletion, and a single patient had a novel missense variation at codon 167. As the phenotype of this latter case is similar to sCJD and in the absence of a family history of CJD, it is unknown whether this is a form of genetic CJD, or simply a neutral polymorphism.
Conclusions
This analysis of PRNP genetic variation in UK CJD patients is the first to show a comprehensive comparison with healthy individuals (n = 970) from the same population, who were genotyped for the three most common variations (codon 129, codon 117, and 24 bp deletion). These latter two genetic variations were equally frequent in UK sCJD or vCJD cases and a normal (healthy blood donor) UK population.
doi:10.1186/1471-2350-10-146
PMCID: PMC2806268  PMID: 20035629
22.  Prion Disease Blood Test Using Immunoprecipitation and Improved Quaking-Induced Conversion 
mBio  2011;2(3):e00078-11.
ABSTRACT
A key challenge in managing transmissible spongiform encephalopathies (TSEs) or prion diseases in medicine, agriculture, and wildlife biology is the development of practical tests for prions that are at or below infectious levels. Of particular interest are tests capable of detecting prions in blood components such as plasma, but blood typically has extremely low prion concentrations and contains inhibitors of the most sensitive prion tests. One of the latter tests is quaking-induced conversion (QuIC), which can be as sensitive as in vivo bioassays, but much more rapid, higher throughput, and less expensive. Now we have integrated antibody 15B3-based immunoprecipitation with QuIC reactions to increase sensitivity and isolate prions from inhibitors such as those in plasma samples. Coupling of immunoprecipitation and an improved real-time QuIC reaction dramatically enhanced detection of variant Creutzfeldt-Jakob disease (vCJD) brain tissue diluted into human plasma. Dilutions of 1014-fold, containing ~2 attogram (ag) per ml of proteinase K-resistant prion protein, were readily detected, indicating ~10,000-fold greater sensitivity for vCJD brain than has previously been reported. We also discriminated between plasma and serum samples from scrapie-infected and uninfected hamsters, even in early preclinical stages. This combined assay, which we call “enhanced QuIC” (eQuIC), markedly improves prospects for routine detection of low levels of prions in tissues, fluids, or environmental samples.
IMPORTANCE
Transmissible spongiform encephalopathies (TSEs) are largely untreatable and are difficult to diagnose definitively prior to irreversible clinical decline or death. The transmissibility of TSEs within and between species highlights the need for practical tests for even the smallest amounts of infectivity. A few sufficiently sensitive in vitro methods have been reported, but most have major limitations that would preclude their use in routine diagnostic or screening applications. Our new assay improves the outlook for such critical applications. We focused initially on blood plasma because a practical blood test for prions would be especially valuable for TSE diagnostics and risk reduction. Variant Creutzfeldt-Jakob disease (vCJD) in particular has been transmitted between humans via blood transfusions. Enhanced real-time quaking-induced conversion (eQuIC) provides by far the most sensitive detection of vCJD to date. The 15B3 antibody binds prions of multiple species, suggesting that our assay may be useful for clinical and fundamental studies of a variety of TSEs of humans and animals.
doi:10.1128/mBio.00078-11
PMCID: PMC3101782  PMID: 21558432
23.  Plasminogen-Based Capture Combined with Amplification Technology for the Detection of PrPTSE in the Pre-Clinical Phase of Infection 
PLoS ONE  2013;8(7):e69632.
Background
Variant Creutzfeldt-Jakob disease (vCJD) is a neurodegenerative infectious disorder, characterized by a prominent accumulation of pathological isoforms of the prion protein (PrPTSE) in the brain and lymphoid tissues. Since the publication in the United Kingdom of four apparent vCJD cases following transfusion of red blood cells and one apparent case following treatment with factor VIII, the presence of vCJD infectivity in the blood seems highly probable. For effective blood testing of vCJD individuals in the preclinical or clinical phase of infection, it is considered necessary that assays detect PrPTSE concentrations in the femtomolar range.
Methodology/Principal Findings
We have developed a three-step assay that firstly captures PrPTSE from infected blood using a plasminogen-coated magnetic-nanobead method prior to its serial amplification via protein misfolding cyclic amplification (PMCA) and specific PrPTSE detection by western blot. We achieved a PrPTSE capture yield of 95% from scrapie-infected material. We demonstrated the possibility of detecting PrPTSE in white blood cells, in buffy coat and in plasma isolated from the blood of scrapie-infected sheep collected at the pre-clinical stage of the disease. The test also allowed the detection of PrPTSE in human plasma spiked with a 10−8 dilution of vCJD-infected brain homogenate corresponding to the level of sensitivity (femtogram) required for the detection of the PrPTSE in asymptomatic carriers. The 100% specificity of the test was revealed using a blinded panel comprising 96 human plasma samples.
Conclusion/Significance
We have developed a sensitive and specific amplification assay allowing the detection of PrPTSE in the plasma and buffy coat fractions of blood collected at the pre-clinical phase of the disease. This assay represents a good candidate as a confirmatory assay for the presence of PrPTSE in blood of patients displaying positivity in large scale screening tests.
doi:10.1371/journal.pone.0069632
PMCID: PMC3722129  PMID: 23894513
24.  Prion infectivity in variant Creutzfeldt–Jakob disease rectum 
Gut  2006;56(1):90-94.
Background
Disease‐related prion protein (PrPSc) is readily detectable in lymphoreticular tissues in variant Creutzfeldt–Jakob disease (vCJD), but not in other forms of human prion disease. This distinctive pathogenesis, with the unknown population prevalence of asymptomatic vCJD infection, has led to significant concerns that secondary transmission of vCJD prions will occur through a wide range of surgical procedures. To date PrPSc:prion infectivity ratios have not been determined in vCJD, and it is unknown whether vCJD prions are similar to experimental rodent prions, where PrPSc concentration typically reflects infectious prion titre.
Aim
To investigate prion infectivity in vCJD tissue containing barely detectable levels of PrPSc.
Methods
Transgenic mice expressing only human PrP (Tg(HuPrP129M+/+Prnpo/o)‐35 and Tg(HuPrP129M+/+Prnpo/o)‐45 mice) were inoculated with brain or rectal tissue from a previously characterised patient with vCJD. These tissues contain the maximum and minimum levels of detectable PrPSc that have been observed in vCJD.
Results
Efficient transmission of prion infection was observed in transgenic mice inoculated with vCJD rectal tissue containing PrPSc at a concentration of 104.7‐fold lower than that in vCJD brain.
Conclusions
These data confirm the potential risks for secondary transmission of vCJD prions via gastrointestinal procedures and support the use of PrPSc as a quantitative marker of prion infectivity in vCJD tissues.
doi:10.1136/gut.2006.091637
PMCID: PMC1856674  PMID: 16763054
25.  Efficient Transmission and Characterization of Creutzfeldt–Jakob Disease Strains in Bank Voles 
PLoS Pathogens  2006;2(2):e12.
Transmission of prions between species is limited by the “species barrier,” which hampers a full characterization of human prion strains in the mouse model. We report that the efficiency of primary transmission of prions from Creutzfeldt–Jakob disease patients to a wild rodent species, the bank vole (Clethrionomys glareolus), is comparable to that reported in transgenic mice carrying human prion protein, in spite of a low prion protein–sequence homology between man and vole. Voles infected with sporadic and genetic Creutzfeldt–Jakob disease isolates show strain-specific patterns of spongiform degeneration and pathological prion protein–deposition, and accumulate protease-resistant prion protein with biochemical properties similar to the human counterpart. Adaptation of genetic Creutzfeldt–Jakob disease isolates to voles shows little or no evidence of a transmission barrier, in contrast to the striking barriers observed during transmission of mouse, hamster, and sheep prions to voles. Our results imply that in voles there is no clear relationship between the degree of homology of the prion protein of the donor and recipient species and susceptibility, consistent with the view that the prion strain gives a major contribution to the species barrier. The vole is therefore a valuable model to study human prion diversity and, being susceptible to a range of animal prions, represents a unique tool for comparing isolates from different species.
Synopsis
Prions are unconventional infectious agents that cause fatal neurodegenerative diseases. The transmission of prions between species is considered a rare event because it is limited by the “species barrier.” Nevertheless, in the past 10 y, more than 180 people worldwide died with variant Creutzfeldt–Jakob disease (vCJD) following consumption of bovine spongiform encephalopathy (BSE)–contaminated food. The vCJD crisis highlights the need for experimental approaches that are able to characterize human prions and to estimate the risk of animal prions for man. The authors used a new animal model, the bank vole, which appears to address these issues. They observed that these rodents are highly susceptible to sporadic Creutzfeldt–Jakob disease (sCJD) and genetic Creutzfeldt–Jakob disease (gCJD), as well as to several animal prions. Transmission to voles indicates that sCJD is caused by at least two distinct prion strains. Surprisingly, voles challenged with gCJD isolates do not show a species barrier, while prions from closely related rodent species encounter a clear barrier in transmitting to voles. Inoculation of voles with scrapie-related and BSE-related strains from several species suggests that the prion strain, and not the donor species, is the major determinant of prion transmissibility between different species. The authors conclude that the vole model is a valuable tool for comparing animal and human prions.
doi:10.1371/journal.ppat.0020012
PMCID: PMC1383487  PMID: 16518470

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