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From: TSS ()
Subject: Prominent and Persistent Extraneural Infection in Human PrP Transgenic Mice Infected with Variant CJD
Date: January 15, 2008 at 1:20 pm PST

Prominent and Persistent Extraneural Infection in Human PrP Transgenic Mice
Infected with Variant CJD

Vincent Béringue1*, Annick Le Dur1, Philippe Tixador1, Fabienne Reine1,
Laurence Lepourry2, Armand Perret-Liaudet3, Stéphane Haïk4,5, Jean-Luc
Vilotte2, Michel Fontés6, Hubert Laude1*

1 Institut Scientifique de Recherche Agronomique (INRA), UR892, Virologie
Immunologie Moléculaires, Jouy-en-Josas, France, 2 Institut Scientifique de
Recherche Agronomique (INRA), UR339, Génétique Biochimique et Cytogénétique,
Jouy-en-Josas, France, 3 Service de Neurobiologie, Centre de Biologie et
Pathologie Est (CBPE), Groupement Hospitalier Est des Hôpitaux de Lyon,
Bron, France, 4 INSERM, Equipe Avenir, Maladies à Prions chez l'Homme,
Paris, France, 5 Assistance Publique - Hôpitaux de Paris (AP-HP),
Laboratoire de Neuropathologie R. Escourolle, Groupe Hospitalier Pitié-
Salpétrière, Paris, France, 6 INSERM UMR 491-IPHM, Faculté de médecine de la
Timone, Marseille, France



The evolution of the variant Creutzfeldt-Jakob disease (vCJD) epidemic is
hazardous to predict due to uncertainty in ascertaining the prevalence of
infection and because the disease might remain asymptomatic or produce an
alternate, sporadic-like phenotype.

Methodology/Principal Findings

Transgenic mice were produced that overexpress human prion protein with
methionine at codon 129, the only allele found so far in vCJD-affected
patients. These mice were infected with prions derived from variant and
sporadic CJD (sCJD) cases by intracerebral or intraperitoneal route, and
transmission efficiency and strain phenotype were analyzed in brain and
spleen. We showed that i) the main features of vCJD infection in humans,
including a prominent involvement of the lymphoid tissues compared to that
in sCJD infection were faithfully reproduced in such mice; ii) transmission
of vCJD agent by intracerebral route could lead to the propagation of either
vCJD or sCJD-like prion in the brain, whereas vCJD prion was invariably
propagated in the spleen, iii) after peripheral exposure, inefficient
neuroinvasion was observed, resulting in an asymptomatic infection with
life-long persistence of vCJD prion in the spleen at stable and elevated


Our findings emphasize the possibility that human-to-human transmission of
vCJD might produce alternative neuropathogical phenotypes and that lymphoid
tissue examination of CJD cases classified as sporadic might reveal an
infection by vCJD-type prions. They also provide evidence for the strong
propensity of this agent to establish long-lasting, subclinical vCJD
infection of lymphoreticular tissues, thus amplifying the risk for
iatrogenic transmission.

Citation: Béringue V, Le Dur A, Tixador P, Reine F, Lepourry L, et al.
(2008) Prominent and Persistent Extraneural Infection in Human PrP
Transgenic Mice Infected with Variant CJD. PLoS ONE 3(1): e1419.

Academic Editor: Adam Ratner, Columbia University, United States of America

Received: September 20, 2007; Accepted: December 17, 2007; Published:
January 9, 2008

Copyright: © 2008 Beringue et al. This is an open-access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.

Funding: This work was supported by INRA, Institut de Veille Sanitaire
(InVS) and the Ministry of Research, France. The sponsors of this study had
no role in study conduct, collection analysis, interpretation of the data,
writing of the report or approval of the manuscript.

Competing interests: The authors have declared that no competing interests

* To whom correspondence should be addressed. E-mail: (HL); (VB)



In this study we used tg650 mice, a newly developed transgenic line
expressing human PrPC, to investigate some aspects of the pathogenesis of
vCJD infection. As main findings, we demonstrate that prion strain
divergence can occur upon transmission of human, primary vCJD to such mice,
and that peripheral challenge leads to an asymptomatic, life-long infection
of the lymphoid compartment. A feature of tg650 mice is that following
primary intracerebral vCJD challenge they developed a neurological disease
with typically 100% attack rate, unlike for previously established
PrP129Met, including overexpressing lines [16], [19]. The mean survival
time – typically around 500 days in homozygous mice - did not change notably
on subpassaging, implying that vCJD agent might clinically infect the tg650
mice with little or no transmission barrier. This discrepant result may
reflect the use of different constructs and genetic backgrounds (Text S1),
and the transgene expression levels, although the latter does not seem to
greatly differ as far as the tg650+/- and tg45 mice [16] are concerned.

A surprising result of these studies is the alternate pattern of disease
that was induced by one of the inoculated vCJD cases, a WHO reference case
here designated vCJD no. 4. Indeed, while vCJD strain features were
faithfully propagated in the majority of tg650 mice, almost half of the vCJD
4-inoculated mice were found to propagate a prion replicating faster than
vCJD agent, and exhibiting sCJD-like PrPres and neuropathological features.
Although strain divergence upon transmission of BSE/vCJD agent to mice was
reported to occur in earlier studies [16], [24], it was unprecedented within
a context of homotypic transmission, i.e. full matching between the donor
and receiver PrP sequences. To address the issue of a possible
contamination, we performed independent transmission experiments, involving
separate inoculum batches of the incriminated case, which all produced
consistent results. Therefore, we consider the data inconsistent with
contamination of the VCJD no. 4 material by a sCJD infectious source within
our laboratory. An alternate possibility, i.e. a cross-contamination of the
source material, was judged highly improbable owing to the procedures
applied during the collect of the specimen and the preparation of the
homogenates ([25] and P. Minor, personal communication). On the other hand,
our observation intriguingly parallels the phenotypic disjunction observed
upon transmission of BSE agent to human PrP129Met mice (tg35 line [16]).
Together, these findings lend support to the hypothesis that a minor strain
component might be created upon cattle-to-human transmission of BSE agent
and could emerge upon subsequent human-to–human transmission. It is also
worth mentioning that, while the probability to detect such a variant
through mouse bioassay would be expected to depend on the amount - and
possibly the regions - of brain tissue taken to establish the source
material, the vCJD-4 homogenate was prepared using a larger amount of tissue
from the same brain than for the other homogenates analyzed in this study
(i.e. 100 mg instead of 1 mg of frontal cortex [25]).

The above finding has obvious implications in terms of public health as it
raises the concern that some humans iatrogenically infected by vCJD agent
may develop a clinical disease that would not be recognized as of vCJD
origin [17], [26]. Strikingly however, all vCJD-4-inoculated mice,
notwithstanding the strain phenotype divergence propagated bona fide vCJD
agent in their spleen, based on the PrPres pattern and the disease phenotype
produced by secondary transmission to tg650 mice. This result is of direct
relevance to the diagnosis of variant and sporadic CJD. Indeed, looking for
peripheral lymphoreticular deposition of abnormal PrP on cases diagnosed as
sporadic CJD might reveal a vCJD infection resulting from human-to-human, or
cattle-to-human transmission. In this respect, it would be of interest to
examine whether BSE-inoculated tg35 mice showing discordant PrPres
signatures [16], or vCJD-challenged PrP129Val transgenic mice producing
‘type 5’ prion in their brain [17] do accumulate PrPvCJD in their spleens.
In any case, our findings provide clear evidence that, as a consequence of
strain-related tropism disparities, the same mouse can propagate different
prions in different tissues following a single infection event.

Another salient finding emerging from this study was the remarkable ability
of vCJD agent to establish asymptomatic infection despite sustained,
life-long propagation in extraneural tissues. When challenged peripherally,
tg650 mice remained asymptomatic over the whole observation period, and did
not accumulate PrPres at detectable levels in their brain before 750 days
pi, near the life end-stage. In the spleen of these mice however, PrPres
accumulation reached its maximum at an early stage of infection, and
remained at stable and substantial levels until death. Plateauing of prion
infection in the spleen is consistent with earlier observations, and has
been suggested to reflect an exhaustion of target cells (for review [22])
Importantly, the spleen tissue was highly infectious as it killed 100% of
intracerebrally challenged mice within the minimal mean incubation time
(~500 days). Altogether these data support the view that the sustained
multiplication of the vCJD prion in lymphoid tissues was not accompanied by
an efficient neuroinvasion in tg650 mice. Such an extremely delayed
neuroinvasion appears to be rare in TSE rodent models, and to our knowledge
was only reported for the mouse-adapted strain 87V on IM mice infected
intraperitoneally with diluted inoculum [27]. Clearly, while early
accumulation of prions in lymphoid tissues may be essential for efficient
neuroinvasion [22], efficient lymphoinvasion does not inevitably lead to
rapid neuroinvasion. This finding strengthens the notion that humans
infected by vCJD from a human source – including individuals of the MM
genotype – might remain clinically asymptomatic for a very prolonged period
of time while harboring relatively high levels of prion infectivity in their
lymphoid tissues from an early stage of infection on, thereby amplifying the
risk of iatrogenic transmission. It also supports the view that the
large-scale survey of lymphoreticular tissues [28] may lead to a reliable
assessment of the actual prevalence of vCJD infection in the UK population.

Finally, the human PrP transgenic model described in this study may help to
further our understanding of peripheral vCJD pathogenesis, for instance in
trying to identify factors that might enhance neuroinvasion efficiency, or
modulate the shedding of prion infectivity from the lymphoreticular to the
blood compartment. Moreover, preliminary results indicate that the search
for abnormal PrP in the spleen of such mice culled at time intervals post
infection [29], [30] could allow the detection of low levels of vCJD
infectivity within a reasonably short time scale.

snip...full text ;


MARCH 26, 2003

In light of the findings of Asante and Collinge et al, there

should be drastic measures to safeguard the medical and surgical arena

from sporadic CJDs and all human TSEs. I only ponder how many sporadic

CJDs in the USA are type 2 PrPSc?

Asante/Collinge et al, that BSE transmission to the 129-methionine

genotype can lead to an alternate phenotype that is indistinguishable

from type 2 PrPSc, the commonest _sporadic_ CJD;

Friday, January 11, 2008


Diagnosis and Reporting of Creutzfeldt-Jakob Disease

Singeltary, Sr et al. JAMA.2001; 285: 733-734.

vCJD case study highlights blood transfusion risk

vCJD transfusion-associated Fourth Case UK

risk factors for sporadic CJD

Creutzfeldt-Jakob Disease, Prion Protein Gene Codon 129VV, and a Novel PrPSc
Type in a Young British Woman

BSE (Mad Cow) Update: Do Reports of sCJD Clusters Matter?

snip... see full text ;

Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in
the United States

Creutzfeldt Jakob Disease



Prominent and Persistent Extraneural Infection in Human PrP Transgenic Mice
Infected with Variant CJD


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