scholarly journals Clinical, neuropathological and immunohistochemical features of sporadic and variant forms of Creutzfeldt–Jakob disease in the squirrel monkey (Saimiri sciureus)

2007 ◽  
Vol 88 (2) ◽  
pp. 688-695 ◽  
Author(s):  
Lawrence Williams ◽  
Paul Brown ◽  
James Ironside ◽  
Susan Gibson ◽  
Robert Will ◽  
...  
Keyword(s):  
Squirrel Monkey ◽  
Transmissible Spongiform Encephalopathy ◽  
Clinicopathological Characteristics ◽  
Saimiri Sciureus ◽  
Spongiform Encephalopathy ◽  
Lymphoid Tissues ◽  
Incubation Periods ◽  
Clinical Surveillance ◽  
Jakob Disease ◽  
Different Strains

The squirrel monkey (Saimiri sciureus) has been shown to be nearly as susceptible as the chimpanzee to experimentally induced Creutzfeldt–Jakob disease (CJD), and has been used extensively in diagnostic and pathogenetic studies. However, no information is available concerning the clinicopathological characteristics of different strains of human transmissible spongiform encephalopathy (TSE) in this species, in particular, strains of sporadic and variant CJD (sCJD and vCJD, respectively). Brain homogenates from patients with sCJD or vCJD were inoculated intracerebrally at dilutions of 10−1 or 10−3 into the left frontal cortex of squirrel monkeys. Animals were kept under continuous clinical surveillance during the preclinical and clinical phases of disease, and regularly underwent standardized behavioural testing. Brains from three animals in the sCJD and vCJD groups were examined histopathologically and immunohistochemically for the presence of pathognomonic misfolded protein (PrPTSE). Overall, incubation periods and durations of illness were slightly shorter in monkeys infected with sCJD than in those infected with vCJD, but the earliest signs of illness (ataxia and tremors) were the same in both groups. Clinical disease in the sCJD monkeys was somewhat more severe and of shorter duration. Post-mortem examinations revealed distinctive patterns of spongiform change and PrPTSE distribution in the brains of sCJD and vCJD animals, similar to those seen in humans except that amyloid plaques were not present. PrPTSE was uniformly absent from peripheral lymphoid tissues in both groups of animals. Human strains of sCJD and vCJD cause distinguishable clinicopathological features in the squirrel monkey that can provide a baseline for the evaluation of future therapeutic studies.

How to Limit the Spread of Creutzfeldt-Jakob Disease

1996 ◽  
Vol 17 (8) ◽  
pp. 521-528
Author(s):  
Dominique Dormont
Keyword(s):  
Blood Donation ◽  
Transmissible Spongiform Encephalopathy ◽  
Infected Individual ◽  
Experimental Models ◽  
Transmissible Spongiform Encephalopathies ◽  
Spongiform Encephalopathy ◽  
Spongiform Encephalopathies ◽  
Corneal Grafting ◽  
Jakob Disease ◽  
Spleen And Lymph Nodes

AbstractTransmissible spongiform encephalopathies are rare lethal diseases induced in humans and animals by unconventional agents called transmissible spongiform encephalopathy agents (TSEAs), virions, or prions. Several cases of iatrogenic Creutzfeldt-Jakob disease (CJD) have been reported in the literature after neuro-surgery, treatment with pituitary-derived hormones, corneal grafting, and use of dura mater lyophilisates. In a given infected individual, TSEA-associated infectiousness depends on the nature of the organ: the central nervous system has the highest infectiousness, spleen and lymph nodes a medium infectiousness, and organs such as bone, skin, or skeletal muscles do not harbor any detectable infectiousness in experimental models. Transmissible spongiform encephalopathy/prions have unconventional properties; in particular, they resist almost all the chemical and physical processes that inactivate conventional viruses. Therefore, prevention of CJD agent transmission must be taken into account in daily hospital practice. Efficient sterilization procedures should be determined. In tissue and blood donation, donors with a neurologic history must be excluded, and patients treated with pituitary-derived hormones should be considered potentially infected with TSEA and excluded.

scholarly journals Transmission and Adaptation of Chronic Wasting Disease to Hamsters and Transgenic Mice: Evidence for Strains

2007 ◽  
Vol 81 (8) ◽  
pp. 4305-4314 ◽  
Author(s):  
Gregory J. Raymond ◽  
Lynne D. Raymond ◽  
Kimberly D. Meade-White ◽  
Andrew G. Hughson ◽  
Cynthia Favara ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Prion Protein ◽  
Chronic Wasting Disease ◽  
Transmissible Spongiform Encephalopathy ◽  
Wild Type Mouse ◽  
Mouse Strains ◽  
Spongiform Encephalopathy ◽  
Wild Type ◽  
Wasting Disease ◽  
Incubation Periods

ABSTRACT In vitro screening using the cell-free prion protein conversion system indicated that certain rodents may be susceptible to chronic wasting disease (CWD). Therefore, CWD isolates from mule deer, white-tailed deer, and elk were inoculated intracerebrally into various rodent species to assess the rodents' susceptibility and to develop new rodent models of CWD. The species inoculated were Syrian golden, Djungarian, Chinese, Siberian, and Armenian hamsters, transgenic mice expressing the Syrian golden hamster prion protein, and RML Swiss and C57BL10 wild-type mice. The transgenic mice and the Syrian golden, Chinese, Siberian, and Armenian hamsters had limited susceptibility to certain of the CWD inocula, as evidenced by incomplete attack rates and long incubation periods. For serial passages of CWD isolates in Syrian golden hamsters, incubation periods rapidly stabilized, with isolates having either short (85 to 89 days) or long (408 to 544 days) mean incubation periods and distinct neuropathological patterns. In contrast, wild-type mouse strains and Djungarian hamsters were not susceptible to CWD. These results show that CWD can be transmitted and adapted to some species of rodents and suggest that the cervid-derived CWD inocula may have contained or diverged into at least two distinct transmissible spongiform encephalopathy strains.

scholarly journals Lymphotoxin-α- and Lymphotoxin-β-Deficient Mice Differ in Susceptibility to Scrapie: Evidence against Dendritic Cell Involvement in Neuroinvasion

2002 ◽  
Vol 76 (9) ◽  
pp. 4357-4363 ◽  
Author(s):  
Michael B. A. Oldstone ◽  
Richard Race ◽  
Diane Thomas ◽  
Hanna Lewicki ◽  
Dirk Homann ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Prion Diseases ◽  
Transmissible Spongiform Encephalopathy ◽  
Oral Intake ◽  
Infectious Agent ◽  
Lymphoid Cells ◽  
Current Evidence ◽  
Spongiform Encephalopathy ◽  
Lymphoid Tissues ◽  
Mesenteric Lymph Nodes

ABSTRACT Transmissible spongiform encephalopathy or prion diseases are fatal neurodegenerative disorders of humans and animals often initiated by oral intake of an infectious agent. Current evidence suggests that infection occurs initially in the lymphoid tissues and subsequently in the central nervous system (CNS). The identity of infected lymphoid cells remains controversial, but recent studies point to the involvement of both follicular dendritic cells (FDC) and CD11c+ lymphoid dendritic cells. FDC generation and maintenance in germinal centers is dependent on lymphotoxin alpha (LT-α) and LT-β signaling components. We report here that by the oral route, LT-α −/− mice developed scrapie while LT-β −/− mice did not. Furthermore, LT-α −/− mice had a higher incidence and shorter incubation period for developing disease following inoculation than did LT-β −/− mice. Transplantation of lymphoid tissues from LT-β −/− mice, which have cervical and mesenteric lymph nodes, into LT-α −/− mice, which do not, did not alter the incidence of CNS scrapie. In other studies, a virus that is tropic for and alters functions of CD11c+ cells did not alter the kinetics of neuroinvasion of scrapie. Our results suggest that neither FDC nor CD11c+ cells are essential for neuroinvasion after high doses of RML scrapie. Further, it is possible that an as yet unidentified cell found more abundantly in LT-α −/− than in LT-β −/− mice may assist in the amplification of scrapie infection in the periphery and favor susceptibility to CNS disease following peripheral routes of infection.

scholarly journals Relevance of oral experimental challenge with classical scrapie in sheep

2010 ◽  
Vol 91 (8) ◽  
pp. 2139-2144 ◽  
Author(s):  
Guillaume Tabouret ◽  
Caroline Lacroux ◽  
Séverine Lugan ◽  
Pierrette Costes ◽  
Fabien Corbière ◽  
...  
Keyword(s):  
Incubation Period ◽  
Prion Protein ◽  
Transmissible Spongiform Encephalopathy ◽  
Classical Scrapie ◽  
Spongiform Encephalopathy ◽  
Lymphoid Tissues ◽  
Relevant Model ◽  
Experimental Conditions ◽  
Oral Inoculation ◽  
Experimental Challenge

Oral inoculation is currently considered as the best approach to mimic natural TSE contamination in ruminants. In this study, we compared the timing of abnormal prion protein (PrPSc) dissemination and accumulation in the organism of susceptible sheep either orally inoculated or naturally infected with classical scrapie. Both animal groups shared a similar PrPSc dissemination scheme and accumulation dynamics in lymphoid tissues. However, orally challenged animals displayed an earlier neuro-invasion and a dramatically shorter incubation period than naturally exposed sheep. No differences were observed between the groups with regards to the neuro-invasion route. These results unambiguously indicate that oral inoculation can have an impact on both the earliness of neuro-invasion and the incubation period. They also support the statement that oral inoculation is a relevant model for investigating transmissible spongiform encephalopathy pathogenesis. Nevertheless, data obtained under such experimental conditions should be used with some caution.

scholarly journals Prion Protein Devoid of the Octapeptide Repeat Region Delays Bovine Spongiform Encephalopathy Pathogenesis in Mice

2017 ◽  
Vol 92 (1) ◽  
Author(s):  
Hideyuki Hara ◽  
Hironori Miyata ◽  
Nandita Rani Das ◽  
Junji Chida ◽  
Tatenobu Yoshimochi ◽  
...  
Keyword(s):  
Bovine Spongiform Encephalopathy ◽  
Prion Protein ◽  
Prion Diseases ◽  
Spongiform Encephalopathy ◽  
Wild Type ◽  
Jakob Disease ◽  
Function Relationship ◽  
Different Strains ◽  
Conformational Conversion

ABSTRACTConformational conversion of the cellular isoform of prion protein, PrPC, into the abnormally folded, amyloidogenic isoform, PrPSc, is a key pathogenic event in prion diseases, including Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy (BSE) in animals. We previously reported that the octapeptide repeat (OR) region could be dispensable for converting PrPCinto PrPScafter infection with RML prions. We demonstrated that mice transgenically expressing mouse PrP with deletion of the OR region on the PrP knockout background, designated Tg(PrPΔOR)/Prnp0/0mice, did not show reduced susceptibility to RML scrapie prions, with abundant accumulation of PrPScΔOR in their brains. We show here that Tg(PrPΔOR)/Prnp0/0mice were highly resistant to BSE prions, developing the disease with markedly elongated incubation times after infection with BSE prions. The conversion of PrPΔOR into PrPScΔOR was markedly delayed in their brains. These results suggest that the OR region may have a crucial role in the conversion of PrPCinto PrPScafter infection with BSE prions. However, Tg(PrPΔOR)/Prnp0/0mice remained susceptible to RML and 22L scrapie prions, developing the disease without elongated incubation times after infection with RML and 22L prions. PrPScΔOR accumulated only slightly less in the brains of RML- or 22L-infected Tg(PrPΔOR)/Prnp0/0mice than PrPScin control wild-type mice. Taken together, these results indicate that the OR region of PrPCcould play a differential role in the pathogenesis of BSE prions and RML or 22L scrapie prions.IMPORTANCEStructure-function relationship studies of PrPCconformational conversion into PrPScare worthwhile to understand the mechanism of the conversion of PrPCinto PrPSc. We show here that, by inoculating Tg(PrPΔOR)/Prnp0/0mice with the three different strains of RML, 22L, and BSE prions, the OR region could play a differential role in the conversion of PrPCinto PrPScafter infection with RML or 22L scrapie prions and BSE prions. PrPΔOR was efficiently converted into PrPScΔOR after infection with RML and 22L prions. However, the conversion of PrPΔOR into PrPScΔOR was markedly delayed after infection with BSE prions. Further investigation into the role of the OR region in the conversion of PrPCinto PrPScafter infection with BSE prions might be helpful for understanding the pathogenesis of BSE prions.

scholarly journals Pathways of Prion Spread during Early Chronic Wasting Disease in Deer

2017 ◽  
Vol 91 (10) ◽  
Author(s):  
Clare E. Hoover ◽  
Kristen A. Davenport ◽  
Davin M. Henderson ◽  
Nathaniel D. Denkers ◽  
Candace K. Mathiason ◽  
...  
Keyword(s):  
Tissue Distribution ◽  
Lymphoid Tissue ◽  
Chronic Wasting Disease ◽  
Natural Infection ◽  
Transmissible Spongiform Encephalopathy ◽  
Carrier State ◽  
Spongiform Encephalopathy ◽  
Lymphoid Tissues ◽  
Wasting Disease ◽  
Terminal Disease

ABSTRACT Among prion infections, two scenarios of prion spread are generally observed: (i) early lymphoid tissue replication or (ii) direct neuroinvasion without substantial antecedent lymphoid amplification. In nature, cervids are infected with chronic wasting disease (CWD) prions by oral and nasal mucosal exposure, and studies of early CWD pathogenesis have implicated pharyngeal lymphoid tissue as the earliest sites of prion accumulation. However, knowledge of chronological events in prion spread during early infection remains incomplete. To investigate this knowledge gap in early CWD pathogenesis, we exposed white-tailed deer to CWD prions by mucosal routes and performed serial necropsies to assess PrPCWD tissue distribution by real-time quaking-induced conversion (RT-QuIC) and tyramide signal amplification immunohistochemistry (TSA-IHC). Although PrPCWD was not detected by either method in the initial days (1 and 3) postexposure, we observed PrPCWD seeding activity and follicular immunoreactivity in oropharyngeal lymphoid tissues at 1 and 2 months postexposure (MPE). At 3 MPE, PrPCWD replication had expanded to all systemic lymphoid tissues. By 4 MPE, the PrPCWD burden in all lymphoid tissues had increased and approached levels observed in terminal disease, yet there was no evidence of nervous system invasion. These results indicate the first site of CWD prion entry is in the oropharynx, and the initial phase of prion amplification occurs in the oropharyngeal lymphoid tissues followed by rapid dissemination to systemic lymphoid tissues. This lymphoid replication phase appears to precede neuroinvasion. IMPORTANCE Chronic wasting disease (CWD) is a universally fatal transmissible spongiform encephalopathy affecting cervids, and natural infection occurs through oral and nasal mucosal exposure to infectious prions. Terminal disease is characterized by PrPCWD accumulation in the brain and lymphoid tissues of affected animals. However, the initial sites of prion accumulation and pathways of prion spread during early CWD infection remain unknown. To investigate the chronological events of early prion pathogenesis, we exposed deer to CWD prions and monitored the tissue distribution of PrPCWD over the first 4 months of infection. We show CWD uptake occurs in the oropharynx with initial prion replication in the draining oropharyngeal lymphoid tissues, rapidly followed by dissemination to systemic lymphoid tissues without evidence of neuroinvasion. These data highlight the two phases of CWD infection: a robust prion amplification in systemic lymphoid tissues prior to neuroinvasion and establishment of a carrier state.

scholarly journals Transmissions of variant Creutzfeldt–Jakob disease from brain and lymphoreticular tissue show uniform and conserved bovine spongiform encephalopathy-related phenotypic properties on primary and secondary passage in wild-type mice

2009 ◽  
Vol 90 (12) ◽  
pp. 3075-3082 ◽  
Author(s):  
Diane L. Ritchie ◽  
Aileen Boyle ◽  
Irene McConnell ◽  
Mark W. Head ◽  
James W. Ironside ◽  
...  
Keyword(s):  
Bovine Spongiform Encephalopathy ◽  
Fragment Size ◽  
Biological Properties ◽  
Mouse Strains ◽  
Spongiform Encephalopathy ◽  
Wild Type ◽  
Phenotypic Properties ◽  
Peripheral Tissues ◽  
Incubation Periods ◽  
Jakob Disease

Prion strains are defined by their biological properties after transmission to wild-type mice, specifically by their incubation periods and patterns of vacuolar pathology (‘lesion profiles’). Preliminary results from transmissions of variant Creutzfeldt–Jakob disease (vCJD) to wild-type mice provided the first compelling evidence for the close similarity of the vCJD agent to the agent causing bovine spongiform encephalopathy (BSE). Complete results from this investigation, including the transmission characteristics of vCJD from brain and peripheral tissues of 10 cases (after primary transmission and subsequent mouse-to-mouse passage), have now been analysed. All 10 vCJD sources resulted in consistent incubation periods and lesion profiles, suggesting that all 10 patients were infected with the same strain of agent. Incubation periods suggested that infectious titres may be subject to regional variation within the brain. Comparison of incubation periods and lesion profiles from transmission of brain and peripheral tissues showed no evidence of tissue-specific modification in the biological properties of the agent. Analysis of the protease-resistant prion protein (PrPres) by Western blotting from primary and subsequent passages in mice showed a glycosylation pattern closely resembling that of vCJD in humans, the so-called BSE ‘glycoform signature’. Minor variations in PrPres fragment size were evident between mouse strains carrying different alleles of the gene encoding PrP both in primary transmissions and on further passages of vCJD brain. Overall, the results closely resembled those of previously reported transmissions of BSE in the same mouse strains, consistent with BSE being the origin of all of these vCJD cases.

scholarly journals Creutzfeldt-Jakob disease surveillance in Australia: update to 31 December 2019

2020 ◽  
Vol 44 ◽  
Author(s):  
Christiane Stehmann ◽  
Matteo Senesi ◽  
Shannon Sarros ◽  
Amelia McGlade ◽  
Marion Simpson ◽  
...  
Keyword(s):  
Prion Disease ◽  
Disease Surveillance ◽  
Prion Diseases ◽  
Transmissible Spongiform Encephalopathy ◽  
Annual Number ◽  
Spongiform Encephalopathy ◽  
Human Prion Disease ◽  
Prospective Surveillance ◽  
Jakob Disease ◽  
Neuropathological Examination

Nationwide surveillance of Creutzfeldt-Jakob disease and other human prion diseases is performed by the Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR). National surveillance encompasses the period since 1 January 1970, with prospective surveillance occurring from 1 October 1993. Over this prospective surveillance period, considerable developments have occurred in pre-mortem diagnostics; in the delineation of new disease subtypes; and in a heightened awareness of prion diseases in healthcare settings. Surveillance practices of the ANCJDR have evolved and adapted accordingly. This report summarises the activities of the ANCJDR during 2019. Since the ANCJDR began offering diagnostic cerebrospinal fluid (CSF) 14-3-3 protein testing in Australia in September 1997, the annual number of referrals has steadily increased. In 2019, 513 domestic CSF specimens were referred for 14-3-3 protein testing and 85 persons with suspected human prion disease were formally added to the national register. As of 31 December 2019, just under half (42 cases) of the 85 suspect case notifications remain classified as ‘incomplete’; 16 cases were excluded through either detailed clinical follow-up (3 cases) or neuropathological examination (13 cases); 20 cases were classified as ‘definite’ and seven as ‘probable’ prion disease. For 2019, sixty-three percent of all suspected human prion disease related deaths in Australia underwent neuropathological examination. No cases of variant or iatrogenic CJD were identified. Two possibly causal novel prion protein gene (PRNP) sequence variations were identified. Keywords: Creutzfeldt-Jakob disease, prion disease, transmissible spongiform encephalopathy, disease surveillance

scholarly journals Increased susceptibility of transgenic mice expressing human PrP to experimental sheep bovine spongiform encephalopathy is not due to increased agent titre in sheep brain tissue

2014 ◽  
Vol 95 (8) ◽  
pp. 1855-1859 ◽  
Author(s):  
Chris Plinston ◽  
Patricia Hart ◽  
Nora Hunter ◽  
Jean C. Manson ◽  
Rona M. Barron
Keyword(s):  
Bovine Spongiform Encephalopathy ◽  
Brain Tissue ◽  
Transmissible Spongiform Encephalopathy ◽  
Small Ruminants ◽  
Infectious Agent ◽  
Spongiform Encephalopathy ◽  
Jakob Disease ◽  
Human Prion Protein ◽  
Sheep Brain ◽  
Increased Susceptibility

Bovine spongiform encephalopathy (BSE) in cattle and variant Creutzfeldt–Jakob disease in humans have previously been shown to be caused by the same strain of transmissible spongiform encephalopathy agent. It is hypothesized that the agent spread to humans following consumption of food products prepared from infected cattle. Despite evidence supporting zoonotic transmission, mouse models expressing human prion protein (HuTg) have consistently shown poor transmission rates when inoculated with cattle BSE. Higher rates of transmission have however been observed when these mice are exposed to BSE that has been experimentally transmitted through sheep or goats, indicating that humans may potentially be more susceptible to BSE from small ruminants. Here we demonstrate that increased transmissibility of small ruminant BSE to HuTg mice was not due to replication of higher levels of infectivity in sheep brain tissue, and is instead due to other specific changes in the infectious agent.

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