Experimental Infection of Cattle With a Novel Prion Derived From Atypical H-Type Bovine Spongiform Encephalopathy
Experimental Infection of Cattle With a Novel Prion Derived From Atypical H-Type Bovine Spongiform Encephalopathy
Show all authors Hiroyuki Okada, Kentaro Masujin, Kohtaro Miyazawa, ...
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Experimental Infection of Cattle With a Novel Prion Derived From Atypical H-Type Bovine Spongiform Encephalopathy
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Abstract
H-type bovine spongiform encephalopathy (H-BSE) is an atypical form of BSE in cattle.
During passaging of H-BSE in transgenic bovinized (TgBoPrP) mice, a novel phenotype of BSE, termed BSE-SW emerged and was characterized by a short incubation time and host weight loss. To investigate the biological and biochemical properties of the BSE-SW prion, a transmission study was conducted in cattle, which were inoculated intracerebrally with brain homogenate from BSE-SW–infected TgBoPrP mice. The disease incubation period was approximately 15 months. The animals showed characteristic neurological signs of dullness, and severe spongiform changes and a widespread, uniform distribution of disease-associated prion protein (PrPSc) were observed throughout the brain of infected cattle. Immunohistochemical PrPSc staining of the brain revealed the presence of intraglial accumulations and plaque-like deposits. No remarkable differences were identified in vacuolar lesion scores, topographical distribution patterns, and staining types of PrPSc in the brains of BSE-SW– vs H-BSE–infected cattle. PrPSc deposition was detected in the ganglia, vagus nerve, spinal nerve, cauda equina, adrenal medulla, and ocular muscle. Western blot analysis revealed that the specific biochemical properties of the BSE-SW prion, with an additional 10- to 12-kDa fragment, were well maintained after transmission.
***These findings indicated that the BSE-SW prion has biochemical properties distinct from those of H-BSE in cattle, although clinical and pathologic features of BSW-SW in cattle are indistinguishable from those of H-BSE. The results suggest that the 2 infectious agents, BSE-SW and H-BSE, are closely related strains.
Emergence of a novel bovine spongiform encephalopathy (BSE) prion from an atypical H-type BSE
Kentaro Masujin, Hiroyuki Okada, Kohtaro Miyazawa, Yuichi Matsuura, Morikazu Imamura, Yoshifumi Iwamaru, Yuichi Murayama & Takashi Yokoyama Scientific Reports 6, Article number: 22753 (2016) doi:10.1038/srep22753
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Infectious-disease diagnosticsMicrobiology
Received: 23 November 2015 Accepted: 19 February 2016 Published online: 07 March 2016
Abstract The H-type of atypical bovine spongiform encephalopathy (H-BSE) was serially passaged in bovinized transgenic (TgBoPrP) mice. At the fourth passage, most challenged mice showed a typical H-BSE phenotype with incubation periods of 223 ± 7.8 days. However, a different phenotype of BSE prion with shorter incubation periods of 109 ± 4 days emerged in a minor subset of the inoculated mice. The latter showed distinct clinical signs, brain pathology, and abnormal prion protein profiles as compared to H-BSE and other known BSE strains in mice. This novel prion was transmitted intracerebrally to cattle, with incubation periods of 14.8 ± 1.5 months, with phenotypes that differed from those of other bovine prion strains.
***These data suggest that intraspecies transmission of H-BSE in cattle allows the emergence of a novel BSE strain.
***Therefore, the continuation of feed ban programs may be necessary to exclude the recycling of H-BSE prions, which appear to arise spontaneously, in livestock. Such measures should help to reduce the risks from both novel and known strains of BSE.
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H-BSE was first reported in France7, and has been subsequently detected in several European countries and North America5,6. In one of two H-BSE cases detected in the U.S., a prion protein (PrP) amino-acid substitution that is associated with familial Creutzfeldt–Jakob disease in humans has been reported. This suggested the possibility that H-BSE might occur spontaneously or sporadically8. Regardless of its origin, previous studies have shown that H-BSE is transmissible to cattle9,10,11,12, as well as to wild type13,14, bovinized, and ovinized PrP transgenic mice that express murine, bovine, or ovine PrPC, respectively15,16,17. Those studies also revealed different characteristics of H-BSE relative to C-BSE and L-BSE.
Serial passages of H-BSE in wild type18,19 and bovinized PrP transgenic mice20 can lead to the emergence of a C-BSE-like phenotype. This suggests that H-BSE-affected cattle harbor heterogeneous prions and that structural variants of H-BSE might generate a C-BSE-like phenotype. This, in turn, raises the possibility that C-BSE originated from H-BSE. To attempt to clarify the origin of C-BSE, we serially passaged H-BSE in bovinized PrP transgenic (TgBoPrP) mice. In contrast to previous studies, we did not detect C-BSE-like prions during serial passages. However, a novel BSE prion—different from C-BSE, L-BSE, and H-BSE prions—was detected in a subset of inoculated mice. When this novel prion was inoculated intracerebrally into cattle, a novel BSE phenotype was confirmed. This study suggests that a novel BSE emerges during intraspecies transmission of H-BSE in cattle.
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Furthermore, our new strain was successfully transmitted to cattle. Standard diagnostic testing for BSE confirmed the presence of spongiform changes associated with PrPSc accumulation in the obex, and the challenged cattle fulfilled BSE criteria (Figs 4 and 5). The disease phenotype and features of PrPSc, different from the known types of BSE, indicated that this prion could cause a novel type of atypical BSE. The shorter incubation periods in cattle were consistent with the relative incubation periods in TgBoPrP mice, and indicate high virulence of this novel prion. Further analysis of diseased cattle is necessary to clarify its characteristics. Such studies could help to elucidate the mechanisms of conformational change in PrPSc, which lead to the propagation of new prion strains.
The ban on meat-and-bone meal in livestock feed has contributed to the decline in C-BSE occurrences6. Recently, easing of the BSE-related regulations and control measures has been discussed. The origin of atypical BSE remains unknown, but it has been proposed to be spontaneous or sporadic29. H-BSE has been reported to transform into a C-BSE-like phenotype during animal passages18,19,20. Furthermore, we have shown here that the sequential transmission of H-BSE in TgBoPrP mice, i.e., to a homologous bovine PrP context, generated a novel type of BSE.
***Considering these observations, a continuous feed ban program may be necessary even after C-BSE is eradicated.
***Prohibiting the recycling of spontaneously occurring H-BSE prions in cattle should help to prevent both re-emerging and emerging types of BSEs.
***Moreover, sporadic disease has never been observed in breeding colonies or primate research laboratories, most notably among hundreds of animals over several decades of study at the National Institutes of Health25, and in nearly twenty older animals continuously housed in our own facility.***
***********OCTOBER 2015*************
*** PRION 2015 ORAL AND POSTER CONGRESSIONAL ABSTRACTS ***
THANK YOU PRION 2015 TAYLOR & FRANCIS, Professor Chernoff, and Professor Aguzzi et al, for making these PRION 2015 Congressional Poster and Oral Abstracts available freely to the public. ...Terry S. Singeltary Sr.
P.108: Successful oral challenge of adult cattle with classical BSE
Sandor Dudas1,*, Kristina Santiago-Mateo1, Tammy Pickles1, Catherine Graham2, and Stefanie Czub1 1Canadian Food Inspection Agency; NCAD Lethbridge; Lethbridge, Alberta, Canada; 2Nova Scotia Department of Agriculture; Pathology Laboratory; Truro, Nova Scotia, Canada
Classical Bovine spongiform encephalopathy (C-type BSE) is a feed- and food-borne fatal neurological disease which can be orally transmitted to cattle and humans. Due to the presence of contaminated milk replacer, it is generally assumed that cattle become infected early in life as calves and then succumb to disease as adults. Here we challenged three 14 months old cattle per-orally with 100 grams of C-type BSE brain to investigate age-related susceptibility or resistance. During incubation, the animals were sampled monthly for blood and feces and subjected to standardized testing to identify changes related to neurological disease. At 53 months post exposure, progressive signs of central nervous system disease were observed in these 3 animals, and they were euthanized. Two of the C-BSE animals tested strongly positive using standard BSE rapid tests, however in 1 C-type challenged animal, Prion 2015 Poster Abstracts S67 PrPsc was not detected using rapid tests for BSE. Subsequent testing resulted in the detection of pathologic lesion in unusual brain location and PrPsc detection by PMCA only.
***Our study demonstrates susceptibility of adult cattle to oral transmission of classical BSE.
We are further examining explanations for the unusual disease presentation in the third challenged animal.
***our findings suggest that possible transmission risk of H-type BSE to sheep and human. Bioassay will be required to determine whether the PMCA products are infectious to these animals.
P.86: Estimating the risk of transmission of BSE and scrapie to ruminants and humans by protein misfolding cyclic amplification
Morikazu Imamura, Naoko Tabeta, Yoshifumi Iwamaru, and Yuichi Murayama National Institute of Animal Health; Tsukuba, Japan
To assess the risk of the transmission of ruminant prions to ruminants and humans at the molecular level, we investigated the ability of abnormal prion protein (PrPSc) of typical and atypical BSEs (L-type and H-type) and typical scrapie to convert normal prion protein (PrPC) from bovine, ovine, and human to proteinase K-resistant PrPSc-like form (PrPres) using serial protein misfolding cyclic amplifi- cation (PMCA).
Six rounds of serial PMCA was performed using 10% brain homogenates from transgenic mice expressing bovine, ovine or human PrPC in combination with PrPSc seed from typical and atypical BSE- or typical scrapie-infected brain homogenates from native host species. In the conventional PMCA, the conversion of PrPC to PrPres was observed only when the species of PrPC source and PrPSc seed matched. However, in the PMCA with supplements (digitonin, synthetic polyA and heparin), both bovine and ovine PrPC were converted by PrPSc from all tested prion strains. On the other hand, human PrPC was converted by PrPSc from typical and H-type BSE in this PMCA condition.
Although these results were not compatible with the previous reports describing the lack of transmissibility of H-type BSE to ovine and human transgenic mice, our findings suggest that possible transmission risk of H-type BSE to sheep and human. Bioassay will be required to determine whether the PMCA products are infectious to these animals.
P.170: Potential detection of oral transmission of H type atypical BSE in cattle using in vitro conversion
***This may be evidence of the first successful oral transmission of H type atypical BSE in cattle and additional investigation of samples from these animals are ongoing.
***P.170: Potential detection of oral transmission of H type atypical BSE in cattle using in vitro conversion
Sandor Dudas, John G Gray, Renee Clark, and Stefanie Czub Canadian Food Inspection Agency; Lethbridge, AB Canada
Keywords: Atypical BSE, oral transmission, RT-QuIC
The detection of bovine spongiform encephalopathy (BSE) has had a significant negative impact on the cattle industry worldwide. In response, governments took actions to prevent transmission and additional threats to animal health and food safety. While these measures seem to be effective for controlling classical BSE, the more recently discovered atypical BSE has presented a new challenge. To generate data for risk assessment and control measures, we have challenged cattle orally with atypical BSE to determine transmissibility and mis-folded prion (PrPSc) tissue distribution. Upon presentation of clinical symptoms, animals were euthanized and tested for characteristic histopathological changes as well as PrPSc deposition.
The H-type challenged animal displayed vacuolation exclusively in rostral brain areas but the L-type challenged animal showed no evidence thereof. To our surprise, neither of the animals euthanized, which were displaying clinical signs indicative of BSE, showed conclusive mis-folded prion accumulation in the brain or gut using standard molecular or immunohistochemical assays. To confirm presence or absence of prion infectivity, we employed an optimized real-time quaking induced conversion (RT-QuIC) assay developed at the Rocky Mountain Laboratory, Hamilton, USA.
Detection of PrPSc was unsuccessful for brain samples tests from the orally inoculated L type animal using the RT-QuIC. It is possible that these negative results were related to the tissue sampling locations or that type specific optimization is needed to detect PrPSc in this animal. We were however able to consistently detect the presence of mis-folded prions in the brain of the H-type inoculated animal. Considering the negative and inconclusive results with other PrPSc detection methods, positive results using the optimized RT-QuIC suggests the method is extremely sensitive for H-type BSE detection.
***This may be evidence of the first successful oral transmission of H type atypical BSE in cattle and additional investigation of samples from these animals are ongoing.
MONDAY, JUNE 23, 2014 PRION 2014 TYPICAL AND ATYPICAL BSE AND CJD REPORT UPDATES
***P.170: Potential detection of oral transmission of H type atypical BSE in cattle using in vitro conversion
Sandor Dudas, John G Gray, Renee Clark, and Stefanie Czub Canadian Food Inspection Agency; Lethbridge, AB Canada
*** This may be evidence of the first successful oral transmission of H type atypical BSE in cattle and additional investigation of samples from these animals are ongoing.
Keywords: Atypical BSE, oral transmission, RT-QuIC
The detection of bovine spongiform encephalopathy (BSE) has had a significant negative impact on the cattle industry worldwide. In response, governments took actions to prevent transmission and additional threats to animal health and food safety. While these measures seem to be effective for controlling classical BSE, the more recently discovered atypical BSE has presented a new challenge. To generate data for risk assessment and control measures, we have challenged cattle orally with atypical BSE to determine transmissibility and mis-folded prion (PrPSc) tissue distribution. Upon presentation of clinical symptoms, animals were euthanized and tested for characteristic histopathological changes as well as PrPSc deposition.
The H-type challenged animal displayed vacuolation exclusively in rostral brain areas but the L-type challenged animal showed no evidence thereof. To our surprise, neither of the animals euthanized, which were displaying clinical signs indicative of BSE, showed conclusive mis-folded prion accumulation in the brain or gut using standard molecular or immunohistochemical assays. To confirm presence or absence of prion infectivity, we employed an optimized real-time quaking induced conversion (RT-QuIC) assay developed at the Rocky Mountain Laboratory, Hamilton, USA.
Detection of PrPSc was unsuccessful for brain samples tests from the orally inoculated L type animal using the RT-QuIC. It is possible that these negative results were related to the tissue sampling locations or that type specific optimization is needed to detect PrPSc in this animal. We were however able to consistently detect the presence of mis-folded prions in the brain of the H-type inoculated animal. Considering the negative and inconclusive results with other PrPSc detection methods, positive results using the optimized RT-QuIC suggests the method is extremely sensitive for H-type BSE detection. This may be evidence of the first successful oral transmission of H type atypical BSE in cattle and additional investigation of samples from these animals are ongoing.
*** This may be evidence of the first successful oral transmission of H type atypical BSE in cattle and additional investigation of samples from these animals are ongoing.
P.126: Successful transmission of chronic wasting disease (CWD) into mice over-expressing bovine prion protein (TgSB3985)
Larisa Cervenakova,1 Christina J Sigurdson,2 Pedro Piccardo,3 Oksana Yakovleva,1 Irina Vasilyeva,1 Jorge de Castro,1 Paula Saá,1 and Anton Cervenak1 1American Red Cross, Holland Laboratory; Rockville, MD USA; 2University of California; San Diego, CA USA; 3Lab TSE/OBRR /CBER/FDA; Rockville, MD USA
Keywords: chronic wasting disease, transmission, transgenic mouse, bovine prion protein
Background. CWD is a disease affecting wild and farmraised cervids in North America. Epidemiological studies provide no evidence of CWD transmission to humans. Multiple attempts have failed to infect transgenic mice expressing human PRNP gene with CWD. The extremely low efficiency of PrPCWD to convert normal human PrPC in vitro provides additional evidence that transmission of CWD to humans cannot be easily achieved. However, a concern about the risk of CWD transmission to humans still exists. This study aimed to establish and characterize an experimental model of CWD in TgSB3985 mice with the following attempt of transmission to TgHu mice.
Materials and Methods. TgSB3985 mice and wild-type FVB/ NCrl mice were intracranially injected with 1% brain homogenate from a CWD-infected Tga20 mouse (CWD/Tga20). TgSB3985 and TgRM (over-expressing human PrP) were similarly injected with 5% brain homogenates from CWD-infected white-tailed deer (CWD/WTD) or elk (CWD/Elk). Animals were observed for clinical signs of neurological disease and were euthanized when moribund. Brains and spleens were removed from all mice for PrPCWD detection by Western blotting (WB). A histological analysis of brains from selected animals was performed: brains were scored for the severity of spongiform change, astrogliosis, and PrPCWD deposition in ten brain regions.
Results. Clinical presentation was consistent with TSE. More than 90% of TgSB3985 and wild-type mice infected with CWD/Tga20, tested positive for PrPres in the brain but only mice in the latter group carried PrPCWD in their spleens. We found evidence for co-existence or divergence of two CWD/ Tga20 strains based on biochemical and histological profiles. In TgSB3985 mice infected with CWD-elk or CWD-WTD, no animals tested positive for PrPCWD in the brain or in the spleen by WB. However, on neuropathological examination we found presence of amyloid plaques that stained positive for PrPCWD in three CWD/WTD- and two CWD/Elk-infected TgSB3985 mice. The neuropathologic profiles in CWD/WTD- and CWD/Elkinfected mice were similar but unique as compared to profiles of BSE, BSE-H or CWD/Tg20 agents propagated in TgSB3985 mice. None of CWD-infected TgRM mice tested positive for PrPCWD by WB or by immunohistochemical detection.
Conclusions. To our knowledge, this is the first established experimental model of CWD in TgSB3985. We found evidence for co-existence or divergence of two CWD strains adapted to Tga20 mice and their replication in TgSB3985 mice. Finally, we observed phenotypic differences between cervid-derived CWD and CWD/Tg20 strains upon propagation in TgSB3985 mice. Further studies are underway to characterize these strains.
P.169: PrPSc distribution in brain areas of a natural German H-type BSE case
Anne Balkema-Buschmann, Grit Priemer, Markus Keller, and Martin H Groschup Friedrich Loeffler Institut, Institute for Novel and Emerging Infectious Diseases; Greifswald, Insel Riems, Germany
Keywords: BSE H-type, brain, muscle
Ten years after the initial description of atypical BSE cases of the H-type and L-type, the distribution of PrPSc in different brain areas and peripheral tissues of natural cases of these BSE forms is still not fully understood. Intracerebral challenge experiments have been performed with both atypical BSE forms in cattle, and the distribution of the abnormal prion protein and infectivity has been analysed in a variety of tissues, confirming the general restriction to the central nervous system as it was already generally acknowledged for classical BSE, but showing a slightly earlier and stronger involvement of the peripheral nervous system and the skeletal muscle.
www.landesbioscience.com Prion 105
However, data from cattle orally challenged with atypical BSE, which might mimic the natural situation, are not yet available. Unfortunately, for most natural cases of atypical BSE, only the obex region is available for further analysis. The PrPSc distribution in the brains of natural L-type BSE cases in Italy has been described in some detail, but comparably few such data are yet available for natural H-type cases. Here we describe the analysis of different brain areas and muscle samples of a natural H-type BSE case diagnosed in Germany in 2014, and compare these data with those obtained from the respective samples collected from cattle challenged intracerebrally with H-type BSE.
P.159: Transgenic mice overexpressing rabbit prion protein are susceptible to BSE, BASE and scrapie prion strains but resistant to CWD and atypical scrapie
Natalia Fernández-Borges,1 Enric Vidal,2 Belén Pintado,4 Hasier Eraña,1 Montserrat Ordóñez,3 Mercedes Márquez,5 Francesca Chianini,6 Dolors Fondevila,5 Manuel A Sánchez-Martín,7 Olivier Andréoletti,8 Mark P Dagleish,6 Martí Pumarola,5 and Joaquín Castilla1,3 1CIC bioGUNE; Parque tecnológico de Bizkaia; Derio; Bizkaia, Spain; 2Centre de Recerca en Sanitat Animal (CReSA); UAB-IR TA, Campus de la Universitat Autònoma de Barcelona; Bellaterra; Barcelona, Catalonia, Spain; 3IKERBASQUE; Basque Foundation for Science; Bilbao, Bizkaia, Spain; 4Centro Nacional de Biotecnología (CNB), Campus de Cantoblanco; Cantoblanco; Madrid, Spain; 5Department of Animal Medicine and Surgery; Veterinary faculty; Universitat Autònoma de Barcelona (UAB); Bellaterra (Cerdanyola del Vallès); Barcelona, Catalonia, Spain; 6Moredun Research Institute; Bush Loan, Penicuik, Scotland, UK; 7Unidad de Generación de OMGs. S.E.A. Department of Medicine; University of Salamanca; Salamanca, Spain; 8Ecole Nationale du Veterinaire; Service de Pathologie du Bétail; Toulouse, France
Interspecies transmission of prions is a well established phenomenon, both experimentally and in field conditions. Upon passage through new hosts prion strains have proven their capacity to change their properties. It is, in fact, a source of strain diversity which needs to be considered when assessing the potential risks associated with consumption of prion contaminated protein sources.
Rabbits were considered for decades a prion resistant species until proven recently otherwise. To determine the extent of rabbit susceptibility to prions and to assess their effects on the passage of different prion strains through this species, a transgenic mouse model overexpressing rabbit PrPC was developed (TgRab). Intracerebral challenges with prion strains originating from a variety of species including field isolates (SSBP1 scrapie, Nor98-like scrapie, BSE, BASE and CWD), experimental murine strains (ME7 and RML), experimentally obtained strains (sheepBSE) and strains obtained by in vitro crossing of the species barrier using saPMCA (BSE-RabPrPres, SSBP1-RabPrPres and CWD-RabPrPres) have been performed.
Interestingly, on first passage, TgRab were susceptible to the majority of prions tested with the exception of SSBP1 scrapie, CWD and Nor98 scrapie. Furthermore TgRab were capable of propagating strain-specific features such as differences in incubation periods, brain lesion and PrPd deposition profiles and PK resistant western blotting band patterns.
***Our results confirm previous studies shattering the myth that rabbits are resistant to prion infection and this should be taken into account when choosing protein sources to feed rabbits.
P.168: Evolution of the biological properties of L-BSE after passage in sheep with susceptible and resistant PrP genotypes
Michele A Di Bari, Umberto Agrimi, Claudia D’Agostino, Geraldina Riccardi, Stefano Marcon, Elena Esposito, Paolo Frassanito, Flavio Torriani, Shimon Simson, and Romolo Nonno Istituto Superiore di Sanità (ISS) Department of Veterinary Public Health and Food Safety; Rome, Italy
Background. Cattle L-BSE was efficiently transmitted to sheep with susceptible (QQ171) and resistant (QR171) PrP genotypes. 1 Notably, the PrPSc signature of L-BSE was preserved in QQ171 sheep but not in QR171 sheep.2 Notwithstanding, bioassay in transgenic mice expressing bovine or ovine (ARQ) PrPC showed that L-BSE strain was preserved in both, QQ171 and QR171 sheep-passaged L-BSE.3
Here we studied the biological properties of sheep-passaged L-BSE by bioassay in bank voles and transgenic mice expressing the ovine VRQ PrP (tg338), both characterized by a comparatively low susceptibility to cattle L-BSE.
Material and Methods. Voles and tg338 mice were intracerebrally inoculated with cattle L-BSE and sheep-passaged (QQ171 and QR171) L-BSE isolates. Survival time, lesion profiles, Pet-blot and WB analysis were used for strain typing. Results. Cattle L-BSE transmitted quite inefficiently to tg338 mice, with survival time >400 days post-infection (d.p.i.), while sheep-passaged inocula were much more efficient and all gave terminal disease by ~140 d.p.i. However, after sub-passage all inocula converged to a survival time of ~145 d.p.i.. and showed overlapping pathological phenotypes.
In voles, cattle L-BSE transmitted with very long survival times (~800 d.p.i.) and was accompanied by an upward shift of the PrPSc type. Again, all sheep-passaged L-BSE isolates transmitted much more efficiently, with similar survival times of ~360 d.p.i.. Upon second passage, three different strains were isolated in vole, characterized by distinct pathological phenotypes. This divergence is epitomized by the different survival times of vole-adapted L-BSE strains, which were ~400 d.p.i. for cattle L-BSE, ~130 d.p.i. for QQ171-passaged L-BSE and ~225 d.p.i. for QR171-passaged L-BSE.
Conclusions. These findings, along with previously published data,3 show that the original L-BSE strain was recovered after passage in sheep when bioassay was performed in animal models expressing bovine or ovine PrPC. In contrast, strain changes were observed in both, QQ171- and QR171-passaged L-BSE by bioassay in vole, a species with divergent PrP sequence compared to ruminants. Importantly, QQ171- and QR171-passaged L-BSE were characterised by different PrPSc types and, accordingly, showed different biological properties when transmitted to voles, but not when transmitted to other animal models.
Overall, our work support the hypothesis that prion isolates are likely composed of multiple prion components, emphasizes the role of host PrP polymorphisms on strain selection and mutation,
***and highlights the risk for new potentially zoonotic strains that could emerge from prion evolution in animal reservoirs.
P.172: BSE exposure risk from bovine intestine and mesentery
Fulvio Barizzone,1 Herbert Budka,2 Christine Fast,3 John N Griffin,4 Giuseppe Ru,5 Pietro Stella1 and Olivier Andréoletti6 1European Food Safety Authority; Parma, Italy; 2Institute of Neuropathology; University Hospital Zurich; Zurich, Switzerland; 3Friedrich-Loeffler-Institut; Institute of Novel and Emerging Infectious Diseases; Isle of Riems, Germany; 4Department of Agriculture, Food and the Marine; Backweston, Celbridge, Co. Kildare, Ireland; 5Istituto Zooprofilattico Sperimentale del Piemonte; Liguria e Valle d’Aosta; Biostatistics Epidemiology and Analysis of Risk (BEAR) unit; Turin, Italy; 6UMR Interactions Hôtes Agents Pathogènes; Ecole Nationale Vétérinaire INR A; ENVT; Toulouse, France
Keywords: Bovine Spongiform Encephalopathy (BSE), cattle, intestine, mesentery, specified risk material (SRM), quantitative risk assessment (QRA)
Bovine intestines and mesenteries in the European Union (EU) are considered among the tissues potentially containing the highest level of BSE infectivity and have to be removed from the food and feed chain. A quantitative assessment of the BSE infectious load potentially entering the food and feed chain yearly in the European Union (EU) was developed. The evolution of the BSE infectious titre and of the weight of the structures accumulating infectivity was considered. The number of BSE infected cattle entering undetected in the food and feed chain yearly was estimated. A model (TSEi) was developed to estimates the evolution of the BSE infectious load in animals and the total yearly infectious load that could enter the food and feed chain. In a BSE infected bovine, the distribution of infectivity in intestines and mesentery varies with the age. Up to 36 months of age the infectivity is mainly associated (on average more than 90%) with the last 4 metres of small intestine and the caecum, over 36 and under 60 months of age, there is an inter-individual variability, from 60 months of age the infectivity is mainly associated (on average more than 90%) with the mesenteric nerves and the celiac and mesenteric ganglion complex. The total amount of infectivity peaks, about 15 BoID50, in animals younger than 18 months, it declines to 8-9 BoID50 (24–48 months of age) and it drops to 0.7 BoID50 in animals older than 60 months. The ileocaecal plate is the most infectious part of the intestine and it can be used to estimate the potential maximum level of exposure for an individual consumer.
In the EU, between 2007 and 2012, the yearly amount of BSE infectivity associated with intestine and mesentery from animals entering the food and feed chain was reduced by a factor of 10 (from about 23,000 to about 2,000 BoID50).
However, the maximum level of exposure to the BSE agent from intestine remained stable (on average about 1.5-1.6 BoID50 per meter).
In case of re-emergence of BSE in the EU there would be an increase of the potential maximum level of exposure to BSE from intestine. According to the TSEi model the removal of the last four metres of the small intestine and of the caecum from the food and feed chain would result in a major reduction of the BSE exposure risk associated with intestine and mesentery in cattle.
P.131: Transmission of sheep-bovine spongiform encephalopathy in pigs
Carlos Hedman,1 Belén Marín,1 Fabian Corbière,3 Hicham Filali,1 Francisco Vázquez, José Luis Pitarch,1 William Jirón,1 Rodrigo S Hernandez,1 Bernardino Moreno,1 Martí Pumarola,2 Olivier Andréoletti,3 Juan José Badiola,1 and Rosa Bolea1 1University of Zaragoza; Zaragoza, Spain; 2University of Barcelona; Barcelona, Spain; 3Institut National de la Recherche (INR A); Toulouse, France
Introduction. The transmissible spongiform encephalopathies (TSE) don´t occur in swine in natural conditions. However, the bovine spongiform encephalopathy (BSE) agent, inoculated by 3 simultaneous routes in pigs, is able to reproduce a neurological disease in these animals. On the other hand, the BSE agent after passage in sheep under experimental conditions (sheep- BSE) exhibits altered pathobiologic properties. This new agent is able to cross the cattle-pig transmission barrier more efficiently than BSE. The potential propagation of TSE in animals from the human food chain, including pigs, needs to be assessed regarding the risk for human infection by animals other than TSE-infected ruminants. The aim of this work was to determine the susceptibility of pigs to the Sheep-BSE agent and describe the pathological findings and PrPSc deposition in different tissues.
Material and Methods. Seven minipigs were challenged intracerebrally with sheep-BSE agent. Clinical observation and postmortem histopathology, immunohistochemistry (antibody 2G11) and Western blotting were performed on central nervous system (CNS), peripheral nervous system (PNS) and other tissues.
*** Results. One pig was culled in an early incubation stage, and remaining six were culled at the presence of clinical sings.
***Pigs developed a clinical disease with locomotor disorders in an average time of 23 months post inoculation, showing clinical findings in most of them earlier than those described in the BSE in pigs experimental infection.
***TSE wasn´t confirmed in the preclinical pig.
***In clinical pigs, the entire cerebral cortex showed severe neuropil vacuolation, extensive and severe vacuolar changes affecting the thalamus, hippocampus and cerebellum.
***PrPSc was found in CNS of all clinical pigs (6/6). Intracellular (intraneuronal and intraglial) and neuropil-associated PrPSc deposition was consistently observed in the brainstem, thalamus, and deeper layers of the cerebral cortex.
***Also, PrPSc was observed in PNS, mainly in the myenteric plexus and also in nerves belonging to the skeleton muscle. Moreover, the glycosylation profile showed a 3 band pattern with a predominant monoglycosylated band in positive pig samples.
*** This features concern on the potential risk of utilization of meat and bound meal of small ruminants in feeding pigs.
P.177: Elements modulating the prion species barrier and its passage consequences
Juan-Carlos Espinosa,1 Patricia Aguilar-Calvo,1 Ana Villa-Diaz,1 Olivier Andréoletti,2 and Juan María Torres1 1Centro de Investigación en Sanidad Animal (CISA-INI A); Valdeolmos, Madrid, Spain; 2UMR INR A-ENVT 1225; Interactions Hôte Agent Pathogène; École Nationale Vétérinaire de Toulouse; Toulouse, France
The phenotypic features of Transmissible Spongiform Encephalopathy (TSE) strains may be modified during passage across a species barrier. In this study we investigated the biochemical and biological characteristics of Bovine Spongiform Encephalopathy (BSE) infectious agent after transmission in both natural host species (cattle, sheep, pigs, and mice) and in transgenic mice overexpressing the corresponding cellular prion protein (PrPC) in comparison with other non-BSE related prions from the same species. After these passages, most characteristics of the BSE agent remained unchanged. BSE-derived agents only showed slight modifications in the biochemical properties of the accumulated PrPSc, which were demonstrated to be reversible upon re-inoculation into transgenic mice expressing bovine-PrPC. Transmission experiments in transgenic mice expressing bovine, porcine or human-PrP revealed that all BSE-derived agents were transmitted with no or a weak transmission barrier. In contrast, a high species barrier was observed for the non-BSE related prions that harboured an identical PrP amino acid sequence such as sheep-scrapie, mouse RML or human sCJD isolates, supporting the theory that the prion transmission barrier is modulated by strain properties (presumably conformation-dependent) rather than by PrP amino acid sequence differences between host and donor.
As identical results were observed with prions propagated either in natural hosts or in transgenic mouse models, we postulate that the species barrier and its passage consequences are uniquely governed by the host PrPC sequence and not influenced by the PrPC expression level or genetic factors other than the PrPC amino acid sequence. All these findings unequivocally demonstrate that the species barrier and its passage consequences are uniquely driven by the PrPC sequence, and not by other host genetic factors, demonstrating the validity of transgenic PrP animals as models for studies of the species barrier.
*** The results presented herein reinforce the idea that the BSE agent is highly promiscuous, infecting other species, maintaining its properties in the new species, and even increasing its capabilities to jump to other species including humans. These data are essential for the development of an accurate risk assessment for BSE.
P.140: BSE monitoring in the Russian Federation in 2011-2013
Alexander Yegorov, Sergey Rybakov, Asya Borisova, and Andrey Pavlov FGBI Federal Centre for Animal Health; Vladimir, Russia
Keywords: BSE, monitoring, BSE risk status of the cattle population
Background. The goal of the study was to improve monitoring of bovine spongiform encephalopathy (BSE) in the Russian Federation (RF) aimed at the solution of the main tasks:
• confirmation of efficacy of imposed in 1989 restrictions on import of feeds, live cattle and beef from some countries, where the level of BSE spread was significant;
• confirmation of efficacy of the introduced in 1990 ban on feeding of ruminant protein to ruminants, as well as brought into force in 1996-2001 measures focused on the improvement of import control and feed production for ruminants.
The solution of these tasks is the area of responsibility of the Federal Service for Veterinary and Phytosanitary Surveillance (FSVPS).
Material and methods. BSE monitoring in 2011-2012 was carried out in 23 RF regions where more than a thousand of bovine animals from controlled BSE risk countries had been imported. In 2013 fifty six RF Subjects were involved in the implementation of the monitoring program; in those Subjects the adult cattle population amounted to 8.35 million or 94.6% of the whole adult cattle population in RF. Bio-Rad diagnostic kits and equipment were used for brain sample testing.
Results. Until 2011 the BSE monitoring was carried out only in several regions of the European part of RF by virtue of the fact that animals were imported into those regions from EU countries, USA and Canada as from 2004. About 8,600 cattle brain samples were tested for BSE in RF before 2011. Cattle brain samples at the rate of 5,258 and 2,598 were collected within monitoring program in 2011 and 2012, respectively. In 2013 11,687 cattle brain tissue samples were tested for BSE. The age of 90% of animals was 3–8 years.
Conclusion. As a result of conducted in 2011-2013 studies the disease agent was detected in none of 19.5 thousand tested samples. The obtained result shows that applied measures aimed at BSE control are effective. It is necessary to examine 3.33% of cattle adult population from all Subjects of RF in proportion to their quantity in order to prove with 95% confidence the absence of BSE in RF. The chief problems in the arrangement of such activities are associated with insufficient number of laboratories certified for carrying out BSE studies as well as need for collection and delivery of samples from huge territories of RF.
*** P.150: Zoonotic potential of L-type BSE prions: A new prion disease in humans? ***
Emilie Jaumain,1 Stéphane Haïk,2 Isabelle Quadrio,3 Laetitia Herzog,1 Fabienne Reine,1 Armand Perret-Liaudet,3 Human Rezaei,1 Hubert Laude,1 Jean-Luc Vilotte,4 and Vincent Béringue1 1INR A (Institut National de la Recherche Agronomique); UR892; Virologie Immunologie Moléculaires; Jouy-en-Josas, France; 2IN SERM; Equipe maladie d’Alzheimer et maladies à Prions; CRicm; UMRS 1127; CNR S; UPMC. R.; ICM, Hôpital de la Salpêtrière; Paris, France; 3Neurobiologie, CMRR , Gériatrie, Hospices Civils de Lyon, Université Lyon 1-CNR S UMR5292-IN SERM U1028; Lyon, France; 3INR A; UMR1313; Génétique Animale et Biologie Intégrative; Jouy-en-Josas, France
Two novel prion strains, referred to as BSE-L and BSE-H, have been recognized in bovines through active prion surveillance programs, both being distinct from the epizootic, ‘classical’, BSE strain (C-BSE). Both H and L-types have been detected worldwide as rare cases occurring in aged animals. Like C-BSE prions, H- and L-types prions can propagate with relative ease in foreign species or in transgenic mouse lines expressing heterologous PrP sequences. A prion exhibiting biological properties similar to C-BSE agent sometimes emerged from these cross-species transmissions. Previously, L-type prions were shown to transmit to transgenic mice expressing human PrP with methionine at codon 129 with higher efficacy than C-BSE prions. Here, we examined whether L-type prions propagate without any apparent transmission barrier in these mice and whether such ‘humanised’ L-type prions share biological properties with CJD prions. L-type prions and a panel of human CJD cases with various genotypes at codon 129 and electrophoretic PrPres signatures were serially transmitted by intracerebral route to human PrP mice. The biological phenotypes induced by these agents were compared by all the standard methods currently used to distinguish between prion strains. At each passage, L-type prions were also transmitted back to bovine PrP mice to assess whether the agent has evolved upon passaging on the human PrP sequence. L-type prions transmitted to human PrP mice at 100% attack rate, without notable alteration in the mean incubation times over 5 passages. At each passage, ‘humanized’ L-type prions were able to transmit back to bovine PrP transgenic mice without apparent transmission barrier, as based on the survival time and the restoration of a L-type BSE phenotype. Comparison of mean incubation times on primary and subsequent passages in human PrP mice showed no overlap between L-type and sporadic CJD agents.
*** While the electrophoretic signature and regional distribution of PrPres in L-type diseased mouse brains resembled that seen after transmission of MM2 CJD strain type, both agents exhibited distinct resistance of the associated PrPres molecules to protease denaturation.
***In summary, L-type prions can be passaged on the human PrP sequence without any obvious transmission barrier.
***The phenotype obtained differs from the classical CJD prion types known so far.
***Careful extrapolation would suggest that the zoonotic transmission of this agent could establish a new prion disease type in humans.
P02.35
Molecular Features of the Protease-resistant Prion Protein (PrPres) in H-type BSE
Biacabe, A-G1; Jacobs, JG2; Gavier-Widén, D3; Vulin, J1; Langeveld, JPM2; Baron, TGM1 1AFSSA, France; 2CIDC-Lelystad, Netherlands; 3SVA, Sweden
Western blot analyses of PrPres accumulating in the brain of BSE-infected cattle have demonstrated 3 different molecular phenotypes regarding to the apparent molecular masses and glycoform ratios of PrPres bands. We initially described isolates (H-type BSE) essentially characterized by higher PrPres molecular mass and decreased levels of the diglycosylated PrPres band, in contrast to the classical type of BSE. This type is also distinct from another BSE phenotype named L-type BSE, or also BASE (for Bovine Amyloid Spongiform Encephalopathy), mainly characterized by a low representation of the diglycosylated PrPres band as well as a lower PrPres molecular mass. Retrospective molecular studies in France of all available BSE cases older than 8 years old and of part of the other cases identified since the beginning of the exhaustive surveillance of the disease in 20001 allowed to identify 7 H-type BSE cases, among 594 BSE cases that could be classified as classical, L- or H-type BSE. By Western blot analysis of H-type PrPres, we described a remarkable specific feature with antibodies raised against the C-terminal region of PrP that demonstrated the existence of a more C-terminal cleaved form of PrPres (named PrPres#2 ), in addition to the usual PrPres form (PrPres #1). In the unglycosylated form, PrPres #2 migrates at about 14 kDa, compared to 20 kDa for PrPres #1. The proportion of the PrPres#2 in cattle seems to by higher compared to the PrPres#1. Furthermore another PK-resistant fragment at about 7 kDa was detected by some more N-terminal antibodies and presumed to be the result of cleavages of both N- and C-terminal parts of PrP. These singular features were maintained after transmission of the disease to C57Bl/6 mice.
***The identification of these two additional PrPres fragments (PrPres #2 and 7kDa band) reminds features reported respectively in sporadic Creutzfeldt-Jakob disease and in Gerstmann-Sträussler-Scheinker (GSS) syndrome in humans.
Discussion: The C, L and H type BSE cases in Canada exhibit molecular characteristics similar to those described for classical and atypical BSE cases from Europe and Japan.
*** This supports the theory that the importation of BSE contaminated feedstuff is the source of C-type BSE in Canada.
*** It also suggests a similar cause or source for atypical BSE in these countries. ***
P.9.21
Molecular characterization of BSE in Canada
Jianmin Yang 1 , Sandor Dudas 2 , Catherine Graham 2 , Markus Czub 3 , Tim McAllister 1 , Stefanie Czub 1 1 Agriculture and Agri-Food Canada Research Centre, Canada; 2 National and OIE BSE Reference Laboratory, Canada; 3 University of Calgary, Canada
Background: Three BSE types (classical and two atypical) have been identified on the basis of molecular characteristics of the misfolded protein associated with the disease. To date, each of these three types have been detected in Canadian cattle. Objectives: This study was conducted to further characterize the 16 Canadian BSE cases based on the biochemical properties of there associated PrPres.
Methods: Immuno-reactivity, molecular weight, glycoform profiles and relative proteinase K sensitivity of the PrPres from each of the 16 confirmed Canadian BSE cases was determined using modified Western blot analysis.
Results: Fourteen of the 16 Canadian BSE cases were C type, 1 was H type and 1 was L type. The Canadian H and L-type BSE cases exhibited size shifts and changes in glycosylation similar to other atypical BSE cases. PK digestion under mild and stringent conditions revealed a reduced protease resistance of the atypical cases compared to the C-type cases. N terminal-specific antibodies bound to PrPres from H type but not from C or L type. The C-terminal-specific antibodies resulted in a shift in the glycoform profile and detected a fourth band in the Canadian H-type BSE.
Discussion: The C, L and H type BSE cases in Canada exhibit molecular characteristics similar to those described for classical and atypical BSE cases from Europe and Japan. This supports the theory that the importation of BSE contaminated feedstuff is the source of C-type BSE in Canada. It also suggests a similar cause or source for atypical BSE in these countries.
see page 176 of 201 pages...tss
WEDNESDAY, MARCH 15, 2017
In vitro amplification of H-type atypical bovine spongiform encephalopathy by protein misfolding cyclic amplification
"When considering the atypical L-BSE and H-BSE diseases of cattle, they have been assessed in both non-human primate and transgenic mouse bioassays (with mice transgenic for human PRNP) and both model systems indicate that H-BSE and L-BSE may have increased zoonotic potential compare with C-BSE.
***The detection of all types of BSE is therefore of significant importance."
*** Singeltary reply ; Molecular, Biochemical and Genetic Characteristics of BSE in Canada Singeltary reply;
***however in 1 C-type challenged animal, Prion 2015 Poster Abstracts S67 PrPsc was not detected using rapid tests for BSE.
***Subsequent testing resulted in the detection of pathologic lesion in unusual brain location and PrPsc detection by PMCA only.
*** IBNC Tauopathy or TSE Prion disease, it appears, no one is sure ***
Posted by Terry S. Singeltary Sr. on 03 Jul 2015 at 16:53 GMT
O.05: Transmission of prions to primates after extended silent incubation periods: Implications for BSE and scrapie risk assessment in human populations
Emmanuel Comoy, Jacqueline Mikol, Valerie Durand, Sophie Luccantoni, Evelyne Correia, Nathalie Lescoutra, Capucine Dehen, and Jean-Philippe Deslys Atomic Energy Commission; Fontenay-aux-Roses, France
Prion diseases (PD) are the unique neurodegenerative proteinopathies reputed to be transmissible under field conditions since decades. The transmission of Bovine Spongiform Encephalopathy (BSE) to humans evidenced that an animal PD might be zoonotic under appropriate conditions. Contrarily, in the absence of obvious (epidemiological or experimental) elements supporting a transmission or genetic predispositions, PD, like the other proteinopathies, are reputed to occur spontaneously (atpical animal prion strains, sporadic CJD summing 80% of human prion cases). Non-human primate models provided the first evidences supporting the transmissibiity of human prion strains and the zoonotic potential of BSE. Among them, cynomolgus macaques brought major information for BSE risk assessment for human health (Chen, 2014), according to their phylogenetic proximity to humans and extended lifetime. We used this model to assess the zoonotic potential of other animal PD from bovine, ovine and cervid origins even after very long silent incubation periods.
*** We recently observed the direct transmission of a natural classical scrapie isolate to macaque after a 10-year silent incubation period,
***with features similar to some reported for human cases of sporadic CJD, albeit requiring fourfold long incubation than BSE. Scrapie, as recently evoked in humanized mice (Cassard, 2014),
***is the third potentially zoonotic PD (with BSE and L-type BSE),
***thus questioning the origin of human sporadic cases. We will present an updated panorama of our different transmission studies and discuss the implications of such extended incubation periods on risk assessment of animal PD for human health.
===============
***thus questioning the origin of human sporadic cases***
***our findings suggest that possible transmission risk of H-type BSE to sheep and human. Bioassay will be required to determine whether the PMCA products are infectious to these animals.
-------- Original Message --------
Subject: re-BSE prions propagate as either variant CJD-like or sporadic CJD
Date: Thu, 28 Nov 2002 10:23:43 -0000 From: "Asante, Emmanuel A" e.asante@ic.ac.uk
To: "'flounder@wt.net'" flounder@wt.net
Dear Terry,
I have been asked by Professor Collinge to respond to your request. I am a Senior Scientist in the MRC Prion Unit and the lead author on the paper. I have attached a pdf copy of the paper for your attention.
Thank you for your interest in the paper.
In respect of your first question, the simple answer is, ***yes.
As you will find in the paper, we have managed to associate the alternate phenotype to type 2 PrPSc, the commonest sporadic CJD.
It is too early to be able to claim any further sub-classification in respect of Heidenhain variant CJD or Vicky Rimmer's version.
It will take further studies, which are on-going, to establish if there are sub-types to our initial finding which we are now reporting.
The main point of the paper is that, as well as leading to the expected new variant CJD phenotype, BSE transmission to the 129-methionine genotype can lead to an alternate phenotype which is indistinguishable from type 2 PrPSc.
I hope reading the paper will enlighten you more on the subject. If I can be of any further assistance please to not hesitate to ask.
Best wishes. Emmanuel Asante <>
____________________________________
Dr. Emmanuel A Asante MRC Prion Unit & Neurogenetics Dept. Imperial College School of Medicine (St. Mary's) Norfolk Place, LONDON W2 1PG Tel: +44 (0)20 7594 3794 Fax: +44 (0)20 7706 3272 email: e.asante@ic.ac.uk (until 9/12/02) New e-mail: e.asante@prion.ucl.ac.uk (active from now)
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end...TSS
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Wednesday, July 15, 2015
Additional BSE TSE prion testing detects pathologic lesion in unusual brain location and PrPsc by PMCA only, how many cases have we missed?
Tuesday, September 06, 2016
A comparison of classical and H-type bovine spongiform encephalopathy associated with E211K prion protein polymorphism in wild type and EK211 cattle following intracranial inoculation
Saturday, July 23, 2016
BOVINE SPONGIFORM ENCEPHALOPATHY BSE TSE PRION SURVEILLANCE, TESTING, AND SRM REMOVAL UNITED STATE OF AMERICA UPDATE JULY 2016
Tuesday, July 26, 2016
Atypical Bovine Spongiform Encephalopathy BSE TSE Prion UPDATE JULY 2016
Monday, June 20, 2016
Specified Risk Materials SRMs BSE TSE Prion Program
*** Consumption of L-BSE–contaminated feed may pose a risk for oral transmission of the disease agent to cattle.
Emerg Infect Dis. 2017 Feb; 23(2): 284–287. doi: 10.3201/eid2302.161416 PMCID: PMC5324790
Oral Transmission of L-Type Bovine Spongiform Encephalopathy Agent among Cattle
Hiroyuki Okada,corresponding author Yoshifumi Iwamaru, Morikazu Imamura, Kohtaro Miyazawa, Yuichi Matsuura, Kentaro Masujin, Yuichi Murayama, and Takashi Yokoyama Author information ► Copyright and License information ► This article has been cited by other articles in PMC. Go to:
Abstract To determine oral transmissibility of the L-type bovine spongiform encephalopathy (BSE) prion, we orally inoculated 16 calves with brain homogenates of the agent. Only 1 animal, given a high dose, showed signs and died at 88 months. These results suggest low risk for oral transmission of the L-BSE agent among cattle.
Keywords: atypical bovine spongiform encephalopathy, cattle, L-type, prion, oral transmission, L-BSE, prions and related diseases, zoonoses The epidemic of bovine spongiform encephalopathy (BSE) in cattle is thought to be caused by oral infection through consumption of feed containing the BSE agent (prion). Since 2003, different neuropathologic and molecular phenotypes of BSE have been identified as causing ≈110 cases of atypical BSE worldwide, mainly in aged cattle. Although the etiology and pathogenesis of atypical BSE are not yet fully understood, atypical BSE prions possibly cause sporadic cases of BSE (1).
The L-type BSE (L-BSE) prion has been experimentally transmitted to cattle by intracerebral challenge, and the incubation period was is shorter than that for classical BSE (C-BSE) prions (2–6). The origin of transmissible mink encephalopathy in ranch-raised mink is thought to be caused by ingestion of L-BSE–infected material (7). Although L-BSE has been orally transmitted to mouse lemurs (8), it remains to be established whether L-BSE can be transmitted to cattle by oral infection. We therefore investigated the transmissibility of L-BSE by the oral route and tissue distribution of disease-associated prion protein (PrPSc) in cattle. All experiments involving animals were performed with the approval of the Animal Ethical Committee and the Animal Care and Use Committee of the National Institute of Animal Health (approval nos. 07–88 and 08–010).
Go to: The Study
snip....
Conclusions Our results suggest that the risk for oral transmission of L-BSE among cattle may be very low; after 88 months, the only case of transmission occurred in a cow that had been inoculated with a high dose of L-BSE–infected brain homogenate. The incubation period was much longer for cattle dosed orally with L-BSE–infected brain homogenate than for cattle dosed orally with C-BSE–infected tissue (34−74 mo for C-BSE) (10). This finding may suggest that the L-BSE prion requires much longer to propagate from the gut to the central nervous system. In addition, the lack of clinical signs, except for difficulty in rising, may present a genuine clinical picture of L-BSE under natural conditions (11). In most cases of naturally occurring atypical BSE identified so far, the animals were >8 years of age, except for 3 cases: 1 H-BSE and 1 L-BSE in Spain (1) and 1 H-BSE in Germany (12). Therefore, we cannot exclude the possibility that L-BSE developed sporadically/spontaneously. However, this case may not have naturally occurred, in view of the low prevalence of L-BSE in Japan during October 2001–August 2016, which was 0.065 cases/1 million tested adult animals. In our study, the remaining live animal, challenged with 50 g of L-BSE brain homogenate, will provide the further information about the oral transmissibility to cattle. Bioassays of brain samples in TgBoPrP mice are ongoing.
The neuroanatomical PrPSc distribution pattern of orally challenged cattle differed somewhat from that described in cattle naturally and intracerebrally challenged with L-BSE (2–6,11,13,14), The conspicuous differences between the case we report and cases of natural and experimental infection are 1) higher amounts of PrPSc in the caudal medulla oblongata and the spinal cord coupled with that in the thalamus and the more rostral brainstem and 2) relatively low amounts of PrPSc in the cerebral cortices and the olfactory bulb. Furthermore, fewer PrPSc deposits in the dorsal motor nucleus of the vagus nerve may indicate that the parasympathetic retrogressive neuroinvasion pathway does not contribute to transport of the L-BSE prion from the gut to the brain, which is in contrast to the vagus-associated transport of the agent in C-BSE (15). PrPSc accumulation in the extracerebral tissues may be a result of centrifugal trafficking of the L-BSE prion from the central nervous system along somatic or autonomic nerve fibers rather than centripetal propagation of the agent (4,6,9).
*** Consumption of L-BSE–contaminated feed may pose a risk for oral transmission of the disease agent to cattle.
MONDAY, JANUARY 09, 2017
Oral Transmission of L-Type Bovine Spongiform Encephalopathy Agent among Cattle CDC Volume 23, Number 2—February 2017
*** Consumption of L-BSE–contaminated feed may pose a risk for oral transmission of the disease agent to cattle.
Volume 23, Number 2—February 2017
Subject: Alabama atypical L-type BASE BSE TSE Prion animal feeds for ruminants rule, 21 CFR 589.200
Subject: Alabama atypical L-type BASE BSE TSE Prion
In conclusion, we propose that VPSPr is transmissible and, therefore, is an authentic prion disease. However, transmissibility cannot be sustained through serial passages presumably because human PrPC (or the mouse brain environment) cannot efficiently convert and propagate the VPSPr PrPSc species. If this is the case, uncovering the properties of human PrP that are required to replicate more efficiently the prion strains associated with VPSPr may help clarify the PrPSc mode of formation in this intriguing disease.
THURSDAY, JULY 20, 2017
USDA OIE Alabama Atypical L-type BASE Bovine Spongiform Encephalopathy BSE animal feeds for ruminants rule, 21 CFR 589.200
TUESDAY, JULY 18, 2017
USDA announces Alabama case of Bovine Spongiform Encephalopathy Alabama
CLINICAL SIGNS OF BOVINE SPONGIFORM ENCEPHALOPATHY IN CATTLE
February 2017 Page 25 EU TSE Reference Laboratory
Introduction
The agent causing BSE in cattle is believed to be a uniform strain based on neuropathological findings in brains of cattle with BSE 15;31;72 and transmission studies in mice 16;29. However, a new type of encephalopathy has first been described in Italy, which differed from BSE in its neuropathological and biochemical properties and was termed BASE (Bovine Amyloidotic Spongiform Encephalopathy) 17. Similar cases have since been detected in other countries and these “unusual” BSE cases have been re-classified as either H-type BSE or L-type BSE (including BASE) depending on the Western blot profile of digested brain material, which showed a protein band of the unglycosylated form of disease-associated PrP of either higher (H-type) or lower (L-type) molecular mass than samples from “classical” BSE 39. All cases have been detected in mainly aged cattle (8-15 years) by surveys of either apparently healthy slaughtered cattle or fallen stock. The following sections describe the clinical signs usually associated with BSE (now called C-type or classical BSE). Other prion diseases in cattle are described further below.
Herd and farm parameters
Clinical BSE is rare. In most cases, only a small proportion of the animals is affected at or near the same time.
Case history
Age, sex, breed and genotype
Most BSE cases have been diagnosed in 4 to 6 year-old cows but – following the meat and bone meal ban – confirmed cases have recently been considerably older (range 20 months – 22 years). Cases have been more frequent in dairy cattle, but this may reflect the differences in feeding practices and life span. The main risk factor for BSE is still believed to be the feeding of contaminated feedstuffs, even for cattle born after the reinforced meat and bone meal ban (BARB cases) in the UK 78. There does not appear to be any clear sex, breed or genotype predisposition that could be used as a clinical criterion despite studies that reported a higher incidence in cattle of certain genotypes 32;41 or breeds 68. A genetic basis for the occurrence of BARB cases in the UK was not found 67.
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Other prion diseases in cattle
Transmission studies of various TSE diseases have been conducted in cattle to inform on the disease phenotype generated by the infection. Although there is currently no evidence that these diseases occur naturally in cattle, it provides some information about the range of clinical signs that can be observed in prion diseases of cattle.
Chronic wasting disease in cattle
Intracerebral inoculation of brain suspension from mule deer naturally affected by chronic wasting disease (CWD) resulted in a disease with relatively unspecific clinical signs: weight loss, inappetence and altered behaviour (apprehension or lethargy, aimless circling) and later recumbency 34. Experimental second passage using brains from affected cattle from the first experiment resulted in similar clinical signs: inappetence, weight loss, dullness, teeth grinding and circling. Although generally unresponsive, cattle reacted to loud noises with exaggerated responses, which included collapsing. All affected animals later became recumbent 36. Similar signs (weight loss, poor appetite, circling and teeth grinding) were also described in cattle infected with elk-derived CWD 33. Further video clips that show the clinical presentation of atypical BSE in cattle can be found in the journals PLoS Pathogens and BMC Veterinary Research article 1 and article 2.
February 2017 Page 24 EU TSE Reference Laboratory
Transmissible mink encephalopathy in cattle
Three different inocula containing the transmissible mink encephalopathy agent (TME) agent (Hayward, Blackfoot, Stetsonville isolates) were used to challenge calves intracerebrally and produced a disease characterised by apprehension, inappetence, and decreased water consumption. The display of excitability, over-reactivity to auditory stimuli, teeth grinding and nystagmus was more variable. Hypermetria and hind limb ataxia developed in later stages, followed by recumbency. Although the course of the disease was similar for all three inocula, the rate of clinical deterioration appeared faster with the Blackfoot isolate 64. Another experimental study conducted in the USA several years later to compare first and second passage of TME in cattle by intracerebral inoculation produced a similar disease: hyperexcitability to unfamiliar objects was displayed to various degrees, sudden falling, low head carriage and aimless circling in the pen were also reported 35.
Classical scrapie in cattle
Cattle parenterally inoculated with the classical scrapie agent from sheep or goats (originating from a flock with endemic scrapie in the USA) developed locomotor abnormalities (stilted, stiff gait of the hind limbs, occasionally stumbling and falling and difficulty rising) and dullness with disorientation. Signs usually associated with BSE, such as apprehension or aggressiveness and exaggerated responses to external stimuli, were absent 19. Similar clinical signs were reported for another study in the USA where cattle were intracerebrally inoculated with a pool of brains from scrapie-affected sheep but most cattle also exhibited inappetence and weight loss 23. The clinical presentation did not change on second passage in cattle 22. Other authors reported signs similar to but more subtle than TME in cattle 64.
In the UK, two groups of 10 cattle were intracerebrally inoculated with two temporally separated sources of sheep classical scrapie, which produced again a disease that was mainly characterised by locomotor abnormalities (ataxia with difficulty rising) and dullness (lowered head, leaning against objects) without over-reactivity to external stimuli. Some cattle were also found lying on the side with their limbs paddling. However, two cattle developed a nervous form of the disease with BSE-like signs, such as nervousness and over-reactivity to external stimuli in addition to ataxia 45;46. Video clips that show both disease presentations are available from an article in BMC Research Notes.
February 2017 Page 25 EU TSE Reference Laboratory
These studies have shown that cattle can develop prion diseases other than BSE, which can be distinguished from BSE by its clinical, pathological and / or biochemical features.
THURSDAY, JULY 13, 2017
EFSA BSE Sixty cases of mad cow disease since 2001 breached feed ban likely the cause
Scientists investigate origin of isolated BSE cases
First evidence of intracranial and peroral transmission of Chronic Wasting Disease (CWD) into Cynomolgus macaques: a work in progress
Stefanie Czub1, Walter Schulz-Schaeffer2, Christiane Stahl-Hennig3, Michael Beekes4, Hermann Schaetzl5 and Dirk Motzkus6 1
University of Calgary Faculty of Veterinary Medicine/Canadian Food Inspection Agency; 2Universitatsklinikum des Saarlandes und Medizinische Fakultat der Universitat des Saarlandes; 3 Deutsches Primaten Zentrum/Goettingen; 4 Robert-Koch-Institut Berlin; 5 University of Calgary Faculty of Veterinary Medicine; 6 presently: Boehringer Ingelheim Veterinary Research Center; previously: Deutsches Primaten Zentrum/Goettingen
This is a progress report of a project which started in 2009. 21 cynomolgus macaques were challenged with characterized CWD material from white-tailed deer (WTD) or elk by intracerebral (ic), oral, and skin exposure routes. Additional blood transfusion experiments are supposed to assess the CWD contamination risk of human blood product. Challenge materials originated from symptomatic cervids for ic, skin scarification and partially per oral routes (WTD brain). Challenge material for feeding of muscle derived from preclinical WTD and from preclinical macaques for blood transfusion experiments. We have confirmed that the CWD challenge material contained at least two different CWD agents (brain material) as well as CWD prions in muscle-associated nerves.
Here we present first data on a group of animals either challenged ic with steel wires or per orally and sacrificed with incubation times ranging from 4.5 to 6.9 years at postmortem. Three animals displayed signs of mild clinical disease, including anxiety, apathy, ataxia and/or tremor. In four animals wasting was observed, two of those had confirmed diabetes. All animals have variable signs of prion neuropathology in spinal cords and brains and by supersensitive IHC, reaction was detected in spinal cord segments of all animals. Protein misfolding cyclic amplification (PMCA), real-time quaking-induced conversion (RT-QuiC) and PET-blot assays to further substantiate these findings are on the way, as well as bioassays in bank voles and transgenic mice.
At present, a total of 10 animals are sacrificed and read-outs are ongoing. Preclinical incubation of the remaining macaques covers a range from 6.4 to 7.10 years. Based on the species barrier and an incubation time of > 5 years for BSE in macaques and about 10 years for scrapie in macaques, we expected an onset of clinical disease beyond 6 years post inoculation.
PRION 2017 DECIPHERING NEURODEGENERATIVE DISORDERS
Subject: PRION 2017 CONFERENCE DECIPHERING NEURODEGENERATIVE DISORDERS VIDEO
PRION 2017 CONFERENCE DECIPHERING NEURODEGENERATIVE DISORDERS
PRION 2017 CONFERENCE VIDEO
Chronic Wasting Disease CWD TSE Prion to Humans, who makes that final call, when, or, has it already happened?
TUESDAY, JUNE 13, 2017
PRION 2017 CONFERENCE ABSTRACT First evidence of intracranial and peroral transmission of Chronic Wasting Disease (CWD) into Cynomolgus macaques: a work in progress
TUESDAY, JUNE 13, 2017
PRION 2017 CONFERENCE ABSTRACT Chronic Wasting Disease in European moose is associated with PrPSc features different from North American CWD
TUESDAY, JULY 04, 2017
*** PRION 2017 CONFERENCE ABSTRACTS ON CHRONIC WASTING DISEASE CWD TSE PRION ***
TUESDAY, JULY 18, 2017
MINK FARMING USA TRANSMISSIBLE MINK ENCEPHALOPATHY TSE PRION DISEASE SURVEILLANCE AND TESTING
WEDNESDAY, APRIL 05, 2017
Disease-associated prion protein detected in lymphoid tissues from pigs challenged with the agent of chronic wasting disease
***Moreover, sporadic disease has never been observed in breeding colonies or primate research laboratories, most notably among hundreds of animals over several decades of study at the National Institutes of Health25, and in nearly twenty older animals continuously housed in our own facility.***
MONDAY, JULY 17, 2017
National Scrapie Eradication Program May 2017 Monthly Report Fiscal Year 2017
VPSPr
Variably protease-sensitive prionopathy (VPSPr), a recently identified and seemingly sporadic human prion disease, is distinct from Creutzfeldt-Jakob disease (CJD) but shares features of Gerstmann-Sträussler-Scheinker disease (GSS). However, contrary to exclusively inherited GSS, no prion protein (PrP) gene variations have been detected in VPSPr, suggesting that VPSPr might be the long-sought sporadic form of GSS.
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In conclusion, we propose that VPSPr is transmissible and, therefore, is an authentic prion disease. However, transmissibility cannot be sustained through serial passages presumably because human PrPC (or the mouse brain environment) cannot efficiently convert and propagate the VPSPr PrPSc species. If this is the case, uncovering the properties of human PrP that are required to replicate more efficiently the prion strains associated with VPSPr may help clarify the PrPSc mode of formation in this intriguing disease.
Friday, January 10, 2014
vpspr, sgss, sffi, TSE, an iatrogenic by-product of gss, ffi, familial type prion disease, what it ???
THURSDAY, JULY 13, 2017
TEXAS CREUTZFELDT JAKOB DISEASE CJD TSE PRION
National Prion Center could lose all funding just as concern about CWD jumping to humans rises
SATURDAY, JULY 15, 2017
*** National Prion Center could lose all funding just as concern about CWD jumping to humans rises
SATURDAY, JULY 22, 2017
Why the U.S. Needs to Continue Prion Disease Surveillance, instead of reducing funding to zero
Terry S. Singeltary Sr.
posted by Terry S. Singeltary Sr. at
12:38 PM
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