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. The recent discovery of chronic wasting disease in cervids (CWD) beyond the
borders of Colorado and Wyoming, as far east as New York and including two
Canadian Provinces, has led to the emergence of CWD as a prion disease of
domestic and international importance. The apparent ease of horizontal
transmission, potentially via environmental contamination or by
prion-containing saliva, creates enormous challenges for disease management.
Ongoing studies of CWD interspecies transmission by exposure of domestic and
non-domestic species directly or using transgenic mice have shed light on
species barriers. Transgenic mice expressing cervid PrP have also proven
useful for assessing the genetic influences of Prnp polymorphisms on CWD
susceptibility. Accumulating evidence of CWD pathogenesis indicates that the
misfolded prion protein, PrPSc, seems to be widely disseminated in many
nonneural organs, and CWD infectivity has been recently detected in blood.
This review highlights recent research findings in this disease of
free-ranging wildlife.
snip...
3. CWD prion spread and target organs
Collectively, CWD pathogenesis studies have revealed extensive deposition of
PrPSc in the central nervous system (CNS) and extraneural tissues (Fig. 1). The
only other natural prion diseases that even approach this degree of systemic involvement are variant Creutzfeldt-Jakob disease (vCJD) in humans, sheep scrapie, and transmissible mink encephalopathy ⎢, 23, 30, 61, 62]. In mule deer, PrPSc is detectable in the retropharyngeal lymph node within only 6 weeks following an oral exposure ⏘]. In a further study of the kinetics of prion 5 infection in mule deer, Fox et al. showed that PrPSc is widely distributed in lymphoid tissues by 3 months post-oral exposure when it is first detected in brain ⎝]. By 9
months, PrPSc was detected in the myenteric and submucosal plexi throughout the
gastrointestinal tract and in the vagus nerve, and by 16 months, PrPSc deposits were detectable throughout the brain and spinal cord. The Prnp genotype seemed to impact the infection kinetics in that mule deer that were SF heterozygous at codon 225 showed a delay in PrPSc spread; PrPSc was not detectable in the brain until 16 months post-inoculation which was 13 months later than the 225SS deer. Perhaps the 225F allele confers a dominant negative effect on the kinetics of this CWD strain, as has been described in sheep, where the 171R allele has been shown to have a dominant negative effect on prion susceptibility ⎠, 33]. CWD pathogenesis seems to vary between deer and elk: PrPSc levels have been found to be lower in lymphoid tissues of elk compared to deer ⏎]. In a report of 226 CWD-infected elk, 28 had no PrPSc in lymphoid tissues despite having PrPSc in brain ⏝].
In addition to lymphoid tissues, PrPSc or infectivity has been detected in other non-CNS
tissues, including pancreas ⎝, 77], adrenal gland ⎝, 77], and skeletal muscle ΐ]. Recently
PrPSc was described in cardiac muscle from 7 of 16 (44%) white-tailed deer and from 12 of
17 (71%) elk ⎯]. This is the first report of PrPSc in cardiac muscle in any TSE.
The cellular and molecular mechanisms of systemic prion spread are under investigation in
many laboratories. A recent report showed that blood from CWD-infected deer contained
infectivity and could transmit prion disease via a blood transfusion ⎾].
This finding recapitulates indirect findings of blood infectivity in vCJD affected humans
⏉] and experimental transfusion studies of scrapie sick sheep ⎬], and indicates
that prion transport throughout the body may include the blood as a potential vehicle.
snip...
*** Thus far,
8 twenty-seven CJD patients who regularly consumed venison were reported to the
Surveillance Center,*** however there have been no unusual or novel prion subtypes that might indicate the appearance of a new prion strain Ε, 41].
snip...
12. Conclusion
CWD in cervids is efficiently transmitted, likely more than any other TSE in animals or
humans. Therefore, it is unlikely that this TSE can be eradicated, but perhaps through an
improved understanding of transmission routes, biological factors influencing pathogenesis,
and the molecular basis of CWD prion conversion, a targeted strategy for interrupting
disease spread may be developed. Acknowledgements I thank Drs. Michael Miller, Jason Bartz and Mathias Heikenwalder for
critical review of the manuscript. see full text ; *** Thus far, 8 twenty-seven CJD patients who regularly consumed venison were reported to the
Surveillance Center,*** however there have been no unusual or novel prion subtypes
that might indicate the appearance of a new prion strain Ε, 41]. ??? GAH WELLS (very important statement here...TSS) HOUND STUDY AS implied in the Inset 25 we must not _ASSUME_ that
transmission of BSE to other species will invariably
present pathology typical of a scrapie-like disease. snip... 2005
DEFRA
Department for Environment,
Food & Rural Affairs
Area 307, London, SW1P 4PQ
Telephone: 0207 904 6000
Direct line: 0207 904 6287
E-mail: h.mcdonagh.defra.gsi.gov.uk
GTN:
FAX:
Mr T S Singeltary
P.O. Box 42
Bacliff
Texas
USA 77518
21 November 2001
Dear Mr Singeltary TSE IN HOUNDS
Thank you for e-mail regarding the hounds survey. I am sorry for the long delay in responding.
As you note, the hound survey remains unpublished. However the Spongiform Encephalopathy Advisory Committee (SEAC), the UK Government's independent Advisory Committee on all aspects related to BSE-like disease, gave the hound study detailed consideration at their meeting in January 1994. As a summary of this meeting published in the BSE inquiry noted, the Committee were clearly concerned about the work that had been carried out, concluding that there had clearly been problems with it, particularly the control on the histology, and that it was more or less inconclusive. However was agreed that there should be a re-evaluation of the pathological material in the study.
Later, at their meeting in June 95, The Committee re-evaluated the hound study to see if any useful results could be gained from it. The Chairman concluded that there were varying opinions within the Committee on further work. It did not suggest any further transmission studies and thought that the lack of clinical data was a major weakness.
Overall, it is clear that SEAC had major concerns about the survey as conducted. As a result it is likely that the authors felt that it would not stand up to r~eer review and hence it was never published. As noted above, and in the detailed minutes of the SEAC meeting in June 95, SEAC considered whether additional work should be performed to examine dogs for evidence of TSE infection. Although the Committee had mixed views about the merits of conducting further work, the Chairman noted that when the Southwood Committee made their recommendation to complete an assessment of possible spongiform disease in dogs, no TSEs had been identified in other species and hence dogs were perceived as a high risk population and worthy of study. However subsequent to the original recommendation, made in 1990, a number of other species had been identified with TSE ( e.g. cats) so a study in hounds was less
critical. For more details see- http://www.bseinquiry, gov.uk/files/yb/1995/06/21005001 .pdf
As this study remains unpublished, my understanding is that the ownership of the data essentially remains with the original researchers. Thus unfortunately, I am unable to help with your request to supply information on the hound survey directly. My only suggestion is that you contact one of the researchers originally involved in the project, such as Gerald Wells. He can be contacted at the following address.
Dr Gerald Wells, Veterinary Laboratories Agency, New Haw, Addlestone, Surrey, KT 15 3NB, UK
You may also wish to be aware that since November 1994 all suspected cases of spongiform encephalopathy in animals and poultry were made notifiable. Hence since that date there has been a requirement for vets to report any suspect SE in dogs for further investigation. To date there has never been positive identification of a TSE in a dog.
I hope this is helpful
Yours sincerely 4
HUGH MCDONAGH
BSE CORRESPONDENCE SECTION
END=======TSS2008 FC5.5.2 Transmission of Italian BSE and BASE Isolates in Cattle Results into
a Typical BSE Phenotype and a Muscle Wasting Disease Zanusso, G1; Lombardi, G2; Casalone, C3; D'Angelo, A4; Gelmetti, D2;
Torcoli, G2; Barbieri, I2; Corona, C3; Fasoli, E1; Farinazzo, A1; Fiorini,
M1; Gelati, M1; Iulini, B3; Tagliavini, F5; Ferrari, S1; Monaco, S1;
Caramelli, M3; Capucci, L2 1University of Verona, Neurological and Visual
Sciences, Italy; 2IZSLER, Italy; 3IZSPLVA, Italy; 4University of Turin,
Animal Pathology, Italy; 5Isituto Carlo Besta, Italy The clinical phenotype of bovine spongiform encephalopathy has been
extensively reported in early accounts of the disorder. Following the
introduction of statutory active surveillance, almost all BSE cases have
been diagnosed on a pathological/molecular basis, in a pre-symptomatic
clinical stage. In recent years, the active surveillance system has
uncovered atypical BSE cases, which are characterized by distinct conformers
of the PrPSc, named high-type (BSE-H) and low-type (BSE-L), whose
clinicopathological phenotypes remain unknown. We recently reported two
Italian atypical cases with a PrPSc type similar to BSE-L, pathologically
characterized by PrP amyloid plaques. Experimental transmission to TgBov
mice has recently disclosed that BASE is caused by a distinct prion strain
which is extremely virulent. A major limitation of transmission studies to
mice is the lack of reliable information on clinical phenotype of BASE in
its natural host. In the present study, we experimentally infected
Fresian/Holstein and Alpine/Brown cattle with Italian BSE and BASE isolates
by i.c. route. BASE infected cattle showed survival times significantly
shorter than BSE, a finding more readily evident in Fresian/Holstein, and in
keeping with previous observations in TgBov mice. Clinically, BSE-infected
cattle developed a disease phenotype highly comparable with that described
in field BSE cases and in experimentally challenged cattle. On the contrary,
BASE-inoculated cattle developed an amyotrophic disorder accompanied by
mental dullness. The molecular and neuropathological profiles, including PrP
deposition pattern, closely matched those observed in the original cases.
This study further confirms that BASE is caused by a distinct prion isolate
and discloses a novel disease phenotype in cattle, closely resembling the
phenotype previous reported in scrapie-inoculated cattle
*** and in some subtypes of inherited and sporadic Creutzfeldt-Jakob
disease. Oral Abstracts 14 P02.35 Molecular Features of the Protease-resistant Prion Protein (PrPres)
in H- type BSE Biacabe, A-G1; Jacobs, JG2; Gavier-Widén, D3; Vulin, J1; Langeveld, JPM2;
Baron, TGM1 1AFSSA, France; 2CIDC-Lelystad, Netherlands; 3SVA, Sweden Western blot analyses of PrPres accumulating in the brain of BSE- infected
cattle have demonstrated 3 different molecular phenotypes regarding to the
apparent molecular masses and glycoform ratios of PrPres bands. We initially
described isolates (H-type BSE) essentially characterized by higher PrPres
molecular mass and decreased levels of the diglycosylated PrPres band, in
contrast to the classical type of BSE. This type is also distinct from
another BSE phenotype named L-type BSE, or also BASE (for Bovine Amyloid
Spongiform Encephalopathy), mainly characterized by a low representation of
the diglycosylated PrPres band as well as a lower PrPres molecular mass.
Retrospective molecular studies in France of all available BSE cases older
than 8 years old and of part of the other cases identified since the
beginning of the exhaustive surveillance of the disease in 20001 allowed to
identify 7 H- type BSE cases, among 594 BSE cases that could be classified
as classical, L- or H-type BSE. By Western blot analysis of H-type PrPres,
we described a remarkable specific feature with antibodies raised against
the C-terminal region of PrP that demonstrated the existence of a more
C-terminal cleaved form of PrPres (named PrPres#2 ), in addition to the
usual PrPres form (PrPres #1). In the unglycosylated form, PrPres #2
migrates at about 14 kDa, compared to 20 kDa for PrPres #1. The proportion
of the PrPres#2 in cattle seems to by higher compared to the PrPres#1.
Furthermore another PK-resistant fragment at about 7 kDa was detected by
some more N-terminal antibodies and presumed to be the result of cleavages
of both N- and C- terminal parts of PrP. These singular features were
maintained after transmission of the disease to C57Bl/6 mice. The
identification of these two additional PrPres fragments (PrPres #2 and 7kDa
band)
*** reminds features reported respectively in sporadic Creutzfeldt-Jakob
disease and in Gerstmann-Sträussler-Scheinker (GSS) syndrome in humans.
FC5.5.1 BASE Transmitted to Primates and MV2 sCJD Subtype Share PrP27-30 and
PrPSc C-terminal Truncated Fragments
Zanusso, G1; Commoy, E2; Fasoli, E3; Fiorini, M3; Lescoutra, N4; Ruchoux,
MM4; Casalone, C5; Caramelli, M5; Ferrari, S3; Lasmezas, C6; Deslys, J-P4;
Monaco, S3 1University of Verona, of Neurological and Visual Sciences,
Italy; 2CEA, IMETI/SEPIA, France; 3University of Verona, Neurological and
Visual Sciences, Italy; 4IMETI/SEPIA, France; 5IZSPLVA, Italy; 6The Scripps
Research Insitute, USA
The etiology of sporadic Creutzfeldt-Jakob disease (sCJD), the most frequent
human prion disease, remains still unknown. The marked disease phenotype
heterogeneity observed in sCJD is thought to be influenced by the type of
proteinase K- resistant prion protein, or PrPSc (type 1 or type 2 according
to the electrophoretic mobility of the unglycosylated backbone), and by the
host polymorphic Methionine/Valine (M/V) codon 129 of the PRNP. By using a
two-dimensional gel electrophoresis (2D-PAGE) and imunoblotting we
previously showed that in sCJD, in addition to the PrPSc type, distinct
PrPSc C-terminal truncated fragments (CTFs) correlated with different sCJD
subtypes. Based on the combination of CTFs and PrPSc type, *** we
distinguished
three PrPSc patterns: (i) the first was observed in sCJD with PrPSc type 1
of all genotypes,; (ii) the second was found in M/M-2 (cortical form); (iii) the third in
amyloidogenic M/V- 2 and V/V-2 subtypes (Zanusso et al., JBC 2004) .
Recently, we showed that sCJD subtype M/V-2 shared molecular and
pathological features with an atypical form of BSE, named BASE, thus
suggesting a potential link between the two conditions. This connection was
further confirmed after 2D-PAGE analysis, which showed an identical PrPSc
signature, including the biochemical pattern of CTFs. To pursue this issue,
we obtained brain homogenates from Cynomolgus macaques intracerebrally
inoculated with brain homogenates from BASE. Samples were separated by using
a twodimensional electrophoresis (2D-PAGE) followed by immunoblotting. We
here show that the PrPSc pattern obtained in infected primates is identical
to BASE and sCJD MV-2 subtype.
*** These data strongly support the link, or at least a common ancestry,
between a sCJD subtype and BASE. This work was supported by Neuroprion (FOOD-CT-2004-506579) ******************************************************* Sunday, March 16, 2008 MAD COW DISEASE terminology UK c-BSE (typical), atypical BSE H or L, and or
Italian L-BASE
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Singeltary, Sr et al. JAMA.2001; 285: 733-734.
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Since this article does not have an abstract, we have provided the first 150
words of the full text and any section headings.
To the Editor:
In their Research Letter, Dr Gibbons and colleagues1 reported that the
annual US death rate due to Creutzfeldt-Jakob disease (CJD) has been stable
since 1985. These estimates, however, are based only on reported cases, and
do not include misdiagnosed or preclinical cases. It seems to me that
misdiagnosis alone would drastically change these figures. An unknown number
of persons with a diagnosis of Alzheimer disease in fact may have CJD,
although only a small number of these patients receive the postmortem
examination necessary to make this diagnosis. Furthermore, only a few states
have made CJD reportable. Human and animal transmissible spongiform
encephalopathies should be reportable nationwide and internationally. Terry S. Singeltary, Sr
Bacliff, Tex 1. Gibbons RV, Holman RC, Belay ED, Schonberger LB. Creutzfeldt-Jakob
disease in the United States: 1979-1998. JAMA. 2000;284:2322-2323. FREE FULL
TEXT JOURNAL OF NEUROLOGY MARCH 26, 2003 In light of the findings of Asante and Collinge et al, there should be drastic measures to safeguard the medical and surgical arena from sporadic CJDs and all human TSEs. I only ponder how many sporadic CJDs in the USA are type 2 PrPSc? snip...see full text 19 pages and other relating data in full here ; A prion disease of cervids: Chronic wasting disease 2008
CWD Update 90 March 7, 2008
USDA CERTIFIED DEAD STOCK DOWNER COW SCHOOL LUNCH PROGRAM LIST OF SCHOOLS
AFFECTED STATE BY STATE (dead stock downers i.e. non-ambulatory, the most high risk for mad cow
disease)
March 28, 2008, 12:10AM FDA lists school districts that got recalled meat
Lawmakers had demanded info be released
snip...
see full text all schools Nationally receiving non-ambulatory dead stock downer cattle
(high risk BSE typical or atypical mad cow) for there school lunch program in every state here ; TSS |