Role of the PRNP S127 allele in experimental infection of goats with classical caprine scrapie.

Abstract

Classical scrapie is a transmissible spongiform encephalopathy affecting domestic goats and sheep and associated with accumulation of a misfolded isoform (PrPSc) of the PRNP gene product. Multiple PRNP polymorphisms have been reported in goats.1, 2 Experimental scrapie inoculation studies revealed that PRNP polymorphisms at codons 146, 154, 211, and 222 can provide resistance or a prolonged incubation period.3-5 A recent study identified the association between a polymorphism at codon 127 (G127S) and reduced probability of developing clinical signs of scrapie in goats with PrPSc detectable in the brain.6 In that study, the length of the incubation period (time from infection to clinical signs) was not known. The aim of this study was to identify whether goats with the heterozygous (G/S127) genotype have an extended incubation period compared with goats homozygous for G127 (G/G127) following classical caprine scrapie inoculation. Intracerebral inoculation was performed with brain homogenates from two natural field cases of scrapie, one G/G127 and one G/S127, as described (Table S1). Data were combined from previous reports4, 5 to achieve efficient animal use. Because the previous report6 suggested a prolonged incubation time for G/S127 goats, a one-tailed nonparametric exact test (see Appendix S1) was used to assess the recipient genotype hypothesis that G/S127 goats have longer incubation times than do G/G127 goats when intracerebrally inoculated with classical caprine scrapie from G/G127 genotype source material. In the absence of preliminary data, two-tailed nonparametric exact tests were used for all other analyses. All inoculated goats developed clinical signs of scrapie (Table S1), with disease confirmed by the detection of PrPSc in brainstem at the obex and most lymphoid tissues by immunohistochemistry8 (Fig. S1). A significant (P = 0.019) increase in incubation time was observed in G/S127 goats following inoculation with the G/G127 caprine brain homogenate (range: 647–1333 days). No significant difference in incubation time was observed for G/G127 versus G/S127 inoculum in G/G127 goats (P = 0.30). Incubation times in control G/G127 goats inoculated with the G/G127 brain homogenate (range: 261–332 days) were significantly shorter than observed in prior work (both P < 0.054, 5). Our findings include the first reported classical scrapie incubation times for G/S127 goats, confirming that S127 is not protective in goats.6, 7 These data suggest that eradication programs need to include extended traceback periods and longer post-exposure monitoring times for infected herds containing G/S127 goats. This work was supported by USDA-ARS Grant 2090-32000-030-00D. We thank Linda Hamburg, Thomas Truscott, Lori Fuller, Dongyue Zhuang, and Emma Karel for technical assistance. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.