Foodborne Transmission of Bovine Spongiform Encephalopathy to Nonhuman Primates
RESEARCH
Foodborne Transmission of Bovine Spongiform Encephalopathy to Nonhuman
Primates
Edgar Holznagel, Barbara Yutzy, Walter Schulz-Schaeffer, Carina Kruip, Uwe
Hahmann, Pär Bierke, Juan-Maria Torres, Yong-Sun Kim, Achim Thomzig, Michael
Beekes, Gerhard Hunsmann, and Johannes Loewer
Risk for human exposure to bovine spongiform encephalopathy (BSE)–inducing
agent was estimated in a nonhuman primate model. To determine attack rates,
incubation times, and molecular signatures, we orally exposed 18 macaques to 1
high dose of brain material from cattle with BSE. Several macaques were
euthanized at regular intervals starting at 1 year postinoculation, and others
were observed until clinical signs developed. Among those who received >5 g
BSE-inducing agent, attack rates were 100% and prions could be detected in
peripheral tissues from 1 year postinoculation onward. The overall median
incubation time was 4.6 years (3.7–5.3). However, for 3 macaques orally exposed
on multiple occasions, incubation periods were at least 7–10 years. Before
clinical signs were noted, we detected a non-type 2B signature, indicating the
existence of atypical prion protein during the incubation period. This finding
could affect diagnosis of variant Creutzfeldt-Jakob disease in humans and might
be relevant for retrospective studies of positive tonsillectomy or appendectomy
specimens because time of infection is unknown.
snip...
Discussion
Because only a few macaques have died, it will take longer than previously
estimated before all data from low-dose (0.05 and 0.005 g) exposures will be
available (data not shown). Although all macaques were originally to be
inoculated with BSE-infected cattle brain material on only 1 occasion, 3 of 6
macaques receiving >5 g of inoculum had to be fed on multiple occasions.
The attack rate after dietary exposure to >5 g BSE brain material in
5-year-old adult 129-MM cynomolgus monkeys was 100% (18/18). PrPres deposits
could be detected outside the GALT in gut-draining lymph nodes from at least 1
year postinoculation onward. These data show that the dose at which 50% of these
nonhuman primates will be infected will be distinctly lower than previously
estimated (4).
For single-dosed animals, the incubation period was 4.6 years (median,
range 3.7–5.3 years). There was no difference between those that received 5 g
and 16 g, indicating that <5 100="" 16="" 1="" 3.7="" 3="" 6.5="" 8.8="" a="" able="" after="" also="" although="" an="" analyses="" at="" by="" clinical="" data="" day="" detected="" developed="" disease="" div="" dose.="" dose="" doses="" excluding="" explain="" extremely="" for="" from="" g="" given="" had="" have="" high="" highly="" however="" immune="" in="" incubation="" inoculated="" inoculum="" ld100="" low="" lower="" macaque="" macaques="" might="" multiple="" not="" occasion.="" occasions="" of="" on="" or="" oral="" period.="" period="" periods="" postinoculation="" probably="" received="" represented="" result="" resulted="" retrospective="" revealed="" s6="" short="" shortest="" shown="" signs="" spongiform="" stimulated="" system="" that="" the="" they="" this="" to="" variability="" variable.="" was="" we="" were="" when="" which="" with="" years="">
Unfortunately, type 2 diabetes developed in all 3 of these macaques as they
aged, and they had to be euthanized for humane reasons at the indicated time
points. At postmortem examinations, lumbar spinal cord segments were PrPres
positive for the 2 macaques (C1 and C2) euthanized 6.5 years postinoculation. We
estimate that incubation periods in these 2 animals must be at least 7 years
because it took >6 months until PrPres deposits were also detectable in the
cerebellum/cortex cerebri, thereby causing clinical signs (data not shown). In
the third macaque (C3) euthanized 8.8 years postinoculation with a cumulative
dose of 16 g, PrPres deposits could only be detected outside the CNS, thereby
indicating an estimated incubation period >10 years. Similar results have
been described for hamsters orally infected with the scrapie strain 263K on a
single or multiple occasions. In that study, a cumulative dose significantly
prolonged incubation periods, although hamsters were given much lower doses than
were the macaques (13). The upper reference margin using 3× the standard
deviation (3σ) of animal group I is 1.52 years, corresponding to a calculated
upper limit of the incubation period of 6.1 years after a single high-dose
exposure (5–16 g each). This calculated incubation period is distinctly lower
than the estimated incubation time of >7–10 years within animals of group
III, indicating a biological effect of the successive BSE challenge mode on the
incubation time in the macaque model.
The discrepancy between the low number of vCJD cases in the United Kingdom
to date and the higher prevalence of infected humans estimated on the basis of
retrospective biopsy analyses (27,28) indicates the existence of pre- or
subclinical cases, perhaps as a result of a low-dose exposure to
BSE-contaminated material or a less susceptible PRNP genotype. We showed that
multiple exposures to high doses of BSE prolonged incubation periods in a
nonhuman primate model. These findings show that a successive BSE challenge mode
might contribute to the development of pre- or subclinical cases despite a
susceptible PRNP phenotype and an LD100. This finding is relevant because it is
quite likely that most of the UK population has been exposed to BSE-contaminated
food on multiple occasions (5,6).
The underlying mechanism of a prolonged incubation period after multiple
exposures to an agent that induces a transmissible spongiform encephalopathy is
not known (6,13). Theoretically, interference between types or strains could
have caused this phenomenon, as has been shown by others (14,19,29,30). However,
Diringer et al. (13) used 1 well-defined laboratory scrapie strain (263K) that
could also cause prolonged incubation periods in Syrian hamsters after multiple
oral exposures. Their finding shows that at least 1 other not-yet identified
mechanism causes prolonged incubation periods after multiple oral exposures to
agents that induce transmissible spongiform encephalopathy.
Unexpectedly, we detected a non–type 2B PrPres pattern in preclinical cases
from 3 years postinoculation onward. Transmission studies in BoTg110 mice showed
that tissues were infectious but that this atypical molecular signature was not
stable after the first passage to transgenic mice carrying the bovine PrP gene
(Figure 7). However, the PK-sensitive N terminal part, the variable region of
PK, and the C-terminal end were detectable in both atypical PrP molecules by
epitope mapping studies. Thus, at least the 17-kDa molecule showed migration
behavior on sodium dodecyl sulfate polyacrylamide gel electrophoresis, which did
not correlate with its formal molecular weight. Posttranslational modifications
can cause a gel-shifting phenomenon (i.e., anomalous gel mobility), as observed
for the phosphorylated tau protein (31). However, it remains to be determined
which mechanism caused this anomalous gel mobility. This atypical signature
probably reflects neither types nor strains but rather an intermediate
conformation of the pathologic PrP.
In conclusion, the LD100 of brain from BSE-infected cattle for 129-MM
5-year-old adult macaques exposed on 1 occasion is <5 a="" analyses="" animals="" be="" biopsy="" cause="" chronic="" did="" disease="" diseases="" div="" dose="" exposed="" exposure="" finding="" foodborne="" for="" from="" g.="" however="" including="" incubation="" likely="" may="" might="" modeling="" molecular="" moreover="" most="" multiple="" not="" occasions.="" of="" on="" or="" pre-="" prion="" prolonged="" relevant="" retrospective="" risks="" samples="" shift="" signature="" subclinical="" the="" this="" time-dependent="" time="" vcjd.="" wasting="" were="" when="" with="" within="">
Wednesday, April 24, 2013
Dissociation between Transmissible Spongiform Encephalopathy (TSE)
Infectivity and Proteinase K-Resistant PrPSc Levels in Peripheral Tissue from a
Murine Transgenic Model of TSE Disease
Saturday, December 15, 2012
Bovine spongiform encephalopathy: the effect of oral exposure dose on
attack rate and incubation period in cattle -- an update 5 December 2012
Friday, April 19, 2013
FDA BSE TSE PRION NEWS FEED AND ANNUAL INSPECTION OF FEED MILLS REPORTS HAS
CEASED TO EXIST
Monday, March 25, 2013
Minnesota Firm Recalls Bone-In Ribeye That May Contain Specified Risk
Materials Recall Release CLASS II RECALL FSIS-RC-024-2013
Tuesday, March 5, 2013
Use of Materials Derived From Cattle in Human Food and Cosmetics; Reopening
of the Comment Period FDA-2004-N-0188-0051 (TSS SUBMISSION)
FDA believes current regulation protects the public from BSE but reopens
comment period due to new studies
Wednesday, March 20, 2013
GAO-13-244, Mar 18, 2013 Dietary Supplements FDA May Have Opportunities to
Expand Its Use of Reported Health Problems to Oversee Product
From: Terry S. Singeltary Sr.
Sent: Tuesday, March 19, 2013 2:46 PM
To: gomezj@gao.gov
Cc: siggerudk@gao.gov ; youngc1@gao.gov ; oighotline@gao.gov
Wednesday, February 20, 2013
World Organization for Animal Health Recommends United States' BSE Risk
Status Be Upgraded
Statement from Agriculture Secretary Tom Vilsack:
Thursday, February 14, 2013
The Many Faces of Mad Cow Disease Bovine Spongiform Encephalopathy BSE and
TSE prion disease
Friday, April 19, 2013
Bovine Spongiform Encephalopathy (BSE) Feed Safety Support Program Grants
Fiscal Year 2011: October 1, 2010 - September 30, 2011 FDA
Friday, April 19, 2013
APHIS 2013 Stakeholder Meeting (March 2013) BSE TSE PRION
Tuesday, April 30, 2013
Mad cow infected blood 'to kill 1,000’
Wednesday, April 24, 2013
Chimpanzees Released After 30 Years Of Testing, Brace Yourself For Smiles
TSS
posted by Terry S. Singeltary Sr. at
3:34 PM
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