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From: TSS ()
Subject: Re: Transmission and adaptation of chronic wasting disease to hamsters and transgenic mice: evidence for strains
Date: March 31, 2007 at 2:04 pm PST

In Reply to: Transmission and adaptation of chronic wasting disease to hamsters and transgenic mice: evidence for strains posted by TSS on February 8, 2007 at 8:33 am:


We have shown that CWD from one or more cervid species can be 1
transmitted into Syrian golden, Chinese, Siberian and Armenian hamsters, and to 2
Tg mice that express Sg hamster prion protein. Transmission of CWD to Sg 3
hamsters was attempted previously without generating disease most likely 4
because animals in that study were incubated for only one year (2). In the 5
present study, inoculated animals were observed for periods exceeding two 6
years for some animals. We found CWD transmission, with the highest attack 7
rate in Chinese hamsters and Tg (haPrP) mice. The other rodent species had 8
much lower attack rates or were not susceptible. The incomplete attack rates in 9
the hamster species and Tg (haPrP) mice indicated that the cervid CWD inocula 10
contained an average of only roughly 1 ID50 (the dose that would infect 50% of 11
the animals) for these species. However, these inocula produced disease in 12
deer PrP Tg mice at a 100% attack rate indicating that the titer for homologous 13
PrP types is greater (R. E. Race, K. Meade-White, B. Chesebro, unpublished 14
data). The lack of transmission of some of the cervid CWD inocula to the other 15
rodent species could be due to small differences in inoculum titer or 16
heterogeneity in the PrP sequences in the pooled inocula rather than 17
fundamental differences in host susceptibility. The amount of normal host PrP 18
expressed in the different hamster species is similar (K. Meade-White, R. E. 19
Race, unpublished data) and is not likely an explanation for the different 20
susceptibilities. Due to the low attack rates and long incubation periods seen 21
with primary passages from cervids, none of these rodent species would be 22
practical for use in direct bioassays for cervid CWD. 23
Nonetheless, the rodent-adapted CWD models we have developed may 1
be useful to experimentally analyze TSE species and strain differences. Despite 2
the low initial attack rate on the first passage of CWD into Sg hamsters, CWD 3
derived initially from elk and mule deer readily adapted to hamsters as evidenced 4
by the 100% infection rate on second and third passages. The average 5
incubation periods were similar for the second and third passages, but 6
considerably shorter than the first passage in the Sg hamsters, suggesting that 7
any species barrier to infection (formally, the shortening of incubation period 8
between the first and subsequent passages in a new species) was overcome 9
quickly. 10
When mule deer CWD was serially passaged into Sg hamsters an isolate 11
was obtained that had a relatively short incubation period, SghaCWDmd-f. When 12
the same inoculum was passaged first into Tg (haPrP) mice followed by serial 13
passage in Sg hamsters, an isolate with a 5-fold longer incubation period 14
developed, SghaCWDmd-s. The CWD inocula from elk and white-tailed deer led 15
only to slow isolates, SghaCWDe-s and SghaCWDwd-s, which were 16
indistinguishable from the slow mule deer isolate, SghaCWDmd-s. The markedly 17
different incubation periods of these two isolates from the mule deer CWD 18
inoculum, as well as the distinct clinical signs, patterns of brain pathology and 19
PrP-res deposition, raise the possibility that different strains of CWD may exist, at 20
least in mule deer, which in turn can lead to distinct CWD strains in Sg hamsters. 21
Another possibility is that the strains diverged upon introduction into the Sg 22
hamsters as has been suggested for the Hy and Dy Sg hamster strains that were 1
from TME-infected mink brain homogenates (1). 2
Differences in PrP-res glycoform patterns analyzed from several CWD- 3
affected deer and elk have also suggested that CWD in mule deer may be more 4
heterogeneous than in elk (19). Curiously, however, this apparent strain 5
difference was not manifested when the identical mule deer CWD inoculum was 6
serially passaged through only one recipient species. Serial passage in Sg 7
hamsters yielded only the fast isolate (Table 1 and Figure 3), while passage first 8
through the Tg (haPrP) mice then into Sg hamsters yielded only the slow isolate 9
(Table 2 and Figure 3). With this in mind, it is important to consider other 10
possible explanations for these results. One possibility is that CWD might be 11
able to undergo a stochastic change into a more rapid and aggressive strain in 12
Sg hamsters, and that this happened to occur after the mule deer CWD 13
inoculations. A similar emergence of both fast and slow strains has been 14
observed upon inoculation of TME into Sg hamsters (5). These strains 15
developed even when a clonal isolate of the TME inoculum was used, suggesting 16
that they arose in the recipient Sg hamsters rather than in the mink source (1). 17
Finally, although extensive precautions were taken, we cannot formally 18
prove that inadvertent contamination of the mule deer CWD inoculum with 19
hamster-derived 263K strain did not occur which potentially could yield short- 20
incubation-period passages in Sg hamsters (Table 1). However, the incubation 21
period observed with the CWD passages (85-89 d) were significantly longer than 22
263K incubation periods observed in our lab (70-75 d) and no mock-infected 23
controls became sick during their lifespan. Also, we saw no 263K-like infectivity 1
develop in the highly susceptible Tg (haPrP) mice even though we used the 2
identical primary inoculum for both recipient species. Interestingly, the similarity 3
of the Sg hamster-adapted CWD fast isolate and 263K might be due to a 4
common origin since there is circumstantial evidence that CWD arose from 5
cervid exposure to sheep scrapie, which was also the origin of the 263K strain in 6
hamsters (14). Furthermore, the Hyper strain derived from TME inoculations has 7
263K-like strain characteristics in Sg hamsters (5). Thus, it would appear that 8
both CWD and TME transmissions into Sg hamsters can result in divergent fast 9
and slow strains.........


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