Unique Properties of the Classical Bovine Spongiform Encephalopathy Strain and Its Emergence From H-Type Bovine Spongiform Encephalopathy Substantiated by VM Transmission Studies
Journal of Neuropathology & Experimental Neurology:
POST AUTHOR CORRECTIONS, 8 February 2013
doi: 10.1097/NEN.0b013e318285c7f9
Original Study: PDF Only
Unique Properties of the Classical Bovine Spongiform Encephalopathy Strain
and Its Emergence From H-Type Bovine Spongiform Encephalopathy Substantiated by
VM Transmission Studies
Bencsik, Anna PhD, HDR; Leboidre, Mikael; Debeer, Sabine PhD; Aufauvre,
Claire; Baron, Thierry DVM, PhD, HDR
Abstract
In addition to classical bovine spongiform encephalopathy (C-BSE), which is
recognized as being at the origin of the human variant form of Creutzfeldt-Jakob
disease, 2 rare phenotypes of BSE (H-type BSE [H-BSE] and L-type BSE [L-BSE])
were identified in 2004. H-type BSE and L-BSE are considered to be sporadic
forms of prion disease in cattle because they differ from C-BSE with respect to
incubation period, vacuolar pathology in the brain, and biochemical properties
of the protease-resistant prion protein (PrPres) in natural hosts and in some
mouse models that have been tested. Recently, we showed that H-BSE transmitted
to C57Bl/6 mice resulted in a dissociation of the phenotypic features, that is,
some mice showed an H-BSE phenotype, whereas others had a C-BSE phenotype. Here,
these 2 phenotypes were further studied in VM mice and compared with cattle
C-BSE, H-BSE, and L-BSE. Serial passages from the C-BSE-like phenotype on VM
mice retained similarities with C-BSE. Moreover, our results indicate that
strains 301V and 301C derived from C-BSE transmitted to VM and C57Bl/6 mice,
respectively, are fundamentally the same strain. These VM transmission studies
confirm the unique properties of the C-BSE strain and support the emergence of a
strain that resembles C-BSE from H-BSE.
(C) 2013 American Association of Neuropathologists, Inc
Research
Classical Bovine Spongiform Encephalopathy by Transmission of H-Type Prion
in Homologous Prion Protein Context
Juan-María Torres , Olivier Andréoletti, Caroline Lacroux, Irene Prieto,
Patricia Lorenzo, Magdalena Larska, Thierry Baron, and Juan-Carlos Espinosa
Author affiliations: Author affiliations: Centro de Investigación en Sanidad
Animal, Madrid, Spain (J.-M. Torres, I. Prieto, P. Lorenzo, M. Larska, J.-C.
Espinosa); Ecole Nationale Vétérinaire de Toulouse, Toulouse, France (O.
Andréoletti, C. Lacroux); Agence Francaise de Sécurité Sanitaire des Aliments,
Lyon, France (T. Baron) Abstract
Bovine spongiform encephalopathy (BSE) and BSE-related disorders have been
associated with a single major prion strain. Recently, 2 atypical, presumably
sporadic forms of BSE have been associated with 2 distinct prion strains that
are characterized mainly by distinct Western blot profiles of abnormal
protease-resistant prion protein (PrPres), named high-type (BSE-H) and low-type
(BSE-L), that also differed from classical BSE. We characterized 5 atypical
BSE-H isolates by analyzing their molecular and neuropathologic properties
during transmission in transgenic mice expressing homologous bovine prion
protein. Unexpectedly, in several inoculated animals, strain features emerged
that were highly similar to those of classical BSE agent. These findings
demonstrate the capability of an atypical bovine prion to acquire classical
BSE–like properties during propagation in a homologous bovine prion protein
context and support the view that the epidemic BSE agent could have originated
from such a cattle prion.
snip...
We show that the transmission of atypical BSE-H isolates in transgenic mice
expressing homologous bovine prion protein (PrP) led to emergence of a clearly
distinct prion with strain features similar to those of the BSE-C agent and that
such similarities were maintained on subsequent passages. These observations
provide new insights into the nature of the events that could have led to the
BSE epizootic.
snip...
Discussion We studied the behavior and stability of the atypical BSE-H
during propagation into a bovine PrP background, thus in the absence of a
species barrier. We used Tg110 mice (29,36) because they express a PrPC
homologous to that of the donors, thus providing a relevant context for
comparing atypical BSE-H and epizootic BSE-C isolates.
Our results showed that all BSE-H isolates induced a typical neurologic
disease on primary transmission, with a 100% attack rate and survival times
similar to those produced by several BSE-C isolates in this mouse line (29,36)
(Figure 1). The longer survival times for some mice infected with BSE-H isolates
could reflect a lower infectivity of this isolate consistent with the reduction
of survival time observed on subpassages, approaching that for BSE-C or BSE-H
isolates of presumably higher titer (i.e., producing no substantial reduction of
survival time on subpassage). These results are also consistent with another
comparative study of BSE-H and BSE-C transmissions in a different bovine PrP
mouse line (27). These data suggest that atypical BSE-H and BSE-C agents have
similar transmission features into Tg110 mice.
Although all BSE-H–inoculated mice showed homogeneous survival times, a
phenotypic divergence was observed in a few animals infected with 2 of the BSE-H
isolates. Surprisingly, these few mice showed phenotypic features clearly
distinct from those in most of the BSE-H–infected mice but similar to those of
BSE-C propagated onto the same mice, according to various criteria. First, a
PrPres profile indistinguishable from that produced by BSE-C agent in these mice
but clearly distinct from that of BSE-H in cattle, in terms of 1) apparent
molecular mass of PrPres, 2) PrPres glycosylation pattern, 3) immunoreactivity
with 12B2 mAb, and 4) pattern of labeling with Saf84 antibody. Second, the
vacuolation profile essentially overlapped that in mice infected with BSE-C,
with slight differences only in the mesencephalic tegmentum area. Third, the
spatial distribution of PrPres in the brain was clearly similar to that of mice
infected with BSE-C. Fourth, PrPSc was consistently detected in the spleen,
similar to mice infected with BSE-C. These similarities with BSE-C were fully
retained after a second passage by using brain homogenate from mice with C-like
features, whereas a BSE-H strain phenotype was maintained in mice inoculated
with mouse brains homogenates containing H-type PrPres.
However, C-like features emerged in only 2 of the 5 isolates tested.
Because only a low proportion of the mice inoculated with these 2 isolates
exhibited these novel features (3/12 and 2/10, respectively), the lack of such
observation in the other 3 isolates, and in 2 other independent studies of 3
BSE-H isolates in different bovine transgenic mouse lines (27), could be due to
the low number of inoculated mice (6 per isolate), which could be statistically
insufficient for such an event. No variability was ever observed in the PrPres
profiles of >100 Tg110 mice inoculated with 4 different BSE-C isolates
(29,36) (Figure 1). However, a divergent evolution of the BSE agent has been
reported after trans-species transmission in both wild-type (11) and human PrP
transgenic mice (12,39,40).
Although further studies are required to clarify the mechanisms associated
with the emergence of distinct phenotypes among individual mice, several factors
would be expected to influence the probability of detecting such a variant
through mouse bioassay. These factors are 1) amount or regions of cattle brain
tissue taken for inoculum preparation, 2) physicochemical treatment during
inoculum preparation (e.g., temperature, homogenization buffer), 3) the precise
site of mouse inoculation, 4) the infectious titer of the inoculum, and 5)
others unknown mouse factor affecting prion propagation and disease evolution.
Because samples used in this study were prepared from the same region
(brainstem) following the same precise protocol and under identical conditions,
differences in inoculum preparation and conditions are unlikely. However, the
possibility that the observations might be influenced by the precise
neuroanatomic origin of the inoculated bovine brainstem homogenate or by other
mouse bioassay–related factors cannot be excluded.
The possible cross-contamination of the BSE-H isolates material (02-2695
and 45 from 2 laboratories in different countries) by a BSE-C infectious source
was judged highly improbable for several reasons. These reasons are 1) the
strict biosafety procedures followed for sample collection, preparation of the
inocula, inoculation scheme, and care of mice; 2) the absence of C-type PrPSc in
the BSE-H inocula used for transmissions as deduced by Western blot analysis;
and 3) 2 independent transmission experiments, involving separate batches of
both incriminated isolates, all produced consistent results.
Together, these observations support 2 possible hypotheses. First, a minor
strain component might be present in BSE-H isolates that could emerge on
subsequent transmission in Tg110 mice. Second, a new strain component has been
generated during propagation of BSE-H agent in Tg110. In both instances,
emergence of the new strain, either in the original cattle or during propagation
in Tg110 mice, could be promoted by specific propagation conditions or by
physicochemical treatment of the inoculum. In this regard, acquisition of novel
properties by a sporadic cattle transmissible spongiform encephalopathy agent by
a physicochemical treatment, such as that applied to carcass-derived products,
has been invoked as a possible origin for the BSE epidemic (7).
Contrary to BSE-H, the atypical BSE-L agent retained unique and distinct
phenotypic features, compared with BSE-C agent, on transmission to both bovine
and human PrP transgenic mice (26–28). This agent, however, acquired phenotypic
traits intriguingly similar to those of the BSE agent during trans-species
transmission in either transgenic mice expressing ovine PrP (28) or inbred mouse
lines. On the basis of these observations, the BSE-C agent already has been
speculated to have originated from atypical BSE-L after conversion in an
intermediate host such as a sheep. However, the capacity of these BSE-L–derived
agents to retain BSE phenotypic traits after reinoculation to bovine PrP
transgenic mice is a key question, remaining to be demonstrated, to show whether
the observed convergence truly reflects a permanent strain shift of the BSE-L
agent rather than a phenotypic convergence in an experimental model.
In contrast, our results suggest that prion strain divergence might occur
on propagation of atypical BSE-H in a homologous bovine PrP context and that
this strain divergence could result from a permanent strain shift of the BSE-H
agent toward a C-like agent that is stable in subsequent passages. These
findings emphasize the potential capacity of prion diversification during
propagation, even in the absence of any species barrier, and represent an
experimental demonstration of the capability of an atypical, presumably
sporadic, bovine prion to acquire C-like properties during propagation in a
homologous bovine PrP context.
Results in transgenic mouse models cannot be directly extrapolated to the
natural host. However, our observations are consistent with the view that the
BSE agent could have originated from a cattle prion, such as BSE-H, and provide
new insights into the nature of the events that could have led to the appearance
of this agent.
Dr Torres is the lead researcher scientist of the Prions Group at the
Centro de Investigación en Sanidad Animal–Instituto Nacional de Investigación y
Tecnología Agraria y Alimentaria, Madrid, Spain. His research interests include
prion strain characterization and evolution and the pathogenesis of prion
diseases and their effects on human and animal health.
2. Demonstrated transmissibility of K211 BSE, a rare genetic form of bovine
spongiform encephalopathy (BSE), to cattle. Cattle containing the rare K211 PRNP
gene have been produced in-house and used in this study conducted by ARS
scientists at the National Animal Disease Center, Ames, IA. These animals have
been inoculated with both K211 BSE and classical BSE. The K211 BSE is
transmissible and progresses far more rapidly in K211 cattle than does classical
BSE. Because of their genetic susceptibility to BSE, K211 PRNP cattle have a
very rapid incubation time and may be more susceptible to TSEs, which are two
characteristics that make them highly desirable for future studies of antemortem
diagnostics and residual infectivity or risk materials after decontamination.
The possibility remains that K211 BSE transmitted to conventional cattle will
result in a disease phenotype similar to classical BSE. If this turns out to be
true, then it will be very important in that it suggests a very rare genetic
form of BSE could have been the original source of brain material responsible
for the U.K. BSE epidemic. Current human and animal feed bans regarding
specified risk materials from cattle protect humans and animals from a
recurrence of such an epidemic.
Atypical H-Type Bovine Spongiform Encephalopathy in a Cow Born after the
Reinforced Feed-Ban on Meat-and-Bone-Meal
Claudia Guldimann1, Michaela Gsponer1, Cord Drögemüller2, Anna Oevermann1
and Torsten Seuberlich1,*
+ Author Affiliations
1NeuroCentre, National and OIE Reference Laboratory for BSE and Scrapie
2Institute of Genetics, Vetsuisse Faculty, University of Berne, Berne,
Switzerland
ABSTRACT
The significance of atypical bovine spongiform encephalopathies (BSE) in
cattle for controlling the BSE epidemic is poorly understood. Here we report a
case of atypical H-type BSE born after the implementation of the reinforced
feed-ban in Europe. This supports an etiology of H-type BSE unrelated to that of
classical BSE.
FOOTNOTES ↵* Corresponding author. Mailing address: NeuroCentre, DCR-VPH,
Bremgartenstrasse 109a, CH-3001 Berne, Switzerland. Phone: 41 31 631 2206. Fax:
41 31 631 2538. E-mail: torsten.seuberlich@vetsuisse.unibe.ch Copyright © 2012,
American Society for Microbiology. All Rights Reserved.
snip...
In contrast, the animal described here was 6.5 years old, CNS specific
neurological signs were not observed, and spongiform lesions as well as PrPd
deposits in the brain were minimal. All this supports that it was in an early,
preclinical stage of the disease. In this regard it is important to point out
that these minimal lesions and PrPd deposits were found in the grey matter
structures of the obex region of the medulla oblongata, the midbrain and the
thalamus. These findings are essentially similar to those in preclinical C-type
BSE (1,12,13,22) and support that sampling of the obex region in surveillance
schemes implemented for C98 type BSE might be similarly suitable for detection
of naturally occurring H-type BSE.
The main disease-control measure of C-type BSE is the ban on mammalian MBM
in ruminant feed. This feed-ban was enforced in Switzerland and the European
Union in the early 1990s and considerably reduced the number of newly infected
cattle. However, the recycling of the C-type BSE agent in the cattle population
was not blocked until the MBM feed-ban was reinforced in 2001, now excluding the
use of animal proteins in feed of all farmed animals (10).
It remains unknown, whether H-type BSE similarly transmits orally in the
cattle population with MBM as a vehicle or not. If oral transmission occurs and
is the sole etiology, the reinforced MBM feed-ban should be an appropriate
measure to prevent the spread of H-type BSE also and no cases should be born
after its implementation, i.e., after 2001 in Switzerland and Germany.
To our knowledge, this is the first report of an H-type BSE affected animal
being born after the reinforced MBM feed-ban in the respective country.
Therefore, this case provides further evidence that the etiology of H-type BSE
may be unrelated to the ingestion of prion contaminated meat-and-bone meal.
Taken together, this supports the widely expressed postulate that H-type BSE
originates from a spontaneous misfolding of cellular PrP with a pathophysiology
similar to sporadic Creutzfeld-Jakob disease in humans (7,20).
Alternatively, other yet unknown routes of transmission or genetic
determinants must be considered. This said, H-type BSE might persist after
eradication of C-type BSE. What are the implications of this scenario? Studies
in mice provided experimental evidence that H-type BSE may shift its disease
phenotype to that of C-type BSE (3) upon transmission. It has therefore been
hypothesized that the C-type BSE epidemic originated from spontaneously
occurring H-type BSE cases. If this was the case there would be a constant risk
that C-type BSE re-emerges in the cattle population once the feed-ban is
discontinued. Consequently, some measures of disease control would need to be
maintained indefinitely. Since the standards for the determination of a
countries’ BSE risk status currently do not differentiate between BSE subtypes
(28), BSE risk assessments will certainly need to take such considerations into
account. This highlights the need for continuing research into the relationship
between classical and atypical BSE variants to provide the scientific basis for
future disease surveillance and control policies.
re-Atypical H-Type Bovine Spongiform Encephalopathy in a Cow Born after the
Reinforced Feed-Ban on Meat-and-Bone-Meal
please note, one decade (10 years), post USA mad cow partial and voluntary
mad cow feed ban of August 4, 1997, the USA was still feeding cows to cows, with
some 10,000,000 pounds of banned blood laced meat and bone meal fed out into
commerce in 2007. 2006 was a banner year for mad cow protein into commerce as
well.
please see banned mad cow feed in commerce USA 1997 to 2007 ;
2007
10,000,000+ LBS. of PROHIBITED BANNED MAD COW FEED I.E. BLOOD LACED MBM IN
COMMERCE USA 2007
Date: March 21, 2007 at 2:27 pm PST
RECALLS AND FIELD CORRECTIONS: VETERINARY MEDICINES -- CLASS II
PRODUCT
Bulk cattle feed made with recalled Darling's 85% Blood Meal, Flash Dried,
Recall # V-024-2007
CODE
Cattle feed delivered between 01/12/2007 and 01/26/2007
RECALLING FIRM/MANUFACTURER
Pfeiffer, Arno, Inc, Greenbush, WI. by conversation on February 5, 2007.
Firm initiated recall is ongoing.
REASON
Blood meal used to make cattle feed was recalled because it was cross-
contaminated with prohibited bovine meat and bone meal that had been
manufactured on common equipment and labeling did not bear cautionary BSE
statement.
VOLUME OF PRODUCT IN COMMERCE
42,090 lbs.
DISTRIBUTION
WI
___________________________________
PRODUCT
Custom dairy premix products:
MNM ALL PURPOSE Pellet, HILLSIDE/CDL Prot- Buffer Meal, LEE, M.-CLOSE UP PX
Pellet, HIGH DESERT/ GHC LACT Meal, TATARKA, M CUST PROT Meal, SUNRIDGE/CDL
PROTEIN Blend, LOURENZO, K PVM DAIRY Meal, DOUBLE B DAIRY/GHC LAC Mineral, WEST
PIONT/GHC CLOSEUP Mineral, WEST POINT/GHC LACT Meal, JENKS, J/COMPASS PROTEIN
Meal, COPPINI - 8# SPECIAL DAIRY Mix, GULICK, L-LACT Meal (Bulk), TRIPLE J -
PROTEIN/LACTATION, ROCK CREEK/GHC MILK Mineral, BETTENCOURT/GHC S.SIDE MK-MN,
BETTENCOURT #1/GHC MILK MINR, V&C DAIRY/GHC LACT Meal, VEENSTRA, F/GHC LACT
Meal, SMUTNY, A- BYPASS ML W/SMARTA, Recall # V-025-2007
CODE
The firm does not utilize a code - only shipping documentation with
commodity and weights identified.
RECALLING FIRM/MANUFACTURER
Rangen, Inc, Buhl, ID, by letters on February 13 and 14, 2007. Firm
initiated recall is complete.
REASON
Products manufactured from bulk feed containing blood meal that was cross
contaminated with prohibited meat and bone meal and the labeling did not bear
cautionary BSE statement.
VOLUME OF PRODUCT IN COMMERCE
9,997,976 lbs.
DISTRIBUTION
ID and NV
END OF ENFORCEMENT REPORT FOR MARCH 21, 2007
please see 2006 and more here ;
Saturday, August 4, 2012
Final Feed Investigation Summary - California BSE Case - July 2012
Wednesday, May 30, 2012
PO-028: Oral transmission of L-type bovine spongiform encephalopathy
(L-BSE) in primate model Microcebus murinus
Wednesday, May 2, 2012
ARS FLIP FLOPS ON SRM REMOVAL FOR ATYPICAL L-TYPE BASE BSE RISK HUMAN AND
ANIMAL HEALTH
Wednesday, July 28, 2010
re-Freedom of Information Act Project Number 3625-32000-086-05, Study of
Atypical BSE UPDATE July 28, 2010
Sent: Wednesday, July 28, 2010 11:42 AM
Subject: re-Freedom of Information Act Project Number 3625-32000-086-05,
Study of Atypical BSE UPDATE
Greetings again Ms Williams et al at FOIA USDA,
Thank You again for your kind reply on this important information. However,
I am concerned that you may not be aware of new transmission studies. You (USDA
et al) state Ma'am ;
================================================
The SCA with Italy was mainly to confirm our respective country’s
diagnostic tests would detect the various atypical BSE cases as seen in each
country), in the meantime, the Italians have published their transmissibility
and pathogenesis work on their BASE cases in the following article:
Lombardi G, Casalone C, A DA, Gelmetti D, Torcoli G, Barbieri I, Corona C,
Fasoli E, Farinazzo A, Fiorini M, Gelati M, Iulini B, Tagliavini F, Ferrari S,
Caramelli M, Monaco S, Capucci L, Zanusso G (2008) Intraspecies transmission of
BASE induces clinical dullness and amyotrophic changes. PLoS Pathog 4:e1000075
The above mentioned paper concludes, “In all experimentally infected
animals, no PrP**TSE was detected in peripheral tissues, including cervical and
mesenteric lymph nodes, spleen, thymus, liver, lung, peripheral nerves and
forelimb and limb muscles, either by standard Western blot analysis or following
phosphotungstic acid precipitation.“
It is not necessary to change SRM removal due to any different tissue
infectivity distribution between classical BSE and atypical BSE. At this time,
there is no scientific evidence to suggest a need for expanding the list of
tissues included in the Specified Risk Material (SRM) ban as a result of
published studies on atypical BSE.
snip...
Moreover, in the paper by Buschmann A, Groschup MH (2005,) Highly bovine
spongiform encephalopathy-sensitive transgenic mice confirm the essential
restriction of infectivity to the nervous system in clinically diseased cattle.
J Infect Dis 192:934-942; the authors, when speaking about the classical BSE
food-borne epidemic in Europe, concluded their “results provide further
indication that the pathogenesis of BSE in cattle is fundamentally different
from that in sheep and mice, due to an exclusive intraneuronal spread of
infectivity from the gut to the central nervous system.”
end...
================================================
Again, in my opinion, the USDA is cherry picking the science they want to
use, and in doing so, I believe they are putting human lives at risk.
I disagree for the following reasons. New studies indeed show that ;
July 10, 2010
see full text ;
Wednesday, July 28, 2010
re-Freedom of Information Act Project Number 3625-32000-086-05, Study of
Atypical BSE UPDATE July 28, 2010
USDA TRIPLE BSE MAD COW FIREWALL, SRM, FEED, AND SURVEILLANCE
2012
***Also, a link is suspected between atypical BSE and some apparently
sporadic cases of Creutzfeldt-Jakob disease in humans. These atypical BSE cases
constitute an unforeseen first threat that could sharply modify the European
approach to prion diseases.
Second threat
snip...
MAD COW USDA ATYPICAL L-TYPE BASE BSE, the rest of the story...
***Oral Transmission of L-type Bovine Spongiform Encephalopathy in Primate
Model
***Infectivity in skeletal muscle of BASE-infected cattle
***feedstuffs- It also suggests a similar cause or source for atypical BSE
in these countries.
***Also, a link is suspected between atypical BSE and some apparently
sporadic cases of Creutzfeldt-Jakob disease in humans.
The present study demonstrated successful intraspecies transmission of
H-type BSE to cattle and the distribution and immunolabeling patterns of PrPSc
in the brain of the H-type BSE-challenged cattle. TSE agent virulence can be
minimally defined by oral transmission of different TSE agents (C-type, L-type,
and H-type BSE agents) [59]. Oral transmission studies with H-type BSEinfected
cattle have been initiated and are underway to provide information regarding the
extent of similarity in the immunohistochemical and molecular features before
and after transmission.
In addition, the present data will support risk assessments in some
peripheral tissues derived from cattle affected with H-type BSE.
Friday, May 11, 2012
Experimental H-type bovine spongiform encephalopathy characterized by
plaques and glial- and stellate-type prion protein deposits
***support risk assessments in some peripheral tissues derived from cattle
affected with H-type BSE
Thursday, June 21, 2012
Clinical and Pathologic Features of H-Type Bovine Spongiform Encephalopathy
Associated with E211K Prion Protein Polymorphism
Justin J. Greenlee1*, Jodi D. Smith1, M. Heather West Greenlee2, Eric M.
Nicholson1
1 National Animal Disease Center, United States Department of Agriculture,
Agricultural Research Service, Ames, Iowa, United States of America, 2 Iowa
State University, Ames, Iowa, United States of America
Abstract
The majority of bovine spongiform encephalopathy (BSE) cases have been
ascribed to the classical form of the disease. Htype and L-type BSE cases have
atypical molecular profiles compared to classical BSE and are thought to arise
spontaneously. However, one case of H-type BSE was associated with a heritable
E211K mutation in the prion protein gene. The purpose of this study was to
describe transmission of this unique isolate of H-type BSE when inoculated into
a calf of the same genotype by the intracranial route. Electroretinograms were
used to demonstrate preclinical deficits in retinal function, and optical
coherence tomography was used to demonstrate an antemortem decrease in retinal
thickness. The calf rapidly progressed to clinical disease (9.4 months) and was
necropsied. Widespread distribution of abnormal prion protein was demonstrated
within neural tissues by western blot and immunohistochemistry. While this
isolate is categorized as BSE-H due to a higher molecular mass of the
unglycosylated PrPSc isoform, a strong labeling of all 3 PrPSc bands with
monoclonal antibodies 6H4 and P4, and a second unglycosylated band at
approximately 14 kDa when developed with antibodies that bind in the C-terminal
region, it is unique from other described cases of BSE-H because of an
additional band 23 kDa demonstrated on western blots of the cerebellum. This
work demonstrates that this isolate is transmissible, has a BSE-H phenotype when
transmitted to cattle with the K211 polymorphism, and has molecular features
that distinguish it from other cases of BSE-H described in the literature.
snip...
Most significantly it must be determined if the molecular phenotype of this
cattle TSE remains stable when transmitted to cattle without the E211K
polymorphism as several other isolates of atypical BSE have been shown to adopt
a molecular profile consistent with classical BSE after passage in transgenic
mice expressing bovine PrPC [40] or multiple passages in wild type mice [23].
Results of ongoing studies, namely passage of the E211K Htype isolate into
wild-type cattle, will lend further insight into what role, if any, genetic and
sporadic forms of BSE may have played in the origins of classical BSE. Atypical
cases presumably of spontaneous or, in the case of E211K BSE-H, genetic origins
highlight that it may not be possible to eradicate BSE entirely and that it
would be hazardous to remove disease control measures such as prohibiting the
feeding of meat and bone meal to ruminants.
P.4.23
Transmission of atypical BSE in humanized mouse models
Liuting Qing1, Wenquan Zou1, Cristina Casalone2, Martin Groschup3, Miroslaw
Polak4, Maria Caramelli2, Pierluigi Gambetti1, Juergen Richt5, Qingzhong Kong1
1Case Western Reserve University, USA; 2Instituto Zooprofilattico Sperimentale,
Italy; 3Friedrich-Loeffler-Institut, Germany; 4National Veterinary Research
Institute, Poland; 5Kansas State University (Previously at USDA National Animal
Disease Center), USA
Background: Classical BSE is a world-wide prion disease in cattle, and the
classical BSE strain (BSE-C) has led to over 200 cases of clinical human
infection (variant CJD). Atypical BSE cases have been discovered in three
continents since 2004; they include the L-type (also named BASE), the H-type,
and the first reported case of naturally occurring BSE with mutated bovine PRNP
(termed BSE-M). The public health risks posed by atypical BSE were largely
undefined.
Objectives: To investigate these atypical BSE types in terms of their
transmissibility and phenotypes in humanized mice. Methods: Transgenic mice
expressing human PrP were inoculated with several classical (C-type) and
atypical (L-, H-, or Mtype) BSE isolates, and the transmission rate, incubation
time, characteristics and distribution of PrPSc, symptoms, and histopathology
were or will be examined and compared.
Results: Sixty percent of BASE-inoculated humanized mice became infected
with minimal spongiosis and an average incubation time of 20-22 months, whereas
only one of the C-type BSE-inoculated mice developed prion disease after more
than 2 years. Protease-resistant PrPSc in BASE-infected humanized Tg mouse
brains was biochemically different from bovine BASE or sCJD. PrPSc was also
detected in the spleen of 22% of BASE-infected humanized mice, but not in those
infected with sCJD. Secondary transmission of BASE in the humanized mice led to
a small reduction in incubation time.*** The atypical BSE-H strain is also
transmissible with distinct phenotypes in the humanized mice, but no BSE-M
transmission has been observed so far.
Discussion: Our results demonstrate that BASE is more virulent than
classical BSE, has a lymphotropic phenotype, and displays a modest transmission
barrier in our humanized mice. BSE-H is also transmissible in our humanized Tg
mice. The possibility of more than two atypical BSE strains will be discussed.
Supported by NINDS NS052319, NIA AG14359, and NIH AI 77774.
P26 TRANSMISSION OF ATYPICAL BOVINE SPONGIFORM ENCEPHALOPATHY (BSE) IN
HUMANIZED MOUSE MODELS
Liuting Qing1, Fusong Chen1, Michael Payne1, Wenquan Zou1, Cristina
Casalone2, Martin Groschup3, Miroslaw Polak4, Maria Caramelli2, Pierluigi
Gambetti1, Juergen Richt5*, and Qingzhong Kong1 1Department of Pathology, Case
Western Reserve University, Cleveland, OH 44106, USA; 2CEA, Istituto
Zooprofilattico Sperimentale, Italy; 3Friedrich-Loeffler-Institut, Germany;
4National Veterinary Research Institute, Poland; 5Kansas State University,
Diagnostic Medicine/Pathobiology Department, Manhattan, KS 66506, USA. *Previous
address: USDA National Animal Disease Center, Ames, IA 50010, USA
Classical BSE is a world-wide prion disease in cattle, and the classical
BSE strain (BSE-C) has led to over 200 cases of clinical human infection
(variant CJD). Two atypical BSE strains, BSE-L (also named BASE) and BSE-H, have
been discovered in three continents since 2004. The first case of naturally
occurring BSE with mutated bovine PrP gene (termed BSE-M) was also found in 2006
in the USA. The transmissibility and phenotypes of these atypical BSE
strains/isolates in humans were unknown. We have inoculated humanized transgenic
mice with classical and atypical BSE strains (BSE-C, BSE-L, BSE-H) and the BSE-M
isolate. We have found that the atypical BSE-L strain is much more virulent than
the classical BSE-C.*** The atypical BSE-H strain is also transmissible in the
humanized transgenic mice with distinct phenotype, but no transmission has been
observed for the BSE-M isolate so far.
III International Symposium on THE NEW PRION BIOLOGY: BASIC SCIENCE,
DIAGNOSIS AND THERAPY 2 - 4 APRIL 2009, VENEZIA (ITALY)
I ask Professor Kong ;
Thursday, December 04, 2008 3:37 PM Subject: RE: re--Chronic Wating Disease
(CWD) and Bovine Spongiform Encephalopathies (BSE): Public Health Risk
Assessment
''IS the h-BSE more virulent than typical BSE as well, or the same as cBSE,
or less virulent than cBSE? just curious.....''
Professor Kong reply ;
.....snip
''As to the H-BSE, we do not have sufficient data to say one way or
another, but we have found that H-BSE can infect humans. I hope we could publish
these data once the study is complete. Thanks for your interest.''
Best regards,
Qingzhong Kong, PhD Associate Professor Department of Pathology Case
Western Reserve University Cleveland, OH 44106 USA
END...TSS
Thursday, December 04, 2008 2:37 PM
"we have found that H-BSE can infect humans."
personal communication with Professor Kong. ...TSS
BSE-H is also transmissible in our humanized Tg mice.
The possibility of more than two atypical BSE strains will be discussed.
Supported by NINDS NS052319, NIA AG14359, and NIH AI 77774.
let's take a closer look at this new prionpathy or prionopathy, and then
let's look at the g-h-BSEalabama mad cow.
This new prionopathy in humans? the genetic makeup is IDENTICAL to the
g-h-BSEalabama mad cow, the only _documented_ mad cow in the world to date like
this, ......wait, it get's better. this new prionpathy is killing young and old
humans, with LONG DURATION from onset of symptoms to death, and the symptoms are
very similar to nvCJD victims, OH, and the plaques are very similar in some
cases too, bbbut, it's not related to the g-h-BSEalabama cow, WAIT NOW, it gets
even better, the new human prionpathy that they claim is a genetic TSE, has no
relation to any gene mutation in that family. daaa, ya think it could be related
to that mad cow with the same genetic make-up ??? there were literally tons and
tons of banned mad cow protein in Alabama in commerce, and none of it
transmitted to cows, and the cows to humans there from ??? r i g h t $$$
ALABAMA MAD COW g-h-BSEalabama
In this study, we identified a novel mutation in the bovine prion protein
gene (Prnp), called E211K, of a confirmed BSE positive cow from Alabama, United
States of America. This mutation is identical to the E200K pathogenic mutation
found in humans with a genetic form of CJD. This finding represents the first
report of a confirmed case of BSE with a potential pathogenic mutation within
the bovine Prnp gene. We hypothesize that the bovine Prnp E211K mutation most
likely has caused BSE in "the approximately 10-year-old cow" carrying the E221K
mutation.
her healthy calf also carried the mutation (J. A. Richt and S. M. Hall PLoS
Pathog. 4, e1000156; 2008).
This raises the possibility that the disease could occasionally be genetic
in origin. Indeed, the report of the UK BSE Inquiry in 2000 suggested that the
UK epidemic had most likely originated from such a mutation and argued against
the scrapierelated assumption. Such rare potential pathogenic PRNP mutations
could occur in countries at present considered to be free of BSE, such as
Australia and New Zealand. So it is important to maintain strict surveillance
for BSE in cattle, with rigorous enforcement of the ruminant feed ban (many
countries still feed ruminant proteins to pigs). Removal of specified risk
material, such as brain and spinal cord, from cattle at slaughter prevents
infected material from entering the human food chain. Routine genetic screening
of cattle for PRNP mutations, which is now available, could provide additional
data on the risk to the public. Because the point mutation identified in the
Alabama animals is identical to that responsible for the commonest type of
familial (genetic) CJD in humans, it is possible that the resulting infective
prion protein might cross the bovine–human species barrier more easily. Patients
with vCJD continue to be identified. The fact that this is happening less often
should not lead to relaxation of the controls necessary to prevent future
outbreaks.
Malcolm A. Ferguson-Smith Cambridge University Department of Veterinary
Medicine, Madingley Road, Cambridge CB3 0ES, UK e-mail: maf12@cam.ac.uk Jürgen
A. Richt College of Veterinary Medicine, Kansas State University, K224B Mosier
Hall, Manhattan, Kansas 66506-5601, USA
NATURE|Vol 457|26 February 2009
Saturday, August 14, 2010
BSE Case Associated with Prion Protein Gene Mutation (g-h-BSEalabama) and
VPSPr PRIONPATHY
(see mad cow feed in COMMERCE IN ALABAMA...TSS)
P.9.21
Molecular characterization of BSE in Canada
Jianmin Yang1, Sandor Dudas2, Catherine Graham2, Markus Czub3, Tim
McAllister1, Stefanie Czub1 1Agriculture and Agri-Food Canada Research Centre,
Canada; 2National and OIE BSE Reference Laboratory, Canada; 3University 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.
Saturday, May 26, 2012
Are USDA assurances on mad cow case 'gross oversimplification'?
SNIP...
What irks many scientists is the USDA’s April 25 statement that the rare
disease is “not generally associated with an animal consuming infected feed.”
The USDA’s conclusion is a “gross oversimplification,” said Dr. Paul Brown,
one of the world’s experts on this type of disease who retired recently from the
National Institutes of Health. "(The agency) has no foundation on which to base
that statement.”
“We can’t say it’s not feed related,” agreed Dr. Linda Detwiler, an
official with the USDA during the Clinton Administration now at Mississippi
State.
In the May 1 email to me, USDA’s Cole backed off a bit. “No one knows the
origins of atypical cases of BSE,” she said
The argument about feed is critical because if feed is the cause, not a
spontaneous mutation, the California cow could be part of a larger outbreak.
SNIP...
2009 UPDATE ON ALABAMA AND TEXAS MAD COWS 2005 and 2006
in the url that follows, I have posted
SRM breaches first, as late as 2011.
then
MAD COW FEED BAN BREACHES AND TONNAGES OF MAD COW FEED IN COMMERCE up until
2007, when they ceased posting them.
then,
MAD COW SURVEILLANCE BREACHES.
Friday, May 18, 2012
Update from APHIS Regarding a Detection of Bovine Spongiform Encephalopathy
(BSE) in the United States Friday May 18, 2012
Wednesday, March 28, 2012
VARIABLY PROTEASE-SENSITVE PRIONOPATHY IS TRANSMISSIBLE, price of prion
poker goes up again $
OR-10 15:25 - 15:40 VARIABLY PROTEASE-SENSITIVE PRIONOPATHY IS
TRANSMISSIBLE IN BANK VOLES Nonno
OR-10: Variably protease-sensitive prionopathy is transmissible in bank
voles
Romolo Nonno,1 Michele Di Bari,1 Laura Pirisinu,1 Claudia D’Agostino,1
Stefano Marcon,1 Geraldina Riccardi,1 Gabriele Vaccari,1 Piero Parchi,2 Wenquan
Zou,3 Pierluigi Gambetti,3 Umberto Agrimi1
1Istituto Superiore di Sanità; Rome, Italy; 2Dipartimento di Scienze
Neurologiche, Università di Bologna; Bologna, Italy; 3Case Western Reserve
University; Cleveland, OH USA
Background. Variably protease-sensitive prionopathy (VPSPr) is a recently
described “sporadic”neurodegenerative disease involving prion protein
aggregation, which has clinical similarities with non-Alzheimer dementias, such
as fronto-temporal dementia. Currently, 30 cases of VPSPr have been reported in
Europe and USA, of which 19 cases were homozygous for valine at codon 129 of the
prion protein (VV), 8 were MV and 3 were MM. A distinctive feature of VPSPr is
the electrophoretic pattern of PrPSc after digestion with proteinase K (PK).
After PK-treatment, PrP from VPSPr forms a ladder-like electrophoretic pattern
similar to that described in GSS cases. The clinical and pathological features
of VPSPr raised the question of the correct classification of VPSPr among prion
diseases or other forms of neurodegenerative disorders. Here we report
preliminary data on the transmissibility and pathological features of VPSPr
cases in bank voles.
Materials and Methods. Seven VPSPr cases were inoculated in two genetic
lines of bank voles, carrying either methionine or isoleucine at codon 109 of
the prion protein (named BvM109 and BvI109, respectively). Among the VPSPr cases
selected, 2 were VV at PrP codon 129, 3 were MV and 2 were MM. Clinical
diagnosis in voles was confirmed by brain pathological assessment and western
blot for PK-resistant PrPSc (PrPres) with mAbs SAF32, SAF84, 12B2 and 9A2.
Results. To date, 2 VPSPr cases (1 MV and 1 MM) gave positive transmission
in BvM109. Overall, 3 voles were positive with survival time between 290 and 588
d post inoculation (d.p.i.). All positive voles accumulated PrPres in the form
of the typical PrP27–30, which was indistinguishable to that previously observed
in BvM109 inoculated with sCJDMM1 cases. In BvI109, 3 VPSPr cases (2 VV and 1
MM) showed positive transmission until now. Overall, 5 voles were positive with
survival time between 281 and 596 d.p.i.. In contrast to what observed in
BvM109, all BvI109 showed a GSS-like PrPSc electrophoretic pattern,
characterized by low molecular weight PrPres. These PrPres fragments were
positive with mAb 9A2 and 12B2, while being negative with SAF32 and SAF84,
suggesting that they are cleaved at both the C-terminus and the N-terminus.
Second passages are in progress from these first successful transmissions.
Conclusions. Preliminary results from transmission studies in bank voles
strongly support the notion that VPSPr is a transmissible prion disease.
Interestingly, VPSPr undergoes divergent evolution in the two genetic lines of
voles, with sCJD-like features in BvM109 and GSS-like properties in BvI109. The
discovery of previously unrecognized prion diseases in both humans and animals
(i.e., Nor98 in small ruminants) demonstrates that the range of prion diseases
might be wider than expected and raises crucial questions about the epidemiology
and strain properties of these new forms. We are investigating this latter issue
by molecular and biological comparison of VPSPr, GSS and Nor98.
Saturday, October 6, 2012
TRANSMISSION, DIFFERENTIATION, AND PATHOBIOLOGY OF TRANSMISSIBLE SPONGIFORM
ENCEPHALOPATHIES 2011 Annual Report
Monday, July 23, 2012
The National Prion Disease Pathology Surveillance Center July 2012
Saturday, December 29, 2012
MAD COW USA HUMAN TSE PRION DISEASE DECEMBER 29 2012 CJD CASE LAB REPORT
Monday, December 31, 2012
Creutzfeldt Jakob Disease and Human TSE Prion Disease in Washington State,
2006–2011-2012
16 YEAR OLD TSE MAD COW TYPE PRION DISEASE DEATH IN USA
Monday, January 14, 2013
Gambetti et al USA Prion Unit change another highly suspect USA mad cow
victim to another fake name i.e. sporadic FFI at age 16 CJD Foundation goes
along with this BSe
MAD COW USDA ATYPICAL L-TYPE BASE BSE, the rest of the story...
Tuesday, November 6, 2012
Transmission of New Bovine Prion to Mice, Atypical Scrapie, BSE, and
Sporadic CJD, November-December 2012 update
Tuesday, June 26, 2012
Creutzfeldt Jakob Disease Human TSE report update North America, Canada,
Mexico, and USDA PRION UNIT as of May 18, 2012
type determination pending Creutzfeldt Jakob Disease (tdpCJD), is on the
rise in Canada and the USA
Saturday, March 5, 2011
MAD COW ATYPICAL CJD PRION TSE CASES WITH CLASSIFICATIONS PENDING ON THE
RISE IN NORTH AMERICA
Sunday, February 12, 2012
National Prion Disease Pathology Surveillance Center Cases Examined1
(August 19, 2011) including Texas
Monday, August 9, 2010
Variably protease-sensitive prionopathy: A new sporadic disease of the
prion protein or just more Prionbaloney ?
Wednesday, March 28, 2012
VARIABLY PROTEASE-SENSITVE PRIONOPATHY IS TRANSMISSIBLE ...price of prion
poker goes up again $
OR-10 15:25 - 15:40 VARIABLY PROTEASE-SENSITIVE PRIONOPATHY IS
TRANSMISSIBLE IN BANK VOLES Nonno
Sunday, August 09, 2009
CJD...Straight talk with...James Ironside...and...Terry Singeltary... 2009
Tuesday, August 18, 2009
BSE-The Untold Story - joe gibbs and singeltary 1999 – 2009
Sunday, February 10, 2013
Creutzfeldt-Jakob disease (CJD) biannual update (February 2013) Infection
report/CJD
Monday, October 10, 2011
EFSA Journal 2011 The European Response to BSE: A Success Story
snip...
EFSA and the European Centre for Disease Prevention and Control (ECDC)
recently delivered a scientific opinion on any possible epidemiological or
molecular association between TSEs in animals and humans (EFSA Panel on
Biological Hazards (BIOHAZ) and ECDC, 2011). This opinion confirmed Classical
BSE prions as the only TSE agents demonstrated to be zoonotic so far but the
possibility that a small proportion of human cases so far classified as
"sporadic" CJD are of zoonotic origin could not be excluded. Moreover,
transmission experiments to non-human primates suggest that some TSE agents in
addition to Classical BSE prions in cattle (namely L-type Atypical BSE,
Classical BSE in sheep, transmissible mink encephalopathy (TME) and chronic
wasting disease (CWD) agents) might have zoonotic potential.
snip...
see follow-up here about North America BSE Mad Cow TSE prion risk factors,
and the ever emerging strains of Transmissible Spongiform Encephalopathy in many
species here in the USA, including humans ;
Thursday, August 12, 2010
Seven main threats for the future linked to prions
First threat
The TSE road map defining the evolution of European policy for protection
against prion diseases is based on a certain numbers of hypotheses some of which
may turn out to be erroneous. In particular, a form of BSE (called atypical
Bovine Spongiform Encephalopathy), recently identified by systematic testing in
aged cattle without clinical signs, may be the origin of classical BSE and thus
potentially constitute a reservoir, which may be impossible to eradicate if a
sporadic origin is confirmed.
***Also, a link is suspected between atypical BSE and some apparently
sporadic cases of Creutzfeldt-Jakob disease in humans. These atypical BSE cases
constitute an unforeseen first threat that could sharply modify the European
approach to prion diseases.
Second threat
snip...
Saturday, June 25, 2011
Transmissibility of BSE-L and Cattle-Adapted TME Prion Strain to Cynomolgus
Macaque
"BSE-L in North America may have existed for decades"
Over the next 8-10 weeks, approximately 40% of all the adult mink on the
farm died from TME.
snip...
The rancher was a ''dead stock'' feeder using mostly (>95%) downer or
dead dairy cattle...
Monday, September 26, 2011
L-BSE BASE prion and atypical sporadic CJD
Wednesday, March 28, 2012
VARIABLY PROTEASE-SENSITVE PRIONOPATHY IS TRANSMISSIBLE, price of prion
poker goes up again $
*** The discovery of previously unrecognized prion diseases in both humans
and animals (i.e., Nor98 in small ruminants) demonstrates that the range of
prion diseases might be wider than expected and raises crucial questions about
the epidemiology and strain properties of these new forms. We are investigating
this latter issue by molecular and biological comparison of VPSPr, GSS and
Nor98.
AS OF AUGUST 2012 ;
CJD UPDATE USA
1 Listed based on the year of death or, if not available, on year of
referral;
2 Cases with suspected prion disease for which brain tissue and/or blood
(in familial cases) were submitted;
3 Disease acquired in the United Kingdom;
4 Disease was acquired in the United Kingdom in one case and in Saudi
Arabia in the other case;
*** 5 Includes 8 cases in which the diagnosis is pending, and 18
inconclusive cases;
*** 6 Includes 10 (9 from 2012) cases with type determination pending in
which the diagnosis of vCJD has been excluded.
*** The Sporadic cases include 16 cases of sporadic Fatal Insomnia (sFI)
and 42 cases of Variably Protease-Sensitive Prionopathy (VPSPr) and 2224 cases
of sporadic Creutzfeldt-Jakob disease (sCJD).
Tuesday, November 6, 2012
Transmission of New Bovine Prion to Mice, Atypical Scrapie, BSE, and
Sporadic CJD, November-December 2012 update
Terry S. Singeltary Sr. on the Creutzfeldt-Jakob Disease Public Health
Crisis
full text with source references ;
Sunday, August 21, 2011
The British disease, or a disease gone global, The TSE Prion Disease (SEE
VIDEO)
U.S.A. HIDING MAD COW DISEASE VICTIMS AS SPORADIC CJD ? (see video at
bottom)
Wednesday, April 25, 2012
USA MAD COW DISEASE AND CJD THERE FROM SINGELTARY ET AL 1999 – 2012
Tuesday, July 29, 2008
Heidenhain Variant Creutzfeldt Jakob Disease Case Report
FINAL AUTOPSY DIAGNOSIS
I. Brain: Creutzfeldt-Jakob disease, Heidenhain variant.
SKROLL down a bit for Mom's autopsy of hvCJD. ...
Monday, February 11, 2013
APHIS USDA Letter to Stakeholders: Trade Accomplishments and failures (BSE,
SCRAPIE, TSE, PRION, AKA MAD COW TYPE DISEASE)
Wednesday, May 16, 2012
Alzheimer’s disease and Transmissible Spongiform Encephalopathy prion
disease, Iatrogenic, what if ?
Proposal ID: 29403
PLEASE REMEMBER ;
The Akron, Ohio-based CJD Foundation said the Center for Disease Control
revised that number in October of 2004 to about one in 9,000 CJD cases per year
in the population group age 55 and older. HAVE YOU GOT YOUR CJD QUESTIONNAIRE
ASKING REAL QUESTIONS PERTAINING TO ROUTE AND SOURCE OF THE TSE AGENT THAT
KILLED YOUR LOVED ONE ???
if not, why not...
Friday, November 30, 2007
CJD QUESTIONNAIRE USA CWRU AND CJD FOUNDATION
layperson
Terry S. Singeltary Sr.
posted by Terry S. Singeltary Sr. at
4:24 PM
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