Highly Efficient Prion Transmission by Blood Transfusion
Olivier Andre´ oletti1*, Claire Litaise1, Hugh Simmons2, Fabien Corbie`
re1, Se´verine Lugan1, Pierrette Costes1, Franc¸ois Schelcher1, Didier Vilette1,
Jacques Grassi3, Caroline Lacroux1 1 UMR INRA ENVT 1225, Interactions Hoˆ tes
Agents Pathoge`nes, Ecole Nationale Ve´te´ rinaire de Toulouse, Toulouse,
France, 2 VLA Weybridge, ASU, New Haw, Addlestone, Surrey, United Kingdom, 3
CEA, Service de Pharmacologie et d’Immunoanalyse, IBiTec-S, DSV, CEA/Saclay, Gif
sur Yvette cedex, France
Abstract
It is now clearly established that the transfusion of blood from variant
CJD (v-CJD) infected individuals can transmit the disease. Since the number of
asymptomatic infected donors remains unresolved, inter-individual v-CJD
transmission through blood and blood derived products is a major public health
concern. Current risk assessments for transmission of v- CJD by blood and blood
derived products by transfusion rely on infectious titers measured in rodent
models of Transmissible Spongiform Encephalopathies (TSE) using intra-cerebral
(IC) inoculation of blood components. To address the biological relevance of
this approach, we compared the efficiency of TSE transmission by blood and blood
components when administrated either through transfusion in sheep or by
intra-cerebral inoculation (IC) in transgenic mice (tg338) overexpressing ovine
PrP. Transfusion of 200 mL of blood from asymptomatic infected donor sheep
transmitted prion disease with 100% efficiency thereby displaying greater
virulence than the transfusion of 200 mL of normal blood spiked with brain
homogenate material containing 103ID50 as measured by intracerebral inoculation
of tg338 mice (ID50 IC in tg338). This was consistent with a whole blood titer
greater than 103.6 ID50 IC in tg338 per mL. However, when the same blood samples
were assayed by IC inoculation into tg338 the infectious titers were less than
32 ID per mL. Whereas the transfusion of crude plasma to sheep transmitted the
disease with limited efficacy, White Blood Cells (WBC) displayed a similar
ability to whole blood to infect recipients. Strikingly, fixation of WBC with
paraformaldehyde did not affect the infectivity titer as measured in tg338 but
dramatically impaired disease transmission by transfusion in sheep. These
results demonstrate that TSE transmission by blood transfusion can be highly
efficient and that this efficiency is more dependent on the viability of
transfused cells than the level of infectivity measured by IC inoculation.
Author Summary
In the UK, several v-CJD cases have been identified in patients that
received blood or blood-derived products prepared from incubating asymptomatic
donors. Since there is no screening test to identify infected donors, procedural
risk reduction measures remain the only protection against v-CJD transfusion
risk. These measures rely, in part, on the assumptions that (i) the level of
infectivity in blood is low and (ii) the risk of blood borne transmission is
directly correlated with the infectious titer of blood and blood products. Using
a transmissible spongiform encephalopathy (TSE) animal model, we have provided
evidence that despite a very low infectious titer in blood as measured by
inoculation into brain, the transfusion of 0.2 mL of blood from asymptomatic
infected donors is sufficient to transmit the disease with a 100% efficacy. We
further demonstrated that this high efficiency of disease transmission is
crucially dependant on the viability of the transfused white blood cells rather
than on their infectious titer. These findings provide new insights into the
pathogenesis of TSE diseases and require revision of some of the key assumptions
of the v-CJD blood borne risk assessments.
snip...
In this study, labile blood products containing viable WBC presented the
greatest risk of transmitting Prion disease. This finding strongly supports the
continuation of universal leucoreduction as currently applied in the EU
countries and Canada to reduce, amongst other potential adverse effects, the
risk of v-CJD transmission [34]. Additional experiments will be necessary to
determine the minimal number of WBC (leukocytes and/or platelets) that is
sufficient to transmit the disease and to identify the WBC cell population(s)
responsible for virulence.
Finally, our results also raise some concerns about the use of the
‘spiking’ models for investigation of blood-borne TSE transmission risk [35,36].
Whereas this approach is very convenient to measure the TSE infectivity
reduction by certain process, it is probably of limited relevance for assessing
the efficacy of devices intended to mitigate the risk of Prion disease
transmission by blood and blood derived products.
Citation: Andre´oletti O, Litaise C, Simmons H, Corbie`re F, Lugan S, et
al. (2012) Highly Efficient Prion Transmission by Blood Transfusion. PLoS Pathog
8(6): e1002782. doi:10.1371/journal.ppat.1002782 Editor: Jason Bartz, Creighton
University, United States of America Received October 18, 2011; Accepted May 16,
2012; Published June 21, 2012 Copyright: 2012 Andre´ oletti 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 funded by DEFRA and the EU FP7 project
‘Priority’ The funders had no role in study design, data collection and
analysis, decision to publish, or preparation of the manuscript. Competing
Interests: The authors have declared that no competing interests exist. *
E-mail: o.andreoletti@envt.fr
Wednesday, June 27, 2012
First US BSE Case Since 2006 Underscores Need for Vigilance
Neurology Today 21 June 2012
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
Sunday, June 24, 2012
FDA Blood Products Advisory Committee June 12, 2012 Overview of the
Laboratory of Bacterial and Transmissible Spongiform Encephalopathy Agents
Saturday, June 23, 2012
The proposed Transmissible Spongiform Encephalopathies (England)
(Amendment) Regulations 2012
OR-34:
An update of transfusion transmission of variant Creutzfeldt-Jakob disease
(vCJD)
Robert G. Will National CJD Research and Surveillance Unit; Edinburgh, UK
There have been 4 vCJD infections linked to blood transfusion in the UK,
but there are a small number of individuals who remain clinically unaffected,
despite being exposed to a blood transfusion derived form an individual who
later developed vCJD. There are number of variables that may influence the risk
of transfusion transmission and these include the time elapsed since the
transfusion, the timing in relation to clinical onset of symptoms in the donor,
the influence of leuco-depletion and the genetic background of recipients.
Mathematical models suggest that there are likely to be further cases of
transfusion transmitted vCJD in the future and that these cases may occur over
an extended time frame. Concerns regarding the potential for transmission of
vCJD through plasma products have been heightened by the identification of
abnormal prion protein in the spleen of a patient with hemophilia, but there is
a potential disparity between estimates of the number of individuals potentially
exposed to significant infection and the absence of observed cases of clinical
vCJD in exposed populations.
OR-36: A new neurological disease in primates inoculated with
prion-infected blood or blood components
Emmanuel Comoy,1 Nina Jaffré,1 Jacqueline Mikol,1 Valérie Durand,1
Christelle Jas-Duval,2 Sophie Luccantoni-Freire,1 Evelyne Correia,1 Vincent
Lebon,1 Justine Cheval,3 Isabelle Quadrio,4 Nathalie Lescoutra-Etchegaray,5
Nathalie Streichenberger,4 Stéphane Haïk,6 Chryslain Sumian,5 Armand
Perret-Liaudet,4 Marc Eloit,7 Philippe Hantraye,1 Paul Brown,1 Jean-Philippe
Deslys1 1Atomic Energy Commission ; Fontenay-aux-Roses, France ; 2Etablissement
Français du Sang; Lille, France; 3Pathoquest; Paris, France; 4Hospices Civils de
Lyon, Lyon, France; 5MacoPharma; Tourcoing, France; 6INSER M; Paris, France;
7Institut Pasteur; Paris, France
Background. Concerns about the blood-borne risk of prion infection have
been confirmed by the occurrence in the UK of four transfusion-related
infections of vCJD (variant Creutzfeldt- Jakob disease), and an apparently
silent infection in an hemophiliac patient. Asymptomatic incubation periods in
prion diseases can extend over decades in humans, and a typical disease may or
may not supervene. We present here unexpected results of independent experiments
to evaluate blood transmission risk in a validated non-human primate model of
prion disease.
Methods. Cynomolgus macaques were inoculated with brain or blood specimens
from vCJD infected humans and vCJD or BSE-infected monkeys. Neuropathological
and biochemical findings were obtained using current methods used for human
patients.
Findings. Thirteen out of 20 primates exposed to human or macaque
blood-derived components or potentially contaminated human plasma-derived Factor
VIII exhibited an original neurological disease (myelopathy) previously not
described either in humans or primates, and which is devoid of the classical
clinical and lesional features of prion disease (front leg paresis in the
absence of central involvement, lesions concentrated in anterior horns of lower
cervical cord, with no spongiosis or inflammation), while the 12
brain-inoculated donor animals and one transfused animal exhibited the classical
vCJD pattern. No abnormal prion protein (PrPres) was detected by standard tests
in use for human prion diagnosis, but higher amounts of protease-sensitive PrP
were detected in cervical cords than in controls. No alternative cause has been
found in an exhaustive search for metabolic, endocrine, toxic, nutritional,
vascular and infectious etiologies, including a search for pathogen genotypes
(‘deep sequencing’). Moreover, all the three animals transfused with blood
treated with a prion removal filter remain asymptomatic with a one-third longer
incubation period than the two animals transfused before filtration, which both
developed the atypical syndrome presented here.
Interpretation. We describe a new neurological syndrome in monkeys exposed
to various prion-infected inocula, including a potentially infected batch of
plasma-derived Factor VIII. Our experimental observations in the absence of
evident alternative etiology is highly suggestive of a prion origin for this
myelopathy, that might be compared under some aspects to certain forms of human
lower motor neuron diseases. Similar human infections, were they to occur, would
not be identified as a prion disease by current diagnostic investigations.
disturbing to say the least. I am seeing more and more atypical TSE disease
that are NOT detectible with any standard TSE test today. the disturbing factor
there would be, not knowing these cases exist, and the iatrogenic transmission
there from via the medical, dental, surgical arenas. ...
Tuesday, May 29, 2012
Transmissible Proteins: Expanding the Prion Heresy
Friday, May 11, 2012
ProMetic Life Sciences Inc.: P-Capt® Filtration Prevents Transmission of
Endogenous Blood-Borne Infectivity in Primates
Wednesday, August 24, 2011
All Clinically-Relevant Blood Components Transmit Prion Disease following a
Single Blood Transfusion: A Sheep Model of vCJD
http://transmissiblespongiformencephalopathy.blogspot.com/2011/08/all-clinically-relevant-blood.html
Wednesday, August 24, 2011
There Is No Safe Dose of Prions
Sunday, May 1, 2011
W.H.O. T.S.E. PRION Blood products and related biologicals May 2011
Monday, February 7, 2011
FDA’s Currently-Recommended Policies to Reduce the Possible Risk of
Transmission of CJD and vCJD by Blood and Blood Products 2011 ???
Sunday, August 01, 2010
Blood product, collected from a donors possibly at increased risk for vCJD
only, was distributed USA JULY 2010
Tuesday, September 14, 2010
Transmissible Spongiform Encephalopathies Advisory Committee; Notice of
Meeting October 28 and 29, 2010 (COMMENT SUBMISSION)
Sunday, July 20, 2008
Red Cross told to fix blood collection or face charges 15 years after
warnings issued, few changes made to ensure safety
Saturday, December 08, 2007
Transfusion Transmission of Human Prion Diseases
Tuesday, October 09, 2007
nvCJD TSE BLOOD UPDATE
Saturday, December 08, 2007
Transfusion Transmission of Human Prion Diseases
Saturday, January 20, 2007
Fourth case of transfusion-associated vCJD infection in the United Kingdom
vCJD case study highlights blood transfusion risk 9 Dec 2006 by Terry S.
Singeltary Sr.
THIS was like closing the barn door after the mad cows got loose. not only
the red cross, but the FDA has failed the public in protecting them from the TSE
aka mad cow agent. TSE agent ie bse, base, cwd, scrapie, tme, ...
vCJD case study highlights blood transfusion risk -
Saturday, May 26, 2012
Are USDA assurances on mad cow case 'gross oversimplification'?
Sunday, May 27, 2012
CANADA PLANS TO IMPRISON ANYONE SPEAKING ABOUT MAD COW or ANY OTHER DISEASE
OUTBREAK
CENSORSHIP IS A TERRIBLE THING
Friday, May 25, 2012
R-CALF USDA’s New BSE Rule Eliminates Important Protections Needed to
Prevent BSE Spread
Sunday, May 27, 2012
GAIN REPORT BSE Case in United States Will Not Affect Trade, States
Canadian Food Inspection Agency
Subject: Bovine Spongiform Encephalopathy; Importation of Bovines and
Bovine Products APHIS-2008-0010-0008 RIN:0579-AC68
Comment from Terry Singeltary Document ID: APHIS-2008-0010-0008 Document
Type: Public Submission This is comment on Proposed Rule: Bovine Spongiform
Encephalopathy; Importation of Bovines and Bovine Products Docket ID:
APHIS-2008-0010 RIN:0579-AC68
Topics: No Topics associated with this document View Document: More
Document Subtype: Public Comment Status: Posted Received Date: March 22 2012, at
12:00 AM Eastern Daylight Time Date Posted: March 22 2012, at 12:00 AM Eastern
Daylight Time Comment Start Date: March 16 2012, at 12:00 AM Eastern Daylight
Time Comment Due Date: May 15 2012, at 11:59 PM Eastern Daylight Time Tracking
Number: 80fdd617 First Name: Terry Middle Name: S. Last Name: Singeltary City:
Bacliff Country: United States State or Province: TX Organization Name: CJD TSE
PRION Submitter's Representative: CONSUMERS
Comment: comment submission Document ID APHIS-2008-0010-0001
Greetings USDA,
OIE et al, what a difference it makes with science, from one day to the
next. i.e. that mad cow gold card the USA once held. up until that fateful day
in December of 2003, the science of BSE was NO IMPORTS TO USA FROM BSE COUNTRY.
what a difference a day makes$ now that the shoe is on the other foot, the USDA
via the OIE, wants to change science again, just for trade $ I implore the OIE
decision and policy makers, for the sake of the world, to refuse any status quo
of the USA BSE risk assessment. if at al, the USA BSE GBR should be raise to BSE
GBR IV, for the following reasons. North America is awash with many different
TSE Prion strains, in many different species, and they are mutating and
spreading. IF the OIE, and whatever policy makers, do anything but raise the
risk factor for BSE in North America, they I would regard that to be highly
suspicious. IN fact, it would be criminal in my opinion, because the OIE knows
this, and to knowingly expose the rest of the world to this dangerous pathogen,
would be ‘knowingly’ and ‘willfully’, just for the almighty dollar, once again.
I warned the OIE about all this, including the risk factors for CWD, and the
fact that the zoonosis potential was great, way back in 2002. THE OIE in
collaboration with the USDA, made the legal trading of the atypical Nor-98
Scrapie a legal global commodity. yes, thanks to the OIE and the USDA et al,
it’s now legal to trade the atypical Nor-98 Scrapie strain all around the globe.
IF you let them, they will do the same thing with atypical BSE and CWD (both
strains to date). This with science showing that indeed these TSE prion strains
are transmissible. I strenuously urge the OIE et al to refuse any weakening to
the USA trade protocols for the BSE TSE prion disease (all strains), and urge
them to reclassify the USA with BSE GBR IV risk factor.
SEE REFERENCE SOURCES IN ATTACHMENTS
PLEASE SEE Terry S. Singeltary Sr. _Attachment_ WORD FILE ;
***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.
Thursday, June 21, 2012
Clinical and Pathologic Features of H-Type Bovine Spongiform Encephalopathy
Associated with E211K Prion Protein Polymorphism
Friday, May 18, 2012
Update from APHIS Regarding a Detection of Bovine Spongiform Encephalopathy
(BSE) in the United States Friday May 18, 2012
Sunday, February 12, 2012
National Prion Disease Pathology Surveillance Center Cases Examined1
(August 19, 2011) including Texas
Sunday, June 3, 2012
A new neurological disease in primates inoculated with prion-infected blood
or blood components
layperson
Terry S. Singeltary Sr.
No comments:
Post a Comment
Note: Only a member of this blog may post a comment.