Friday, June 29, 2012

Highly Efficient Prion Transmission by Blood Transfusion

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






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.


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