The kuru infectious agent is a unique geographic isolate distinct from Creutzfeldt–Jakob disease and scrapie agents
Laura Manuelidis1, Trisha Chakrabarty, Kohtaro Miyazawa, Nana-Aba Nduom, and Kaitlin Emmerling Section of Neuropathology, Yale University Medical School, 333 Cedar Street, New Haven, CT 06510 Communicated by Sheldon Penman, Massachusetts Institute of Technology, Brookline, MA, May 27, 2009 (received for review March 27, 2009)
Human sporadic Creutzfeldt–Jakob disease (sCJD), endemic sheep scrapie, and epidemic bovine spongiform encephalopathy (BSE) are caused by a related group of infectious agents. The new U.K. BSE agent spread to many species, including humans, and clarifying the origin, specificity, virulence, and diversity of these agents is critical, particularly because infected humans do not develop disease for many years. As with viruses, transmissible spongiform encephalopathy (TSE) agents can adapt to new species and become more virulent yet maintain fundamentally unique and stable identities. To make agent differences manifest, one must keep the host genotype constant. Many TSE agents have revealed their independent identities in normal mice. We transmitted primate kuru, a TSE once epidemic in New Guinea, to mice expressing normal and 8-fold higher levels of murine prion protein (PrP). High levels of murine PrP did not prevent infection but instead shortened incubation time, as would be expected for a viral receptor. Sporadic CJD and BSE agents and representative scrapie agents were clearly different from kuru in incubation time, brain neuropathology, and lymphoreticular involvement. Many TSE agents can infect monotypic cultured GT1 cells, and unlike sporadic CJD isolates, kuru rapidly and stably infected these cells. The geographic independence of the kuru agent provides additional reasons to explore causal environmental pathogens in these infectious neurodegenerative diseases.
snip...
Discussion The kuru agent stands out from the other CJD and scrapie agents here on the basis of incubation times, behavior, and neuropathology in 2 mouse genotypes. There was no evidence that it resembles or derives from sCJD. The clearly unique behavioral changes documented with each different agent in mice are compatible with the vastly different regional neuropathological changes that they induce. Additionally, whereas 15 independent sCJD isolates readily transmitted to hamsters (8), the kCJD sample did not. Remarkably, even after several prolonged 350-day serial passages in mice, the sCJD agent retained its capacity to reinfect hamsters with a short 150-day incubation and provoked the original widespread hamster lesions (8). The stability of sCJD agents, regardless of whether first passaged in multiple or in no other species, is also evident in the invariant scratching behavior and the highly restricted thalamic lesions produced in mice. The GT1 culture experiments recapitulated major kCJD and sCJD differences. Whereas sCJD produced negligible PrP-res, kCJD brain homogenates reproducibly infected and stably induced large amounts of PrP-res in GT1 cells. As in brain, kCJD did not provoke any unique agent-specific PrP-res band pattern that bred true. Rather, it showed only the standard GT1 pattern. On the basis of previous results, the GT1 PrP-res pattern confers no demonstrable change in the fundamental identity and behavior of TSE infectious agents (9, 16, 34).
Spleen studies further separated kuru and sCJD agents. The kCJD agent induced major accumulations of abnormal PrP in FDCs of the lymphoreticular system, whereas sCJD isolates provoked very few. Although different species infected with a single agent can show different levels of infectivity and pathological PrP deposits in the spleen, abnormal PrP in the spleen has important biological consequences, given the person-to-person transmission of vCJD by transfusion (11). The observation of abundant deposits in kCJD-infected mouse spleen, in addition to the infectivity of kCJD in primate spleens (31), supports transmission of kuru not only through ingestion but also via the bloodstream from wounds incurred during ritual cannibalism (1). The bloodstream is an excellent conduit for rapid and effective infection of many tissues, including the gastrointestinal tract (12, 35).
We have shown 100% transmission of the infectious kuru agent to both normal and Tg mice with WT murine PrP. Recently, kuru was transmitted to Tg mice overexpressing human PrP sequences (22) but not to normal mice. High numbers of PrP copies can enhance the development of rapid murine models, and the kCJD model here, like the vCJD model previously (11), yielded shorter incubation times than humanized PrP mice. Thus, the TSE infec- tious particle rather than the host’s PrP sequence defines crossspecies virulence. The sCJD agent is also relatively incapable of adaptive evolution in mice. Even after 8 passages, it has a very prolonged incubation time of 300 days, in contrast to kCJD and vCJD. Current and previous data do not support a conversion of homologous PrP to an infectious form, but are in accord with the proposal that host PrP is a required agent receptor that can modulate disease expression. Host receptor differences often modulate viral infection and disease progression. The kCJD and other TSE agents here maintain their fundamental identity, despite their adaptation to a new species and to monotypic cells with disparate cell-type-specific PrP bands.
The PrP-res band patterns often are presumed to encode agentspecific information, yet they are a relatively poor indicator of the biological diversity and stability of TSE agents. In the present studies, only the vCJD agent elicited a consistent PrP-res marker in different species and cell types that bred true. Eleven other independent isolates did not (11, 32). In contrast, incubation times are clearly distinctive for each agent group and nonoverlapping when both CD-1 and Tga20 values are considered. The extreme precision of incubation time with each type of agent is really quite remarkable and remains unexplained by prion theory. It also begs the question of what type of viral (nucleic acid) sequence could lead to this diversity, and this further underscores both complex and subversive interactions between these TSE agents and their hosts. The differential susceptibility of neuronal subtypes with the same PrP to the various TSE agents presents yet another conundrum for prion theory.
There are many aspects of TSE agent biology and structure that remain unresolved, but these agents clearly encode individual virus-like properties. None of these diverse biological properties can be explained parsimoniously by the prion hypothesis or by actual PrP observations. The many distinct geographic TSE agents, the local outbreak of epidemic kuru and BSE, the rare but sudden mutation or progressive selection of new virulent strains (14, 15), and the endemic perpetuation of infection only in exposed hosts (as in sheep scrapie) strongly implicate a viral structure in the environment (10). On a structural level, the presence of nucleic acid in all infectious preparations and the consistent observation of virus-like ultrastructural particles support this hypothesis. Although host PrP as well as other factors may modulate susceptibility to infection and disease phenotype, there is also no simple genetic inheritance pattern, nor evidence for a spontaneous conversion of PrP into an infectious form.
The clear distinction of kuru from western sCJD, its occurrence only in New Guinea, and the observation that Japanese CJD is limited to Asia make one suspect that additional geographic TSE isolates in the environment may be uncovered. The U.S. stopped its scrapie eradication program years ago, before comparative rodent and culture models were introduced. Since then, scrapie agents with new properties may have evolved, possibly facilitating their spread to deer in the U.S. Geographic French scrapie agents are different (31), and Europe appears to be free of U.S. cervid TSE. An understanding of the origin, relative virulence, individual properties, and molecular structure of TSE agents remains a fundamental problem and a public health issue. The distinctive biology of a wide variety of TSE agents revealed in mice and in monotypic cultures already has defined intrinsic agent properties, and simplified cultures may allow one to follow and develop ways to limit the spread of different environmental TSE agents.
Methods
snip...see full text ;
http://www.pnas.org/content/early/2009/07/23/0905825106.full.pdf+html
Sent: Monday, July 27, 2009 10:31 PM
CJD-L] [BSE-L] U.S.A. HIDING MAD COW DISEASE VICTIMS AS SPORADIC CJD ?
FINALLY, GOT IT UPLOADED !
SEE THE VIDEO NOW AT THE BOTTOM OF THE BLOG BELOW ;
http://creutzfeldt-jakob-disease.blogspot.com/2009/07/usa-hiding-mad-cow-disease-victims-as.html
Tuesday, July 21, 2009
Transmissible mink encephalopathy - review of the etiology
http://transmissible-mink-encephalopathy.blogspot.com/2009/07/transmissible-mink-encephalopathy.html
Saturday, June 13, 2009
Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States 2003 revisited 2009
http://cjdusa.blogspot.com/2009/06/monitoring-occurrence-of-emerging-forms.html
Monday, May 11, 2009
Rare BSE mutation raises concerns over risks to public health
http://bse-atypical.blogspot.com/2009/05/rare-bse-mutation-raises-concerns-over.html
Monday, June 01, 2009
Biochemical typing of pathological prion protein in aging cattle with BSE
http://bse-atypical.blogspot.com/2009/06/biochemical-typing-of-pathological.html
Sunday, June 07, 2009
L-TYPE-BSE, H-TYPE-BSE, C-TYPE-BSE, IBNC-TYPE-BSE, TME, CWD, SCRAPIE, CJD, NORTH AMERICA
http://bse-atypical.blogspot.com/2009/06/l-type-bse-h-type-bse-c-type-bse-ibnc.html
Sunday, May 10, 2009
Identification and characterization of bovine spongiform encephalopathy cases diagnosed and not diagnosed in the United States
http://bse-atypical.blogspot.com/2009/05/identification-and-characterization-of.html
Sunday, May 17, 2009
WHO WILL WATCH THE CHILDREN ? SCHOOL LUNCH PROGRAM FROM DOWNER CATTLE UPDATE
http://downercattle.blogspot.com/2009/05/who-will-watch-children.html
Saturday, April 04, 2009
An unusually presenting case of sCJD-The VV1 subtype Volume 111, Issue 3, Pages 282-291 (April 2009)
http://creutzfeldt-jakob-disease.blogspot.com/2009/04/unusually-presenting-case-of-scjdthe.html
IT seems we have come full circle from the 'ORIGINAL 10' i.e. the 1st 10 adolescents in the UKBSEnvCJD only theory. and now we find us at the 1st 10 in USA, or is it the first 10, or the tip of the iceburg, many that went undocumented ???
lets look at the full circle, to date ;
http://cjdmadcowbaseoct2007.blogspot.com/2008/07/new-prionopathy-update-july-10-2008.html
Sunday, August 10, 2008 A New Prionopathy OR more of the same old BSe and sporadic CJD
http://creutzfeldt-jakob-disease.blogspot.com/2008/08/new-prionopathy-or-more-of-same-old-bse.html
HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD only theory JUNE 2008
snip...
Tissue infectivity and strain typing of the many variants Manuscript of the human and animal TSEs are paramount in all variants of all TSE. There must be a proper classification that will differentiate between all these human TSE in order to do this. With the CDI and other more sensitive testing coming about, I only hope that my proposal will some day be taken seriously. ...
snip...
http://cjdmadcowbaseoct2007.blogspot.com/2008/06/human-and-animal-tse-classifications-ie.html
Elsevier Editorial System(tm) for The Lancet Infectious Diseases Manuscript Draft Manuscript Number: Title: HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD only theory Article Type: Personal View Corresponding Author: Mr. Terry S. Singeltary, Corresponding Author's Institution: na First Author: Terry S Singeltary, none Order of Authors: Terry S Singeltary, none; Terry S. Singeltary
Abstract:
TSEs have been rampant in the USA for decades in many species, and they all have been rendered and fed back to animals for human/animal consumption. I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2007. snip...
see full text 31 pages ;
http://www.regulations.gov/fdmspublic/ContentViewer?objectId=090000648027c28e&disposition=attachment&contentType=pdf
Friday, November 30, 2007
CJD QUESTIONNAIRE USA CWRU AND CJD FOUNDATION
http://cjdquestionnaire.blogspot.com/
Friday, May 29, 2009
Characterization of a U.S. Sheep Scrapie Isolate with Short Incubation Time
http://scrapie-usa.blogspot.com/2009/05/characterization-of-us-sheep-scrapie.html
Wednesday, July 1, 2009
Nor98 scrapie identified in the United States J Vet Diagn Invest 21:454-463 (2009)
http://nor-98.blogspot.com/2009/07/nor98-scrapie-identified-in-united.html
Monday, June 01, 2009 Biochemical typing of pathological prion protein in aging cattle with BSE
SOMETHING TO PONDER ???
O.K. confusious asks, IF all these new atypical BSEs i.e. new strains of mad cow disease is just an 'OLD COW PRION DISEASE', why then can not the 'old human prion disease' such as the sporadic CJD, be from an 'old cow prion disease', same as the nvCJD 'young people mad cow disease' (which also happens in 74 year old), but why cannot the 'old cow prion diseases', i.e. l-BSE, h-BSE, and ibncBSE, cause the 'old people prion disease', which looks like sporadic CJD. seems that is what some of the pathology is showing ???
OH, that probably makes too much sense, and that the only answer could be that it's all just a happenstance of bad luck and or a spontaneous event, that just happens out of the clear blue sky $$$
IF this is the case, then where are all the SPONTANEOUS BSE CASES OF MAD COW DISEASE IN THE U.S.A., AND WHERE HAVE THEY BEEN BURIED IN THE USA OVER THE LAST 25 YEARS ???
http://bse-atypical.blogspot.com/2009/06/biochemical-typing-of-pathological.html
Sunday, April 12, 2009
CWD UPDATE Infection Studies in Two Species of Non-Human Primates and one Environmental reservoir infectivity study and evidence of two strains
http://chronic-wasting-disease.blogspot.com/2009/04/cwd-update-infection-studies-in-two.html
Thursday, April 03, 2008
A prion disease of cervids: Chronic wasting disease
2008 1: Vet Res. 2008 Apr 3;39(4):41
A prion disease of cervids: Chronic wasting disease
Sigurdson CJ.
snip...
*** twenty-seven CJD patients who regularly consumed venison were reported to the Surveillance Center***,
snip...
full text ;
http://chronic-wasting-disease.blogspot.com/2008/04/prion-disease-of-cervids-chronic.html
From: TSS (216-119-163-189.ipset45.wt.net)
Subject: CWD aka MAD DEER/ELK TO HUMANS ???
Date: September 30, 2002 at 7:06 am PST
From: "Belay, Ermias"
To:
Cc: "Race, Richard (NIH)" ; ; "Belay,
Ermias"
Sent: Monday, September 30, 2002 9:22 AM
Subject: RE: TO CDC AND NIH - PUB MED- 3 MORE DEATHS - CWD - YOUNG HUNTERS
Dear Sir/Madam,
In the Archives of Neurology you quoted (the abstract of which was
attached to your email), we did not say CWD in humans will present like
variant CJD.
That assumption would be wrong. I encourage you to read the whole
article and call me if you have questions or need more clarification
(phone: 404-639-3091). Also, we do not claim that "no-one has ever been
infected with prion disease from eating venison." Our conclusion stating
that we found no strong evidence of CWD transmission to humans in the
article you quoted or in any other forum is limited to the patients we
investigated.
Ermias Belay, M.D.
Centers for Disease Control and Prevention
-----Original Message-----
From:
Sent: Sunday, September 29, 2002 10:15 AM
To: mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000146/!x-usc:mailto:rr26k@nih.gov; mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000146/!x-usc:mailto:rrace@niaid.nih.gov; mhtml:%7B33B38F65-8D2E-434D-8F9B-8BDCD77D3066%7Dmid://00000146/!x-usc:mailto:ebb8@CDC.GOV
Subject: TO CDC AND NIH - PUB MED- 3 MORE DEATHS - CWD - YOUNG
HUNTERS
Sunday, November 10, 2002 6:26 PM ......snip........end..............TSS
also,
A. Aguzzi - Chronic Wasting Disease (CWD) also needs to be addressed. Most
serious because of rapid horizontal spread and higher prevalence than BSE in
UK, up to 15% in some populations. Also may be a risk to humans - evidence
that it is not dangerous to humans is thin.
http://www.tseandfoodsafety.org/activities/bse_conference_basel_april_02/2summar
SNIP...END...TSS
Chronic Wasting Disease and Potential Transmission to Humans
Ermias D. Belay,* Ryan A. Maddox,* Elizabeth S. Williams,? Michael W. Miller,? Pierluigi Gambetti,§ and Lawrence B. Schonberger*
*Centers for Disease Control and Prevention, Atlanta, Georgia, USA; ?University of Wyoming, Laramie, Wyoming, USA; ?Colorado Division of Wildlife, Fort Collins, Colorado, USA; and §Case Western Reserve University, Cleveland, Ohio, USA
Suggested citation for this article: Belay ED, Maddox RA, Williams ES, Miller MW, Gambetti P, Schonberger LB. Chronic wasting disease and potential transmission to humans. Emerg Infect Dis [serial on the Internet]. 2004 Jun [date cited]. Available from:
http://www.cdc.gov/ncidod/EID/vol10no6/03-1082.htm
Chronic wasting disease (CWD) of deer and elk is endemic in a tri-corner area of Colorado, Wyoming, and Nebraska, and new foci of CWD have been detected in other parts of the United States. Although detection in some areas may be related to increased surveillance, introduction of CWD due to translocation or natural migration of animals may account for some new foci of infection. Increasing spread of CWD has raised concerns about the potential for increasing human exposure to the CWD agent. The foodborne transmission of bovine spongiform encephalopathy to humans indicates that the species barrier may not completely protect humans from animal prion diseases. Conversion of human prion protein by CWD-associated prions has been demonstrated in an in vitro cell-free experiment, but limited investigations have not identified strong evidence for CWD transmission to humans. More epidemiologic and laboratory studies are needed to monitor the possibility of such transmissions.
snip...full text ;
http://www.cdc.gov/ncidod/EID/vol10no6/03-1082.htm
please see ;
http://chronic-wasting-disease.blogspot.com/
Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518
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