Tuesday, April 30, 2013

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="">







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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






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