Distinct Transmissibility Features of TSE Sources Derived from Ruminant Prion Diseases by the Oral Route in a Transgenic Mouse Model (TgOvPrP4) Overexpressing the Ovine Prion Protein Jean-Noël Arsac, Affiliation: Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (Anses), Unité Maladies Neuro-dégénératives, Lyon, France
X Thierry Baron mail * E-mail: firstname.lastname@example.org
Affiliation: Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (Anses), Unité Maladies Neuro-dégénératives, Lyon, France
X Published: May 05, 2014 DOI: 10.1371/journal.pone.0096215
Transmissible spongiform encephalopathies (TSEs) are a group of fatal neurodegenerative diseases associated with a misfolded form of host-encoded prion protein (PrP). Some of them, such as classical bovine spongiform encephalopathy in cattle (BSE), transmissible mink encephalopathy (TME), kuru and variant Creutzfeldt–Jakob disease in humans, are acquired by the oral route exposure to infected tissues. We investigated the possible transmission by the oral route of a panel of strains derived from ruminant prion diseases in a transgenic mouse model (TgOvPrP4) overexpressing the ovine prion protein (A136R154Q171) under the control of the neuron-specific enolase promoter. Sources derived from Nor98, CH1641 or 87V scrapie sources, as well as sources derived from L-type BSE or cattle-passaged TME, failed to transmit by the oral route, whereas those derived from classical BSE and classical scrapie were successfully transmitted. Apart from a possible effect of passage history of the TSE agent in the inocula, this implied the occurrence of subtle molecular changes in the protease-resistant prion protein (PrPres) following oral transmission that can raises concerns about our ability to correctly identify sheep that might be orally infected by the BSE agent in the field. Our results provide proof of principle that transgenic mouse models can be used to examine the transmissibility of TSE agents by the oral route, providing novel insights regarding the pathogenesis of prion diseases.
It is indeed apparent that the orally transmissible sources derived from classical BSE and scrapie were also able to propagate readily in the spleens of TgOvPrP4 mice, after both intra-cerebral and oral challenges. Among other sources that failed to transmit by the oral route, only L-BSE and bovine TME were lymphotropic by the intra-cerebral route at least during serial passages . As regards the scrapie sources and their transmissibility by peripheral routes, failure to transmit 87V by the oral route had already been reported in sheep, whereas the ME7, 79A and 22A murine strains were transmissible . Very low efficiency in transmitting this 87V strain was also reported in mice by intra-peritoneal route . Also, concerning the ovine scrapie sources, failure to transmit CH1641 scrapie by subcutaneous inoculation was reported in sheep . Oral transmission of Nor98 scrapie has been reported in sheep, but only of the A136 H154 Q171 homozygous prnp genotype , thus differing in this respect from TgOvPrP4 mice. The failure of both sources derived from L-BSE and bovine TME to be transmitted by the oral route in TgOvPrP4 is more intriguing. These are the most rapid ruminant TSEs in TgOvPrP4 mice by intra-cerebral route, which makes the results even more significant as transmission of the disease might be expected to occur within the life span of the mice, as observed for sources derived from classical BSE. Moreover we previously reported that L-BSE was readily transmissible from cattle by the oral route in another experimental model, the mouse lemur . In the case of TME, our strain typing studies in several experimental models highlighted similarities with L-BSE and suggested that TME could be the result of a food borne transmission of L-BSE in ranch-raised minks , . Transmission of these TSEs might involve particular pathways that could be affected in the TgOvPrP4 transgenic mouse model. Besides, our results could be influenced by the protocol used for experimental challenge involving intra-gastric administration, meaning that the inocula were not chewed by the mice, whereas in the case of experiments with L-BSE in lemurs, inocula were mixed to food. Alternatively, we can again consider the hypothesis that oral transmissibility could have been reduced by previous passages by the intra-cerebral route during the two passages in TgOvPrP4 mice, while initial brain samples of ruminants were not analyzed in this first oral route study.
However our results reveal the transmissibility of some TSEs by the oral route in a transgenic mouse model. Interestingly, some of our data suggest a possible influence of the passage history of inocula, including the inoculation routes or host features. These need careful consideration when interpreting data on the pathobiological properties of TSE agents in experimental models. To the best of our knowledge, this is the first report of oral transmission in a transgenic model expressing the prion protein of a species naturally affected by TSEs. It provides proof of principle that such models can constitute useful experimental tools for studies of oral transmission of prion diseases.
*** we have found a link between BSE and CH1641, a C-group of scrapie. Disease susceptibility of sheep to these isolates is associated with different PrP genotypes compared to SSBP/1 scrapie...
Transmission of BSE in sheep, goats and mice.
BSE has been transmitted in two lines of genetically selected sheep (differeing in their susceptibilities to the SSBP/1 source of scrapie), and to goats by intracerebral injection AND BY ORAL DOSING.
Also, intermediate passage of BSE in sheep or goats did not alter these primary transmission properties. Hamsters were susceptible to BSE only after intervening passage through mice...
NEW URL ;
> *** we have found a link between BSE and CH1641, a C-group of scrapie. ***
Wednesday, January 18, 2012
Selection of Distinct Strain Phenotypes in Mice Infected by Ovine Natural Scrapie Isolates Similar to CH1641 Experimental Scrapie
Journal of Neuropathology & Experimental Neurology:
February 2012 - Volume 71 - Issue 2 - p 140–147
why do we not want to do TSE transmission studies on chimpanzees $
5. A positive result from a chimpanzee challenged severly would likely create alarm in some circles even if the result could not be interpreted for man. I have a view that all these agents could be transmitted provided a large enough dose by appropriate routes was given and the animals kept long enough. Until the mechanisms of the species barrier are more clearly understood it might be best to retain that hypothesis.
1: J Infect Dis 1980 Aug;142(2):205-8
Oral transmission of kuru, Creutzfeldt-Jakob disease, and scrapie to nonhuman primates.
Gibbs CJ Jr, Amyx HL, Bacote A, Masters CL, Gajdusek DC.
Kuru and Creutzfeldt-Jakob disease of humans and scrapie disease of sheep and goats were transmitted to squirrel monkeys (Saimiri sciureus) that were exposed to the infectious agents only by their nonforced consumption of known infectious tissues. The asymptomatic incubation period in the one monkey exposed to the virus of kuru was 36 months; that in the two monkeys exposed to the virus of Creutzfeldt-Jakob disease was 23 and 27 months, respectively; and that in the two monkeys exposed to the virus of scrapie was 25 and 32 months, respectively. Careful physical examination of the buccal cavities of all of the monkeys failed to reveal signs or oral lesions. One additional monkey similarly exposed to kuru has remained asymptomatic during the 39 months that it has been under observation.
The successful transmission of kuru, Creutzfeldt-Jakob disease, and scrapie by natural feeding to squirrel monkeys that we have reported provides further grounds for concern that scrapie-infected meat may occasionally give rise in humans to Creutzfeldt-Jakob disease.
Recently the question has again been brought up as to whether scrapie is transmissible to man. This has followed reports that the disease has been transmitted to primates. One particularly lurid speculation (Gajdusek 1977) conjectures that the agents of scrapie, kuru, Creutzfeldt-Jakob disease and transmissible encephalopathy of mink are varieties of a single "virus". The U.S. Department of Agriculture concluded that it could "no longer justify or permit scrapie-blood line and scrapie-exposed sheep and goats to be processed for human or animal food at slaughter or rendering plants" (ARC 84/77)" The problem is emphasised by the finding that some strains of scrapie produce lesions identical to the once which characterise the human dementias"
Whether true or not. the hypothesis that these agents might be transmissible to man raises two considerations. First, the safety of laboratory personnel requires prompt attention. Second, action such as the "scorched meat" policy of USDA makes the solution of the acrapie problem urgent if the sheep industry is not to suffer grievously.
Nature. 1972 Mar 10;236(5341):73-4.
Transmission of scrapie to the cynomolgus monkey (Macaca fascicularis).
Gibbs CJ Jr, Gajdusek DC.
Nature 236, 73 - 74 (10 March 1972); doi:10.1038/236073a0
Transmission of Scrapie to the Cynomolgus Monkey (Macaca fascicularis)
C. J. GIBBS jun. & D. C. GAJDUSEK
National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, Maryland
SCRAPIE has been transmitted to the cynomolgus, or crab-eating, monkey (Macaca fascicularis) with an incubation period of more than 5 yr from the time of intracerebral inoculation of scrapie-infected mouse brain. The animal developed a chronic central nervous system degeneration, with ataxia, tremor and myoclonus with associated severe scrapie-like pathology of intensive astroglial hypertrophy and proliferation, neuronal vacuolation and status spongiosus of grey matter. The strain of scrapie virus used was the eighth passage in Swiss mice (NIH) of a Compton strain of scrapie obtained as ninth intracerebral passage of the agent in goat brain, from Dr R. L. Chandler (ARC, Compton, Berkshire).
Wednesday, February 16, 2011
SCRAPIE TRANSMISSION TO CHIMPANZEES
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"
PLEASE NOTE *
Over the next 8-10 weeks, approximately 40% of all the adult mink on the farm died from TME.
*** The rancher was a ''dead stock'' feeder using mostly (>95%) downer or dead dairy cattle...
Sunday, June 26, 2011
Risk Analysis of Low-Dose Prion Exposures in Cynomolgus Macaque
2011 Monday, September 26, 2011
L-BSE BASE prion and atypical sporadic CJD
*** October 2009 O.11.3
*** Infectivity in skeletal muscle of BASE-infected cattle
Silvia Suardi1, Chiara Vimercati1, Fabio Moda1, Ruggerone Margherita1, Ilaria Campagnani1, Guerino Lombardi2, Daniela Gelmetti2, Martin H. Groschup3, Anne Buschmann3, Cristina Casalone4, Maria Caramelli4, Salvatore Monaco5, Gianluigi Zanusso5, Fabrizio Tagliavini1 1Carlo Besta" Neurological Institute,Italy; 2IZS Brescia, Italy; 33FLI Insel Riems, D, Germany; 4CEA-IZS Torino, Italy; 5University of Verona, Italy
Background: BASE is an atypical form of bovine spongiform encephalopathy caused by a prion strain distinct from that of BSE. Upon experimental transmission to cattle, BASE induces a previously unrecognized disease phenotype marked by mental dullness and progressive atrophy of hind limb musculature. Whether affected muscles contain infectivity is unknown. This is a critical issue since the BASE strain is readily transmissible to a variety of hosts including primates, suggesting that humans may be susceptible.
Objectives: To investigate the distribution of infectivity in peripheral tissues of cattle experimentally infected with BASE. Methods: Groups of Tg mice expressing bovine PrP (Tgbov XV, n= 7-15/group) were inoculated both i.c. and i.p. with 10% homogenates of a variety of tissues including brain, spleen, cervical lymph node, kidney and skeletal muscle (m. longissimus dorsi) from cattle intracerebrally infected with BASE. No PrPres was detectable in the peripheral tissues used for inoculation either by immunohistochemistry or Western blot.
Results: Mice inoculated with BASE-brain homogenates showed clinical signs of disease with incubation and survival times of 175±15 and 207±12 days. Five out of seven mice challenged with skeletal muscle developed a similar neurological disorder, with incubation and survival times of 380±11 and 410±12 days. At present (700 days after inoculation) mice challenged with the other peripheral tissues are still healthy. The neuropathological phenotype and PrPres type of the affected mice inoculated either with brain or muscle were indistinguishable and matched those of Tgbov XV mice infected with natural BASE.
Discussion: Our data indicate that the skeletal muscle of cattle experimentally infected with BASE contains significant amount of infectivity, at variance with BSE-affected cattle, raising the issue of intraspecies transmission and the potential risk for humans. Experiments are in progress to assess the presence of infectivity in skeletal muscles of natural BASE.
*** 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.
Wednesday, March 28, 2012
VARIABLY PROTEASE-SENSITVE PRIONOPATHY IS TRANSMISSIBLE, price of prion poker goes up again $
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)
Monday, May 5, 2014
FSA H R Jasper & Son Limited prosecuted failing to remove specified risk material (SRM) from sheep carcasses destined for the food chain
H R Jasper & Son Limited prosecuted
*** These results would seem to suggest that CWD does indeed have zoonotic potential, at least as judged by the compatibility of CWD prions and their human PrPC target. Furthermore, extrapolation from this simple in vitro assay suggests that if zoonotic CWD occurred, it would most likely effect those of the PRNP codon 129-MM genotype and that the PrPres type would be similar to that found in the most common subtype of sCJD (MM1).
Saturday, April 19, 2014
Exploring the zoonotic potential of animal prion diseases: In vivo and in vitro approaches
CANADA SEE STEADY INCREASE OF THE SPORADIC CJD’S AND THE VPSPR’S (sporadic CJD’s). ...tss
PLEASE NOTE, type determination pending Creutzfeldt Jakob Disease (tdpCJD) in Canada is also on a steady increase.
please see ;
> 3. Final classification of 50 cases from 2009, 2010, 2011 and 2012 is pending.
CJD Deaths Reported by CJDSS1, 1994-20122
CJD Deaths Reported by CJDSS1, 1994-20122
As of May 31, 2012
SEE DECEMBER 2012 CANADA
USA SEE STEADY INCREASE OF THE SPORADIC CJD’S AND THE VPSPR’S (sporadic CJD’s). ...tss
National Prion Disease Pathology Surveillance Center
(May 18, 2012)
5 Includes 14 cases in which the diagnosis is pending, and 18 inconclusive cases;
6 Includes 17 (16 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 2118 cases of sporadic Creutzfeldt-Jakob disease (sCJD).
> 6 Includes
> 17 (16 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 2118 cases of sporadic Creutzfeldt-Jakob disease (sCJD).
WELL, it seems the USA mad cow strains in humans classified as type determination pending tdpCJD, VPSPr, sFFI, and sCJD) have steadily increased over the years, and the same old song and dance continues with sporadic CJD cases $$$
Creutzfeldt-Jakob Disease CJD cases rising North America updated report August 2013
*** Creutzfeldt-Jakob Disease CJD cases rising North America with Canada seeing an extreme increase of 48% between 2008 and 2010 ***
Sunday, October 13, 2013
*** CJD TSE Prion Disease Cases in Texas by Year, 2003-2012
Tuesday, April 01, 2014
Questions linger in U.S. CJD cases 2005, and still do in 2014
Sunday, March 09, 2014
A Creutzfeldt-Jakob Disease (CJD) Lookback Study: Assessing the Risk of Blood Borne Transmission of Classic Forms of Creutzfeldt-Jakob Disease
FDA TSEAC CIRCUS AND TRAVELING ROAD SHOW FOR THE TSE PRION DISEASES
Sunday, April 06, 2014
SPORADIC CJD and the potential for zoonotic transmission there from, either directly or indirectly via friendly fire iatrogenic mode, evidence to date
Wednesday, December 11, 2013
*** Detection of Infectivity in Blood of Persons with Variant and Sporadic Creutzfeldt-Jakob Disease ***