Unexpected decrease of full-length prion protein in macaques inoculated with prion-contaminated blood products
Jérôme Delmotte, Jacqueline Mikol, Jean-Philippe Deslys and Emmanuel Comoy*
Commissariat à l’Energie Atomique, DRF/IBFJ/SEPIA, Fontenay-aux-Roses, France
The presence of prion infectivity in the blood of patients affected by variant Creutzfeldt–Jakob disease (v-CJD), the human prion disease linked to the bovine spongiform encephalopathy (BSE), poses the risk of inter-human transmission of this fatal prion disease through transfusion. In the frame of various experiments, we have previously described that several cynomolgus macaques experimentally exposed to prion-contaminated blood products developed c-BSE/v-CJD, but the vast majority of them developed an unexpected, fatal disease phenotype focused on spinal cord involvement, which does not fulfill the classical diagnostic criteria of v-CJD. Here, we show that extensive analyses with current conventional techniques failed to detect any accumulation of abnormal prion protein (PrPv−CJD) in the CNS of these myelopathic animals, i.e., the biomarker considered responsible for neuronal death and subsequent clinical signs in prion diseases. Conversely, in the spinal cord of these myelopathic primates, we observed an alteration of their physiological cellular PrP pattern: PrP was not detectable under its full-length classical expression but mainly under its physiological terminal-truncated C1 fragment. This observed disappearance of the N-terminal fragment of cellular PrP at the level of the lesions may provide the first experimental evidence of a link between loss of function of the cellular prion protein and disease onset. This original prion-induced myelopathic syndrome suggests an unexpected wide extension in the field of prion diseases that is so far limited to pathologies associated with abnormal changes of the cellular PrP to highly structured conformations.
snip...
Discussion In the context of our transfusion experiments in cynomolgus macaque to model the risk of iatrogenic transmission of v-CJD, we have observed an original, previously undescribed pathological entity in which no PrPd accumulation was detected with the different techniques classically used to date, including not only the classical biochemical tests used for prion surveillance but also improved IHC techniques and misfolded protein amplification techniques (Comoy et al., 2017; 2018). This situation was reminiscent of our seminal observations of primary transmission of BSE from cattle to mice (Lasmezas et al., 1997), in which 50% of the animals developed a transmissible fatal disease in the absence of any detectable PrPres, which appeared after subsequent transmissions.
In this study, an extensive analysis of the CNS of myelopathic primates confirmed the absence of abnormal PrPv−CJD in its classical, abnormally folded, protease-resistant, hydrophobic, and aggregated configuration. This study incidentally showed that the topographical pattern of PrPres distribution in the CNS of macaques was not statistically different after they were infected with samples initially contaminated with c-BSE or v-CJD. This supports the idea that c-BSE and v-CJD are caused by a single prion strain (Bruce et al., 1997).
Despite the absence of classical PrPv−CJD, we kept on testing the prion hypothesis for this myelopathic syndrome based on its peculiar epidemiology, i.e., the occurrence of this disease only in animals exposed to blood products derived from c-BSE/v-CJD-infected donors. In both myelopathic and c-BSE/v-CJD-infected primates, the spinal cord showed reduced amounts of total PrP detectable by direct analysis in comparison to healthy controls. This observation confirms the involvement of the prion protein in the pathophysiology of the myelopathy syndrome observed. It should be noted that a decrease in PrPc has also been observed in a transgenic mouse model (Dupuis et al., 2002) and human cases of amyotrophic lateral sclerosis (Kovacs et al., 2002) and is also evoked in multiple sclerosis (Scalabrino, 2022), suggesting that these two other spinal cord diseases might probably share common neurodegenerative mechanisms and the decrease in PrPc, involved in several neurodegenerative disorders, could be a key element.
Further analyses based on the comparison of folded and unfolded states by heat treatment in the presence of denaturing agents showed that the lack of detection in the two groups of our animals had different origins. In myelopathic primates, the lack of detection was related to a strong deficiency of full-length PrP, whereas in BSE/v-CJD primates, full-length PrP was detectable after unfolding, indicating that it was preserved from degradation by an aggregated form of PrPd that impairs recognition of certain epitopes by antibodies without a prior denaturation step as classically reported (Safar et al., 2000). In both cases, the functional role of fl-PrP should be altered, but in myelopathic primates, we face a unique experimental situation in which a loss of function of PrPc is clearly uncorrelated with the classical additional neurotoxic effect of PrPd aggregates.
The majority of normal PrP is known to be expressed as a GPI-linked cell surface glycoprotein, and surprisingly, in transgenic mice expressing PrP devoid of GPI anchoring, a classical prion strain (RML scrapie) does not induce clinical disease despite the presence of amyloid PrPres and replication of scrapie infectivity (Chesebro et al., 2005). In contrast, in our experimental model without amyloid PrPres, we observed clinical signs linked to a spinal cord involvement that is consistent with lesions in the cervical spinal cord in which the majority of PrP has lost its N-terminus, suggesting a link with a loss of function of this corrupted PrP.
Several studies report that the truncation of its N-terminus somehow alters the normal biological activity of PrPc in a way that produces neurotoxic effects (Shmerling et al., 1998; Li et al., 2007; Sonati et al., 2013; Le et al., 2019). However, all these artificial transgenic models question their relevance to a natural situation that integrates multiple highly regulated molecular mechanisms (Wulf et al., 2017). Neuronal expression of membrane-anchored PrPc is known to be required for prion-induced neurodegeneration in vivo (Brandner et al., 1996; Mallucci et al., 2003; Chesebro et al., 2005). The elegant seminal experiments of grafting neural tissue overexpressing PrPC into the brain of PrP-deficient mice (Prnp0/0) demonstrated not only that after prion infection (scrapie RML strain), only the grafts were destroyed with PrPsc toxic accumulation but also that surrounding tissue devoid of PrPC remained healthy despite the diffusion of PrPsc aggregates from the grafts (Brandner et al., 1996). Here, we face a reverse situation in myelopathic primates, with the absence of toxic aggregated PrP and a pathology associated with the natural N-terminal truncation of the majority of PrPc in their spinal cord. It should be noted that the absence of N-terminal regions of PrPc is suspected to induce vulnerability to the ischemic brain, heart, or kidney damage, with higher apoptotic cell death and higher oxidative stress in the damaged tissues (Hara and Sakaguchi, 2020). The preferential involvement of the cervical spinal cord in the lesions of our myelopathic primates might be related to a higher vulnerability of this portion to trauma, according to its daily solicitation.
From an evolutionary point of view, the remarkable conservation of PrPc in vertebrates, especially in mammals, its high turnover rate, and its expression in all tissues strongly suggest important physiological functions of this protein (van Rheede et al., 2003; Aguzzi et al., 2008; Gasperini and Legname, 2014; Hirsch et al., 2017). Among the multiple functions suggested for PrP, the maintenance of myelin in peripheral nerves is the main role gathering relative consensus. Mice ablated for PrP (first-generation PrP knockout mice and prnp-ablated mice generated through genome editing) (Bremer et al., 2010; Nuvolone et al., 2016) and goats lacking PrP (Skedsmo et al., 2020) develop a progressive peripheral demyelinating neuropathy, whose mechanism is now foreseen. The N-terminal flexible tail of PrP activates the adhesion of G-protein-coupled receptor Adgrgr6 on Schwann cells, whose activation is necessary for the maintenance of myelin (Küffer et al., 2016).
In contrast to this well-documented situation in the peripheral nerves, the role of PrP in myelin physiology at the level of the central nervous system is less clear in the literature. Oligodendrocytes are classically considered resistant to infection, and neuropathological alterations, although extensive and variable, have been considered limited to cortical and subcortical gray matter in human CJD. However, cases of the “panencephalopathic” type of CJD initially reported in Japan (Mizutani et al., 1981) suggested the possibility of primary involvement of white matter, at least with some prion strains, and the description of oligodendrocytes engulfed within the cytoplasm of hypertrophic astrocytes (emperipolesis) was later reported to be common in the cerebral white matter of sporadic CJD patients (Shintaku and Yutani, 2004). More recently, oligodendrocyte vulnerability and myelin alterations were reported in the advanced stages of murine CJD (Andrés-Benito et al., 2021). Our data suggest that PrPc would also play a key role in the maintenance of myelin in the central nervous system, and its loss of function would be involved in the myelopathic lesions observed in the spinal cord with demyelination of the posterior tracts, which is coherent with the loss of sensitivity that we observed in our primates.
To our knowledge, here we observe the first experimental situation of detection of a specific biochemical signature in a prion disease without detectable PrPres. However, while the natural resistance to degradation of aggregated PrPd allows detection of even minute amounts among normal cellular PrP, here we are in the opposite situation of an abnormally fragile corrupted PrP that becomes undetectable among total cellular PrP unless it becomes the majority. This is the case in the spinal cord lesions that we tested.
All the prion disease entities that have been described so far for decades are based on PrPc that undergoes conformational changes towards more structured states, which provide to the resulting PrPd different properties that tend to overall increase their resistance to degradation compared to PrPc; even diseases that are described as intermediate or protease-sensitive forms (Nor98 and vPSPr) are associated with PrPd that exhibit a more structured conformation than PrPc. These properties pave the way for different approaches used for decades to diagnose prion diseases in the absence of conformational antibodies. The less-resistant physiological PrP is classically eliminated so that PrPd remains the only form detectable by specific anti-PrP antibodies.
Here, the PrP in the spinal cord of the myelopathic primates is apparently cleaved in greater amounts than the classical physiological PrPc in the spinal cord of their healthy counterparts, indicating a greater sensitivity of this abnormal PrP to proteolytic processes. We hypothesized that in these animals, pathological conformational changes would occur that lead to pathological PrP with less structured conformations than physiological PrPc, which would then make this PrPd more susceptible to enzymatic degradation and, thus, to natural elimination.
Furthermore, this excess of C1 production might be considered a cellular mechanism of defense against prion infection. Our studies of physiological PrP fragments have shown that depletion of fl-PrP in the spinal cord of our myelopathic primates is associated with a depletion of the C2 fragment, while C1 apparently remains present in normal amounts; this abnormal pattern suggests an imbalance of α- and β-cleavages compared to healthy macaques, as the signature of a profound alteration in PrP physiology in contrast to the normal pattern of fl-PrP expression in the brains of these animals.
Although several studies report conflicting results regarding the roles of ADAM9, ADAM10, and ADAM17 in α-cleavage of PrPc, it is generally admitted that alpha-cleavage and C1 are protective against prion misfolding (Westergard et al., 2011). Furthermore, the α-cleavage site located in the neurotoxic domain is suspected to be involved in the misfolding of PrPc into PrPd; therefore, the absence of this domain in C1 has been proposed to explain why only fl-PrP and C2 could be misfolded into PrPd (Chen et al., 1995). According to this hypothesis, in our myelopathic macaques, the disappearance of fl-PrP and the absence of C2 would protect against any mechanism of prion conversion to PrPd but would also result in a loss of the physiological signal for the maintenance of myelin. This molecular shift could then correspond to a natural cellular mechanism for fighting a prion infection, with three possible outcomes:
- In most situations, this mechanism would prevent low prion infectious doses from initiating a perennial replication and allow the elimination of residual infectivity by cellular catabolism in individuals who would remain apparently healthy
- At the other extreme, if this mechanism is saturated by a high infectious dose and/or an aggressive prion strain, the infection would lead to the onset of classical prion disease
- Finally, in the third scenario, with low infectious doses and a sufficiently aggressive strain, such as the one responsible for vCJD, this mechanism is sufficient to contain the infection but not to eliminate it, and such low-level replication keeps this physiological mechanism abnormally active in the long term with the pathological consequences on the myelin that we observe in our myelopathic animals.
In conclusion, we have identified here for the first time a new specific biochemical signature that supports the prion origin of the myelopathic syndrome that we observe in our macaques exposed to contaminated blood products and potentially a natural cellular defense mechanism against prions that failed in diseased animals. This myelopathic syndrome opens new perspectives in the field of prion diseases towards alternative conformations of abnormal PrP never studied before, i.e., abnormal forms less resistant than the physiological PrP and, therefore, complex to evidence. This concept justifies the need to revisit several neurodegenerative diseases, in particular those affecting the spinal cord, in light of our observations in primates, for which the search for abnormal PrP by conventional techniques is inadequate.
Data availability statement...snip...end
''This concept justifies the need to revisit several neurodegenerative diseases, in particular those affecting the spinal cord, in light of our observations in primates, for which the search for abnormal PrP by conventional techniques is inadequate.''
Saturday, February 2, 2019
CWD GSS TSE PRION SPINAL CORD, Confucius Ponders, What if?
snip...
***> In particular the US data do not clearly exclude the possibility of human (sporadic or familial) TSE development due to consumption of venison. The Working Group thus recognizes a potential risk to consumers if a TSE would be present in European cervids.'' Scientific opinion on chronic wasting disease (II) <***
REVIEW
***> In conclusion, sensory symptoms and loss of reflexes in Gerstmann-Sträussler-Scheinker syndrome can be explained by neuropathological changes in the spinal cord. We conclude that the sensory symptoms and loss of lower limb reflexes in Gerstmann-Sträussler-Scheinker syndrome is due to pathology in the caudal spinal cord. <***
***> The clinical and pathological presentation in macaques was mostly atypical, with a strong emphasis on spinal cord pathology.<***
***> The notion that CWD can be transmitted orally into both new-world and old-world non-human primates asks for a careful reevaluation of the zoonotic risk of CWD. <***
***> All animals have variable signs of prion neuropathology in spinal cords and brains and by supersensitive IHC, reaction was detected in spinal cord segments of all animals.<***
***> In particular the US data do not clearly exclude the possibility of human (sporadic or familial) TSE development due to consumption of venison. The Working Group thus recognizes a potential risk to consumers if a TSE would be present in European cervids.'' Scientific opinion on chronic wasting disease (II) <***
Thursday, March 8, 2018
Familial human prion diseases associated with prion protein mutations Y226X and G131V are transmissible to transgenic mice expressing human prion protein
Thursday, March 8, 2018
Familial human prion diseases associated with prion protein mutations Y226X and G131V are transmissible to transgenic mice expressing human prion protein
snip...see full text;
Saturday, February 2, 2019
CWD GSS TSE PRION SPINAL CORD, Confucius Ponders, What if?
Successful transmission of the chronic wasting disease (CWD) agent to white-tailed deer by intravenous blood transfusion
Najiba Mammadova a b, Eric Cassmann a b, Justin J. Greenlee a
a Virus and Prion Research Unit, National Animal Disease Center, USDA, Agricultural Research Service, 1920 Dayton Avenue, Ames, IA 50010, USA b Oak Ridge Institute for Science and Education (ORISE), USA
Received 7 May 2020, Revised 9 October 2020, Accepted 14 October 2020, Available online 16 October 2020, Version of Record 7 December 2020.
While a previous and larger study showed similar results, we determined that only 100 mL of CWD-infected blood (~2.5 times less than previously shown in (Mathiason et al., 2010)) contained sufficient levels of prion infectivity to cause disease. The identification of blood-borne transmission of the CWD agent is important in reinforcing the risk of exposure to CWD via blood as well as the possibility of hematogenous transmission of the CWD agent through insect vector. Finally, these results further highlight the importance of developing a sensitive and reproducible blood-based test to detect pre-clinical CWD, and warrant the continued advancement and evaluation of sensitive antemortem diagnostic tests for the detection of PrPSc in blood of asymptomatic cervids early in the incubation period.
Comment from Terry Singeltary
Posted by the Food and Drug Administration on Feb 2, 2020
Greetings FDA et al,
I would again kindly like to comment on Docket Number: FDA-2012-D-0307, Docket Number: FDA-2012-D-0307 Recommendations to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease by Blood and Blood Components; Draft Guidance for Industry Draft Guidance for Industry.
I still believe, that it is extremely dangerous to continue to base the safety of blood from the TSE Prion, by only believing the nvcjd only theory.
TSE Prion disease have expanded to other species i.e. the camel, and we now know that cwd and scrapie will transmit to pigs by oral routes.
Chronic Wasting Disease CWD TSE Prion in cervid has exploded across the USA, Canada, Mexico has now clue, Norway, Sweden, Finland, S. Korea, and we know that cwd is detected in the blood of cervid. CWD TSE Prion is highly infectious, and the risk factors from blood there from are very real.
we also know that all iatrogenic CJD is, is sporadic CJD, until the iatrogenic event is discovered, traced back, proven, documented in the academic domain, and finally the public domain, which very seldom happens due to lack of trace back efforts, thus, all iatrogeic events stay as sporadic cjd.
with the blood of cervid and cwd tse prion being detected there from, the science showing that cwd zoonotic potential is now real, the many different strains of cwd to date, with no real factor of how many different strains there are, with science now showing that indeed BSE, Scrapie, and CWD, both typical and atypical strains, showing scientific links to sporadic cjd, and that cwd in humans would would NOT look like nvcjd, but science shows that it would look like sporadic cjd, therefore, iatrogenic cjd from human cwd exposure is very real threat, i find these weakening of rules for blood risk factors from all the different strains of sporadic cjd very worrisome, especially now that officials are classifying vpspr, sgss, sffi, as sporadic cjd cases. we have no clue whether or not these are from iatrogenic events or not. this will be a foolish move if we put once again, corporate interest over human and animal health, but does not surprise me.
THIS will be very dangerous, and a foolish move for people who need blood, and for the medical and surgical theaters, and humans there from, and simply are not based on sound science imo, but are based on corporate greed.
WE KNOW now that the real statistics on human TSE Prion IS NOT one in a million, but data now shows that sporadic CJD, 85%+ of all human TSE Prion, the read statistics now show that those figures are one in 5,000. and sporadic cjd is NOT a single strain, but many, many, different strains, and the routes and sources are simply unknown.
NO WHERE IN SCIENCE LITERATURE HAS THE SPONTANEOUS CJD EVER BEEN PROVEN, without route and source, a happenstance of bad luck, this is simply wishful thinking$
TO weaken, instead of enhance and strengthen the risk of sporadic CJD tse prion from blood products by this Docket Number FDA-2012-D-0307 Recommendations, will only enhance the risk of TSE Prion to hemophiliacs, the medical and surgical arenas around the globe yes, human tse prion are now 1 in 5,000. let that sink in.
THURSDAY, JANUARY 30, 2020
Docket Number: FDA-2012-D-0307 Recommendations to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease and Variant Creutzfeldt-Jakob Disease by Blood and Blood Components; Draft Guidance for Industry Draft Guidance for Industry Singeltary Submission
PLEASE SEE MORE in PDF download file
see full text submission here;
ACDP_Minutes _126
ADVISORY COMMITTEE ON DANGEROUS PATHOGENS
The 126th meeting of ACDP held on Thursday 2nd March 2023
Microsoft Teams Meeting
MINUTES
Snip…
2.6. Action: Member to keep a watching brief on the work of Hannaoui et al., on “Transmission of cervid prions to humanized mice demonstrates the zoonotic potential of CWD” and related work and report back to the committee. Ongoing. The Committee received an update on prion diseases at this meeting (see below).
2.7. Action: Member to keep watching brief on appendix studies as they are published and report back to ACDP regularly. Ongoing. The Committee received an update on prion diseases at this meeting (see below).
2.8. The ACDP to make a suggestion that prion diseases should be considered for inclusion in the UK risk assessment register given that BSE cases have occurred in the UK. Completed and ongoing. The Committee’s suggestion has been recorded in the November 2022 meeting minutes; other places to convey this message are being considered. The chair stated that prion diseases have been included in the risk register in Scotland. A member stated that non-inclusion of prion-diseases on the risk register is an omission and there are major impact risks relating to prion diseases that should be listed on the register. It was agreed that risks related to prions can be considered for inclusion when the risk register undergoes a refresh as it does regularly. A member stated that they would contribute to identifying the specific prion risks for inclusion into this register.
Snip…
4. Prions and prion diseases update
4.1. The chair invited a member to provide a verbal scientific update. The member gave an update on UK surveillance for prion diseases and stated that there are no major changes to the figures collected by the National CJD research and surveillance unit since the last meeting. The total number of deaths from probable or definite prion diseases (mainly CJD) have remained between 134 and 151 for the last six years. The vast majority of these deaths are attributed to sporadically occurring CJD (which comprises 90% of the total). There have been 5 cases of transmitted CJD in the last five years, all related to the use of cadaveric human growth hormone in the 1970s. The small numbers of cases represent the right tail of the outbreak where 80 total cases have been in reported in the UK (several hundred worldwide).
4.2. The member provided an update on chronic wasting disease. The disease was first detected in the USA and this is where extensive surveillance relating to zoonotic potential is being carried out. There are no significant updates relating to CWD findings in Scandinavia.
4.3. The member provided an update on the situation relating to BSE and stated that late sequalae of BSE are monitored carefully. Currently, the UK is in a situation where onerous measures established to protect public health in this area are being relaxed, in contrast to the situation at the peak of the BSE epidemic when there was considerably more uncertainty relating to adverse outcomes. The member highlighted the issue of surveillance of prevalence of BSE in the UK human population, studied by investigation of archival appendices in a series of studies organised by DHSC. Results estimated a prevalence of 1 in 2000 carriers in the human population. The member stated that cases of vCJD have not been observed in recent years; the last case was diagnosed in 2016.
4.4. A number of scientific studies were commissioned to further understand the above 1 in 2000 estimated prevalence rate, one of these studies was detailed at the November 2022 meeting. The member asked the chair whether any discussions had taken place with DHSC around how the scientific data generated from these studies will be interpreted and any updates needed to be made to risk management advice in light of the findings. The member stated that it could be appropriate to establish a prion diseases subgroup to review all the evidence from the studies and subsequently issue updated advice. DHSC stated that it had recently submitted a witness statement to the infected blood inquiry concerning historic measures that had 1 Communicable disease threats report, 30 January - 5 February 2023, week 5 (europa.eu)been put in place regarding vCJD and are awaiting the final report and recommendations from the infected blood inquiry in the summer. It is expected that there will be recommendations on ensuring the ongoing safety of blood in the UK and to provide reassurances on the current blood safety regime. DHSC has also been approached by the vCJD trust responsible for compensation payments to individuals who have developed BSE as a result of consuming BSE-infected beef, around the lack of cases since 2016 and around the possibility of undertaking a review of the charities articles and functioning. DHSC stated that it is an appropriate time to re- examine the risk of vCJD in the UK population. This is an area that should be on the longer term workplan (in the next 12 months), but it is important to obtain the results of the infected blood inquiry initially and considering the Government response to this report. Action: DHSC to discuss this issue with the chair as part of the ACDP work programme. The chair agreed that establishing a subgroup would be appropriate in the near future.
4.5. The member stated that it is important to update the guidelines for healthcare settings which are over 20 years old and this was an area that they would take forward. Action: It was agreed that a specialist subgroup could be established to do this at an appropriate time.
The 126th meeting of ACDP held on Thursday 2nd March 2023
2.6. Action: Member to keep a watching brief on the work of Hannaoui et al., on “Transmission of cervid prions to humanized mice demonstrates the zoonotic potential of CWD” and related work and report back to the committee. Ongoing. The Committee received an update on prion diseases at this meeting (see below).
Prions and proteopathic seeds: Safe Working and the Prevention of Infection
PART 3
Laboratory containment and control measures
Advisory Committee on Dangerous Pathogens TSE subgroup minutes, papers and agendas
Variant Creutzfeldt–Jakob Disease Diagnosed 7.5 Years after Occupational Exposure
July 2, 2020
N Engl J Med 2020; 383:83-85
DOI: 10.1056/NEJMc2000687
Thursday, June 15, 2023
nvCJD or vCJD TSE PrP, and Blood, updated information
This years WOHA OIE End to atypical BSE reporting
Tuesday, May 30, 2023
World Organisation for Animal Health 90th General Session of the World Assembly of Delegates BSE TSE Prion 2023
RECENT MAD COW CASES
Wednesday, May 24, 2023
WAHIS, WOAH, OIE, United States of America Bovine spongiform encephalopathy Immediate notification
Monday, March 20, 2023
WAHIS, WOAH, OIE, REPORT United Kingdom Bovine Spongiform Encephalopathy Atypical H-Type
WAHIS, WOAH, OIE, REPORT Switzerland Bovine Spongiform Encephalopathy Atypical L-Type
Switzerland Bovine Spongiform Encephalopathy Atypical L-Type
Switzerland - Bovine spongiform encephalopathy - Immediate notification
BRAZIL BSE START DATE 2023/01/18
BRAZIL BSE CONFIRMATION DATE 2023/02/22
BRAZIL BSE END DATE 2023/03/03
SPAIN BSE START DATE 2023/01/21
SPAIN BSE CONFIRMATION DATE 2023/02/03
SPAIN BSE END DATE 2023/02/06
NETHERLANDS BSE START DATE 2023/02/01
NETHERLANDS BSE CONFIRMATION DATE 2023/02/01
NETHERLANDS BSE END DATE 2023/03/13
***Moreover, sporadic disease has never been observed in breeding colonies or primate research laboratories, most notably among hundreds of animals over several decades of study at the National Institutes of Health25, and in nearly twenty older animals continuously housed in our own facility.***
Even if the prevailing view is that sporadic CJD is due to the spontaneous formation of CJD prions, it remains possible that its apparent sporadic nature may, at least in part, result from our limited capacity to identify an environmental origin.
OIE Conclusions on transmissibility of atypical BSE among cattle
Given that cattle have been successfully infected by the oral route, at least for L-BSE, it is reasonable to conclude that atypical BSE is potentially capable of being recycled in a cattle population if cattle are exposed to contaminated feed. In addition, based on reports of atypical BSE from several countries that have not had C-BSE, it appears likely that atypical BSE would arise as a spontaneous disease in any country, albeit at a very low incidence in old cattle. In the presence of livestock industry practices that would allow it to be recycled in the cattle feed chain, it is likely that some level of exposure and transmission may occur. As a result, since atypical BSE can be reasonably considered to pose a potential background level of risk for any country with cattle, the recycling of both classical and atypical strains in the cattle and broader ruminant populations should be avoided.
Annex 7 (contd) AHG on BSE risk assessment and surveillance/March 2019
34 Scientific Commission/September 2019
3. Atypical BSE
The Group discussed and endorsed with minor revisions an overview of relevant literature on the risk of atypical BSE being recycled in a cattle population and its zoonotic potential that had been prepared ahead of the meeting by one expert from the Group. This overview is provided as Appendix IV and its main conclusions are outlined below. With regard to the risk of recycling of atypical BSE, recently published research confirmed that the L-type BSE prion (a type of atypical BSE prion) may be orally transmitted to calves1 . In light of this evidence, and the likelihood that atypical BSE could arise as a spontaneous disease in any country, albeit at a very low incidence, the Group was of the opinion that it would be reasonable to conclude that atypical BSE is potentially capable of being recycled in a cattle population if cattle were to be exposed to contaminated feed. Therefore, the recycling of atypical strains in cattle and broader ruminant populations should be avoided.
4. Definitions of meat-and-bone meal (MBM) and greaves
The L-type BSE prion is much more virulent in primates and in humanized mice than is the classical BSE prion, which suggests the possibility of zoonotic risk associated with the L-type BSE prion
Consumption of L-BSE–contaminated feed may pose a risk for oral transmission of the disease agent to cattle.
Thus, it is imperative to maintain measures that prevent the entry of tissues from cattle possibly infected with the agent of L-BSE into the food chain.
Atypical L-type bovine spongiform encephalopathy (L-BSE) transmission to cynomolgus macaques, a non-human primate
Fumiko Ono 1, Naomi Tase, Asuka Kurosawa, Akio Hiyaoka, Atsushi Ohyama, Yukio Tezuka, Naomi Wada, Yuko Sato, Minoru Tobiume, Ken'ichi Hagiwara, Yoshio Yamakawa, Keiji Terao, Tetsutaro Sata
Affiliations expand
PMID: 21266763
Abstract
A low molecular weight type of atypical bovine spongiform encephalopathy (L-BSE) was transmitted to two cynomolgus macaques by intracerebral inoculation of a brain homogenate of cattle with atypical BSE detected in Japan. They developed neurological signs and symptoms at 19 or 20 months post-inoculation and were euthanized 6 months after the onset of total paralysis. Both the incubation period and duration of the disease were shorter than those for experimental transmission of classical BSE (C-BSE) into macaques. Although the clinical manifestations, such as tremor, myoclonic jerking, and paralysis, were similar to those induced upon C-BSE transmission, no premonitory symptoms, such as hyperekplexia and depression, were evident. Most of the abnormal prion protein (PrP(Sc)) was confined to the tissues of the central nervous system, as determined by immunohistochemistry and Western blotting. The PrP(Sc) glycoform that accumulated in the monkey brain showed a similar profile to that of L-BSE and consistent with that in the cattle brain used as the inoculant. PrP(Sc) staining in the cerebral cortex showed a diffuse synaptic pattern by immunohistochemistry, whereas it accumulated as fine and coarse granules and/or small plaques in the cerebellar cortex and brain stem. Severe spongiosis spread widely in the cerebral cortex, whereas florid plaques, a hallmark of variant Creutzfeldt-Jakob disease in humans, were observed in macaques inoculated with C-BSE but not in those inoculated with L-BSE.
see full text;
''H-TYPE BSE AGENT IS TRANSMISSIBLE BY THE ORONASAL ROUTE''
This study demonstrates that the H-type BSE agent is transmissible by the oronasal route. These results reinforce the need for ongoing surveillance for classical and atypical BSE to minimize the risk of potentially infectious tissues entering the animal or human food chains.
IBNC Tauopathy or TSE Prion disease, it appears, no one is sure
Terry S. Singeltary Sr., 03 Jul 2015 at 16:53 GMT
***however in 1 C-type challenged animal, Prion 2015 Poster Abstracts S67 PrPsc was not detected using rapid tests for BSE.
***Subsequent testing resulted in the detection of pathologic lesion in unusual brain location and PrPsc detection by PMCA only.
*** IBNC Tauopathy or TSE Prion disease, it appears, no one is sure ***
SATURDAY, SEPTEMBER 24, 2022
Transmission of CH1641 in cattle
MONDAY, NOVEMBER 30, 2020
***> REPORT OF THE MEETING OF THE OIE SCIENTIFIC COMMISSION FOR ANIMAL DISEASES Paris, 9–13 September 2019 BSE, TSE, PRION
see updated concerns with atypical BSE from feed and zoonosis...terry
Monday, May 22, 2023
BSE TSE Prion MAD COW TESTING IN THE USA COMPARED TO OTHER COUNTRIES?
CDC says ''5 cases per million in persons 55 years of age or older.''
MONDAY, APRIL 24, 2023
Prion Disease on the Rise in the U.S., Now the question is, why?
''5 cases per million in persons 55 years of age or older.''
Terry S. Singeltary Sr.
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