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From: TSS ()
Subject: Re: A Bovine Prion Acquires an Epidemic Bovine Spongiform Encephalopathy Strain-Like Phenotype on Interspecies Transmission
Date: June 28, 2007 at 7:21 am PST

In Reply to: A Bovine Prion Acquires an Epidemic Bovine Spongiform Encephalopathy Strain-Like Phenotype on Interspecies Transmission posted by TSS on June 27, 2007 at 11:10 am:

FURTHER into this study, some interesting points of discussion ;

We examined the strain behavior of a class of cattle prion isolates
newly identified by their atypical PrPres signature compared with
the classical BSE agent (Casalone et al., 2004; Buschmann et al.,
2006), designated BSE-L in the present study. During transmission
to transgenic mice, the different isolates analyzed shared
identical molecular and biological features, supporting the view
that a unique infectious agent is actually involved in the cases
named L-type BSE and BASE, depending on the authors (see
Introduction). The main finding emerging from this study is that
the BSE-L agent, although displaying phenotypic traits distinct
from those of BSE and BSE-related agents on the other transgenic
mouse lines studied, acquired a BSE-like strain phenotype during
transmission to mice expressing ovine PrP.
When serially transmitted to mice expressing the same PrP
sequence as the natural host (tgBov), BSE-L (four cases) and BSE
(three cases) maintained separate, stable phenotypes. Thus,
BSE-L isolates showed (1) faster disease transmission than cattle
BSE and related agents, as was reported recently for a German
case (Buschmann et al., 2006), (2) a distinctive PrPres signature,
as in cattle, and (3) distinguishable PrP deposition and vacuolation
patterns in the brain. Primary transmission to mouse or
human PrP transgenic mice also revealed striking differences between
the two agents. Thus, unlike that seen with various sources
of BSE or the vCJD agent, BSE-L provoked no overt disease or
detectable PrPres accumulation in tga20 mice. Inversely, it induced
an early PrPres accumulation in the brain of tgHu mice
relative to cattle BSE, with either agent retaining its distinctive
PrPres profile. A worrying implication of this latter result is that
the BSE-L agent might be transmissible to and possibly more
virulent in humans than classical BSE, an issue that deserves to be
investigated further.
In contrast, the BSE-L agent appeared to undergo a strain
phenotype shift during transmission to tgOv mice, despite an
incubation period during primary inoculation (400 d) much
shorter than with cattle BSE (700 d) or BSE-H (600 d)

(Beringue et al., 2006), suggesting a lower transmission barrier
from cattle to tgOv for BSE-L. Surprisingly, this novel strain phenotype
appeared very similar to that of cattle BSE and related
agents propagated onto the same mice, according to various criteria.
First, the survival times observed after stabilization on tgOv
differed by 5% at most between BSE-L and BSE-type agents,
which is unlikely to be significant. Second, the spatial distribution
of PrPres in the brain showed only a few, minor differences, although
being clearly distinct from the patterns observed with
several classes of transmissible spongiform encephalopathy
(TSE) agents characterized on these mice, including the BSE-H
agent (Le Dur et al., 2005; Beringue et al., 2006) (our unpublished
data). Third, the vacuolation profiles observed from the second
passage on, once the spongiform changes became substantial,
essentially overlapped. Fourth, the PrPres molecular profiles of
BSE-L and BSE agents on tgOv mice were indistinguishable.
The available typing methods, relying on the comparison of
neuropathological features or a PrPres signature
(Fraser and Dickinson, 1968;
Hecker et al., 1992), arguably have inherent
limitations and may be considered of
higher value in differentiating two strains
than in looking for a potential strain identity.
Another issue is the number and the
diversity of isolates propagated on the recipient
host. In this regard, it is worth emphasizing
that 136 prion infectious
sources from various species, including
100 natural sheep or goat scrapie isolates,
have been transmitted successfully
to tgOv mice to date (supplemental Table
S1, available at as supplemental
material). Remarkably, a PrPres
profile with unglycosylated species of intermediate
molecular size (20 kDa) and
prominent diglycoforms has been
uniquely and consistently observed with
cattle BSE or BSE-related agents, until
BSE-L isolates were analyzed. All other
sources generated unglycosylated species
with either higher or lower (e.g., CH1641
scrapie isolate) mobility (Vilotte et al.,
2001; Le Dur et al., 2005; Beringue et al.,
2006). Therefore, the observed phenotypic
convergence between BSE-L and
BSE during transmission on tgOv mice
appears as an uncommon event, so far involving
only these two strains, both of bovine
Our findings may represent a novel,
striking example of the evolutionary potential
of prion agents during transmission
to a foreign host, which can promote
strain shift and emergence of unprecedented
properties in a yet unpredictable
manner (Kimberlin et al., 1987; Scott et
al., 1997; Bartz et al., 2000; Wadsworth et
al., 2004). It is unclear in the present state
of our investigations which type of mechanism,
selection or de novo emergence,
may account for the apparent conversion
of BSE-L toward the classical BSE strain.
Preferential selection in these mice of a
classical-type BSE agent that would preexist as a minor component
in the brain tissue of BSE-L-infected cattle is one possibility.
Indeed, recent observations have questioned the strain homogeneity
of the agent present in cattle BSE infectious sources. Thus,
transmission of BSE isolates to C57BL and SJL mice expressing
the same mouse PrP allele was reported to result in a divergent
strain phenotype among the two lines (Asante et al., 2002; Lloyd
et al., 2004). Also, biochemical analyses revealed a dual PrPres
signature in BSE (and vCJD) brain homogenates (Yull et al.,
2006), which may suggest, albeit not exclusively, the presence of a
secondary, minor strain component. However, favored propagation
of a BSE-like component preexisting in BSE-L-infected brain
tissues is unlikely to explain our observation because, as mentioned
above, the BSE agent produces much prolonged incubation
periods compare with BSE-L in tgOv mice. A still missing
piece of information is whether the observed convergence truly
reflects a permanent strain shift of the BSE-L agent, because both

reversible and irreversible changes have been reported to occur
during heterologous transmission of a biologically cloned prion
strain (Kimberlin et al., 1987; Scott et al., 1997). Experiments are
underway to determine whether the “ovinized” BSE-L agent
would retain BSE phenotypic traits during reinoculation to tgBov
mice, as we found it to be the case for the ovinized BSE agent. It
would also be of interest to learn whether BSE-L would behave
similarly on mice expressing an ovine PrP allotype other than
Val136Arg154Gln171 as in the present study, because even single
amino acid differences in the PrP sequence might be crucial in
promoting a strain phenotype shift (Bruce, 2003; Wadsworth et
al., 2004).
In conclusion, the findings reported in the present study provide
new insight into the nature of the events that could have
contributed to the emergence of the BSE epidemic. The various
theories currently proposed regarding the origin of the BSE agent
invoke two kinds of mechanisms (Colchester and Colchester,
2005; Baron and Biacabe, 2006): an intrinsic cause, i.e., a spontaneously
diseased cattle attributable for instance to somatic or
germ-line mutation of PrP, or an extrinsic cause, i.e., the infection
of cattle by a prion from another species, involving a strain
change or not. Our observation is consistent with the view that
the epidemic BSE agent could have originated from an endogenous,
cattle prion. It also points to the theoretical possibility of a
multiple causative event, in which a prion sporadically present in
cattle may have “mutated” through passage on an intermediary
host such as a sheep.
During the review process of this paper, a study performed on
conventional mice has been published that reports converging
features of BASE-subpassaged mice toward BSE-inoculated mice
(Capobianco et al., 2007), thus strengthening the notion that the
BSE-L agent tends to acquire epidemic BSE-like properties during
transmission to a heterologous host.
References J. Neurosci., June 27, 2007 • 27(26):6965– 6971 • 6971...snip...end...tss

Aug 30, 2005 USDA Texas BSE Investigation—Final Epidemiology Report!ut/p/_s.7_0_A/7_0_1OB?contentidonly=true&contentid=2005/08/0336.xml

ALABAMA BSE Investigaion Final Epidemiology Report!ut/p/_s.7_0_A/7_0_1OB?contentidonly=true&contentid=2006/03/0090.xml


18 January 2007 - Draft minutes of the SEAC 95 meeting (426 KB) held on 7
December 2006 are now available.


64. A member noted that at the recent Neuroprion meeting, a study was
presented showing that in transgenic mice BSE passaged in sheep may be more
virulent and infectious to a wider range of species than bovine derived BSE.

Other work presented suggested that BSE and bovine amyloidotic spongiform
encephalopathy (BASE) MAY BE RELATED. A mutation had been identified in the


3:30 Transmission of the Italian Atypical BSE (BASE) in Humanized Mouse

Models Qingzhong Kong, Ph.D., Assistant Professor, Pathology, Case Western Reserve

Bovine Amyloid Spongiform Encephalopathy (BASE) is an atypical BSE strain
discovered recently in Italy, and similar or different atypical BSE cases
were also reported in other countries. The infectivity and phenotypes of
these atypical BSE strains in humans are unknown. In collaboration with
Pierluigi Gambetti, as well as Maria Caramelli and her co-workers, we have
inoculated transgenic mice expressing human prion protein with brain
homogenates from BASE or BSE infected cattle. Our data shows that about half
of the BASE-inoculated mice became infected with an average incubation time
of about 19 months; in contrast, none of the BSE-inoculated mice appear to
be infected after more than 2 years.

***These results indicate that BASE is transmissible to humans and suggest that BASE is more virulent than
classical BSE in humans.***

6:30 Close of Day One

1997 TO 2006. SPORADIC CJD CASES TRIPLED, with phenotype
of 'UNKNOWN' strain growing. ...

There is a growing number of human CJD cases, and they were presented last
week in San Francisco by Luigi Gambatti(?) from his CJD surveillance

He estimates that it may be up to 14 or 15 persons which display selectively
SPRPSC and practically no detected RPRPSC proteins.

Research Project: Study of Atypical Bse

Location: Virus and Prion Diseases of Livestock

Project Number: 3625-32000-073-07
Project Type: Specific C/A

Start Date: Sep 15, 2004
End Date: Sep 14, 2007

The objective of this cooperative research project with Dr. Maria Caramelli from the Italian BSE Reference Laboratory in Turin, Italy, is to conduct comparative studies with the U.S. bovine spongiform encephalopathy (BSE) isolate and the atypical BSE isolates identified in Italy. The studies will cover the following areas: 1. Evaluation of present diagnostics tools used in the U.S. for the detection of atypical BSE cases. 2. Molecular comparison of the U.S. BSE isolate and other typical BSE isolates with atypical BSE cases. 3. Studies on transmissibility and tissue distribution of atypical BSE isolates in cattle and other species.

This project will be done as a Specific Cooperative Agreement with the Italian BSE Reference Laboratory, Istituto Zooprofilattico Sperimentale del Piemonte, in Turin, Italy. It is essential for the U.S. BSE surveillance program to analyze the effectiveness of the U.S diagnostic tools for detection of atypical cases of BSE. Molecular comparisons of the U.S. BSE isolate with atypical BSE isolates will provide further characterization of the U.S. BSE isolate. Transmission studies are already underway using brain homogenates from atypical BSE cases into mice, cattle and sheep. It will be critical to see whether the atypical BSE isolates behave similarly to typical BSE isolates in terms of transmissibility and disease pathogenesis. If transmission occurs, tissue distribution comparisons will be made between cattle infected with the atypical BSE isolate and the U.S. BSE isolate. Differences in tissue distribution could require new regulations regarding specific risk material (SRM) removal.

Volume 12, Number 12–December 2006


On the Question of Sporadic

or Atypical Bovine SpongiformEncephalopathy and

Creutzfeldt-Jakob Disease

Paul Brown,* Lisa M. McShane,† Gianluigi Zanusso,‡ and Linda Detwiler§

Strategies to investigate the possible existence of sporadic

bovine spongiform encephalopathy (BSE) require

systematic testing programs to identify cases in countries

considered to have little or no risk for orally acquired disease,

or to detect a stable occurrence of atypical cases in

countries in which orally acquired disease is disappearing.

To achieve 95% statistical confidence that the prevalence

of sporadic BSE is no greater than 1 per million (i.e., the

annual incidence of sporadic Creutzfeldt-Jakob disease

[CJD] in humans) would require negative tests in 3 million

randomly selected older cattle. A link between BSE and

sporadic CJD has been suggested on the basis of laboratory

studies but is unsupported by epidemiologic observation.

Such a link might yet be established by the discovery

of a specific molecular marker or of particular combinations

of trends over time of typical and atypical BSE and various

subtypes of sporadic CJD, as their numbers are influenced

by a continuation of current public health measures that

exclude high-risk bovine tissues from the animal and

human food chains.


Sporadic CJD
The possibility that at least some cases of apparently sporadic CJD might be due to infection by sporadic cases of BSE cannot be dismissed outright. Screening programs needed to identify sporadic BSE have yet to be implemented, and we know from already extant testing programs that at least a proportion of infected animals have no symptoms and thus would never be identified in the absence of systematic testing. Thus, sporadic BSE (or for that matter, sporadic disease in any mammalian species) might be occurring on a regular basis at perhaps the same annual frequency as sporadic CJD in humans, that is, in the range of 1 case per million animals.

Whether humans might be more susceptible to atypical forms of BSE cannot be answered at this time. Experimentally transmitted BASE shows shorter incubation periods than BSE in at least 1 breed of cattle, bovinized transgenic mice, and Cynomolgus monkeys (12,13). In humanized transgenic mice, BASE transmitted, whereas typical BSE did not transmit (13). Paradoxically, the other major phenotype (H) showed an unusually long incubation period in bovinized transgenic mice (12).

The limited experimental evidence bearing on a possible relationship between BSE and sporadic CJD is difficult to interpret. The original atypical BASE strain of BSE had a molecular protein signature very similar to that of 1 subtype (type 2 M/V) of sporadic CJD in humans (5). In another study, a strain of typical BSE injected into humanized mice encoding valine at codon 129 showed a glycopattern indistinguishable from the same subtype of sporadic CJD (15). In a third study, the glycopatterns of both the H and L strains of atypical BSE evidently did not resemble any of the known sporadic CJD subtypes (12).

To these molecular biology observations can be added the epidemiologic data accumulated during the past 30 years. The hypothesis that at least some cases of apparently sporadic CJD are due to unrecognized BSE infections cannot be formally refuted, but if correct, we might expect by now to have some epidemiologic evidence linking BSE to at least 1 cluster of apparently sporadic cases of CJD. Although only a few clusters have been found (and still fewer published), every proposed cluster that has been investigated has failed to show any common exposure to bovines. For that matter, no common exposure has been shown to any environmental vehicles of infection, including the consumption of foodstuffs from bovine, ovine, and porcine sources, the 3 livestock species known to be susceptible to transmissible spongiform encephalopathies. Additional negative evidence comes from several large case-control studies in which no statistically significant dietary differences were observed between patients with sporadic CJD and controls (16,17).

On the other hand, the difficulty of establishing a link between BSE and CJD may be compounded by our ignorance of the infectious parameters of a sporadic form of BSE (e.g., host range, tissue distribution of infectivity, route of transmission, minimum infectious dose for humans, whether single or multiple). Presumably, these parameters would resemble those of variant CJD; that is, high infectivity central nervous system and lymphoreticular tissues of an infected cow find their way into products consumed by humans. Transmissions that might have occurred in the past would be difficult to detect because meat products are generally not distributed in a way that results in detectable geographic clusters.

Barring the discovery of a specific molecular signature (as in variant CJD), the most convincing clue to an association will come from the observation of trends over time of the incidence of typical and atypical BSE and of sporadic and variant CJD. With 4 diseases, each of which could have increasing, unchanging, or decreasing trends, there could be 81 (34) possible different combinations. However, it is highly likely that the trends for typical BSE and variant CJD will both decrease in parallel as feed bans continue to interrupt recycled contamination. The remaining combinations are thus reduced to 9 (32), and some of them could be highly informative.

For example, if the incidence of atypical BSE declines in parallel with that of typical BSE, its candidacy as a sporadic form of disease would be eliminated (because sporadic disease would not be influenced by current measures to prevent oral infection). If, on the other hand, atypical BSE continues to occur as typical BSE disappears, this would be a strong indication that it is indeed sporadic, and if in addition at least 1 form of what is presently considered as sporadic CJD (such as the type 2 M/V subtype shown to have a Western blot signature like BASE) were to increase, this would suggest (although not prove) a causal relationship (Figure 5).

Recognition of the different forms of BSE and CJD depends upon continuing systematic testing for both bovines and humans, but bovine testing will be vulnerable to heavy pressure from industry to dismantle the program as the commercial impact of declining BSE cases ceases to be an issue. Industry should be aware, however, of the implications of sporadic BSE. Its occurrence would necessitate the indefinite retention of all of the public health measures that exclude high-risk bovine tissues from the animal and human food chains, whereas its nonoccurrence would permit tissues that are now destroyed to be used as before, once orally acquired BSE has disappeared.




From: Terry S. Singeltary Sr. <[log in to unmask]>
Date: Wed, 11 Apr 2007 15:08:15 -0500


----- Original Message -----
From: "Terry S. Singeltary Sr."
Sent: Wednesday, June 27, 2007 1:44 PM
Subject: A Bovine Prion Acquires an Epidemic Bovine Spongiform Encephalopathy Strain-Like Phenotype on Interspecies Transmission

Subject: A Bovine Prion Acquires an Epidemic Bovine Spongiform
Encephalopathy Strain-Like Phenotype on Interspecies Transmission
Date: June 27, 2007 at 11:10 am PST

Neurobiology of Disease
A Bovine Prion Acquires an Epidemic Bovine Spongiform Encephalopathy
Strain-Like Phenotype on Interspecies Transmission

Vincent Béringue,1 Olivier Andréoletti,2 * Annick Le Dur,1 * Rachid
Essalmani,3 Jean-Luc Vilotte,3 Caroline Lacroux,2 Fabienne Reine,1 Laëtitia
Herzog,1 Anne-Gaëlle Biacabé,4 Thierry Baron,4 Maria Caramelli,5 Cristina
Casalone,5 and Hubert Laude1

1Institut National de la Recherche Agronomique (INRA), Unité de Recherche
892, Virologie Immunologie Moléculaires, F-78350 Jouy-en-Josas, France,
2INRA, Unité Mixte de Recherche 1225, Interactions Hôtes-Agents Pathogènes,
Ecole Nationale Vétérinaire, F-31000 Toulouse, France, 3INRA, Unité de
Recherche 339, Génétique Biochimique et Cytogénétique, F-78350
Jouy-en-Josas, France, 4Agence Française de Sécurité Sanitaire des Aliments,
Unité Agents Transmissibles Non Conventionnels, F-69000 Lyon, France, and
5Instituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle,
d'Aosta, Torino, Italy

Correspondence should be addressed to either Hubert Laude or Vincent
Béringue, Institut National de la Recherche Agronomique, Unité de Recherche
892, Virologie Immunologie Moléculaires, F-78350 Jouy-en-Josas, France.
Email: or Email:

Implementation in Europe of large-scale testing to detect bovine spongiform
encephalopathy (BSE)-infected cattle and prevent the transmission of this
prion disease to humans has recently led to the discovery of novel types of
bovine prions. We characterized atypical isolates called BSE L-type by
analyzing their molecular and neuropathological properties during
transmission to several mouse lines transgenic for the prion protein (PrP).
Unexpectedly, such isolates acquired strain features closely similar to
those of BSE-type agents when propagated in mice expressing ovine PrP,
although they retained phenotypic traits distinct from BSE in other lines,
including bovine PrP mice. These findings further underline the relationship
between the crossing of species barrier and prion strain diversification,
and, although the origin of the epidemic BSE agent has only been speculative
until now, they provide new insight into the nature of the events that could
have led to the appearance of this agent.

Key words: bovine prion; BSE; atypical BSE; strain evolution; degeneration;

Received Feb. 15, 2007; revised April 25, 2007; accepted April 28, 2007.

Correspondence should be addressed to either Hubert Laude or Vincent
Béringue, Institut National de la Recherche Agronomique, Unité de Recherche
892, Virologie Immunologie Moléculaires, F-78350 Jouy-en-Josas, France.
Email: or Email:


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