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P.126: Successful transmission of chronic wasting disease (CWD) into mice over-expressing bovine prion protein (TgSB3985)
Larisa Cervenakova,1 Christina J Sigurdson,2 Pedro Piccardo,3 Oksana Yakovleva,1 Irina Vasilyeva,1 Jorge de Castro,1 Paula Saá,1 and Anton Cervenak1 1American Red Cross, Holland Laboratory; Rockville, MD USA; 2University of California; San Diego, CA USA; 3Lab TSE/OBRR /CBER/FDA; Rockville, MD USA
Keywords: chronic wasting disease, transmission, transgenic mouse, bovine prion protein
Background. CWD is a disease affecting wild and farmraised cervids in North America. Epidemiological studies provide no evidence of CWD transmission to humans. Multiple attempts have failed to infect transgenic mice expressing human PRNP gene with CWD. The extremely low efficiency of PrPCWD to convert normal human PrPC in vitro provides additional evidence that transmission of CWD to humans cannot be easily achieved. However, a concern about the risk of CWD transmission to humans still exists. This study aimed to establish and characterize an experimental model of CWD in TgSB3985 mice with the following attempt of transmission to TgHu mice.
Materials and Methods. TgSB3985 mice and wild-type FVB/ NCrl mice were intracranially injected with 1% brain homogenate from a CWD-infected Tga20 mouse (CWD/Tga20). TgSB3985 and TgRM (over-expressing human PrP) were similarly injected with 5% brain homogenates from CWD-infected white-tailed deer (CWD/WTD) or elk (CWD/Elk). Animals were observed for clinical signs of neurological disease and were euthanized when moribund. Brains and spleens were removed from all mice for PrPCWD detection by Western blotting (WB). A histological analysis of brains from selected animals was performed: brains were scored for the severity of spongiform change, astrogliosis, and PrPCWD deposition in ten brain regions.
Results. Clinical presentation was consistent with TSE. More than 90% of TgSB3985 and wild-type mice infected with CWD/Tga20, tested positive for PrPres in the brain but only mice in the latter group carried PrPCWD in their spleens. We found evidence for co-existence or divergence of two CWD/ Tga20 strains based on biochemical and histological profiles. In TgSB3985 mice infected with CWD-elk or CWD-WTD, no animals tested positive for PrPCWD in the brain or in the spleen by WB. However, on neuropathological examination we found presence of amyloid plaques that stained positive for PrPCWD in three CWD/WTD- and two CWD/Elk-infected TgSB3985 mice. The neuropathologic profiles in CWD/WTD- and CWD/Elkinfected mice were similar but unique as compared to profiles of BSE, BSE-H or CWD/Tg20 agents propagated in TgSB3985 mice. None of CWD-infected TgRM mice tested positive for PrPCWD by WB or by immunohistochemical detection.
Conclusions. To our knowledge, this is the first established experimental model of CWD in TgSB3985. We found evidence for co-existence or divergence of two CWD strains adapted to Tga20 mice and their replication in TgSB3985 mice. Finally, we observed phenotypic differences between cervid-derived CWD and CWD/Tg20 strains upon propagation in TgSB3985 mice. Further studies are underway to characterize these strains.
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