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brief communications
2. Greenwald, A. G., McGhee, J. L. & Schwartz, J. L. J. Person. Soc. and J.F., unpublished results). However, the †South Wales Forensic Psychiatric Service, Psychol. 74, 1464–1480 (1998).
3. Rice, M. E., Harris, G. T. & Cormier, C. A. Law Hum. Behav. 16,
Caswell Clinic, Glanrhyd Hospital, probably too small to rule out susceptibility 4. Hare, R. D. The Hare Psychopathy Checklist Revised (Multi- even if the surviving animals remain free ‡Department of Psychological Medicine, University of Wales College of Medicine, Heath 5. Cooke, D. L. & Michie, C. J. Abnorm. Psychol. 108, 58–68 (1999).
6. Nelson, H. National Adult Reading Test (NART) Manual for pigs, in which no natural case of BSE §HM Prisons, Grendon and Springhill, 7. Hare, R. D. Without Conscience (Guilford, New York, 1999).
8. Gray, N. S. et al. J. Forens. Psychiat. Psychol. 14, 27–43 (2003).
9. Bellezza, F. S., Greenwald, A. G. & Banaji, M. R. Behav. Res. Methods Instr. Comp. 18, 299–303 (1986).
520–1,130 days, whereas those exposed to 1. Cleckley, H. The Mask of Sanity (Mosby, St Louis, 1941).
Competing financial interests: declared none.
repeated oral challenge remained healthyfor up to 2,550 days after infection11. Even if ARR/ARR sheep exposed to nat- Prion diseases
BSE in sheep bred for
(495–671 days) was shortest in ARQ/ARQ disease, they might be able to act as sub- sheep, with 17 out of 19 being affected. So clinical carriers of infection. However, no resistance to infection
far, four out of ten VRQ/VRQ and two out abnormal PrP (and, by implication, infec- of ten VRQ/ARQ Cheviot sheep have also tivity) was detected in the lymphoid tissues Selective breeding for disease-resistant succumbed to disease after incubation peri- of any of the ARR/ARRsheep cases of BSE ods of 881–1,092 days. Unexpectedly, 3 out reported here. Likewise, neither clinically of 19 BSE-challenged ARR/ARR sheep also normal ARR/ARR sheep in scrapie-endem- spongiform encephalopathy (BSE), if it is showed clinical symptoms after incubation ic flocks, nor those challenged orally with that the genotype associated with the respectively, but none of the ARR hetero- highest resistance can still be infected with zygotes has been clinically affected to date. although here again the number of animals BSE by intracerebral inoculation. Although examined is small6,12. These results indicate protease-resistant fraction of PrP (PrPSc) that ARR/ARR sheep are unlikely to excrete exposed to natural infection remains to be the infectious agent, although transmission determined, it may have important implica- chemical labelling of disease-associated PrP of infection to in-contact animals in the tions for disease-eradication strategies.
in brain sections from the ARR/ARR sheep absence of detectable abnormal PrP cannot Susceptibility and resistance to transmis- (Fig. 1) were consistent with experimental BSE in ARQ/ARQ sheep8,9. This contrasts with the results of in vitro cell-free conver- intracerebrally with a high dose of BSE, but the gene that encodes prion protein (PrP).
there is, as yet, no evidence to suggest that Representing the resulting alleles as the they are susceptible when exposed by nat- The susceptibility of ARR/ARR sheep to ural routes of infection. But the fact that the tibility to scrapie is strongly associated with intracerebral injection with BSE indicates valine (V) at position 136 and/or glutamine to a pathological isoform in vivo raises (Q) at position 171, and susceptibility to having absolute genetic resistance to TSE questions about the basic mechanisms that infection. The significance of this result for antly with the alanine-arginine-glutamine sheep that are exposed to natural TSE infec- Fiona Houston*, Wilfred Goldmann†,
tion remains to be determined. In ongoing Angela Chong†, Martin Jeffrey‡,
The ARR allele is associated with resis- experiments, ARR/ARR sheep orally dosed Lorenzo González‡, James Foster†,
tance to natural scrapie — the disease is with BSE have remained free from clinical David Parnham†, Nora Hunter†
rare in ARR heterozygotes3 and only one disease or evidence of preclinical infection *Institute for Animal Health, Compton, Newbury, unconfirmed case has ever been reported in for up to 2,100 days after BSE challenge (ref. 6 a homozygote4. The limited data available suggest that ARR/ARR sheep are also resis- †IAH Neuropathogenesis Unit, Ogston Building, scrapie and BSE5,6. Britain has therefore ‡Veterinary Laboratories Agency Lasswade, initiated the National Scrapie Plan, which Pentlands Science Park, Penicuik, aims eventually to eradicate scrapie (as well 1. Hunter, N. Trends Microbiol. 5, 331–334 (1997).
of increasing the frequency of the ARR 2. Goldmann, W., Hunter, N., Smith, G., Foster, J. & Hope, J. allele and decreasing that of the VRQ allele. J. Gen. Virol. 75, 989–995 (1994).
3. van Keulen, L. J. et al. J. Clin. Microbiol. 34, 1228–1231 (1996).
4. Ikeda, T. et al. J. Gen. Virol. 76, 2577–2581 (1995).
sheep are still resistant to transmission of 5. O’Rourke, K. I. et al. J. Gen. Virol. 78, 975–978 (1997).
Figure 1 Immunohistochemical labelling of abnormal PrP protein
6. Jeffrey, M. et al. J. Comp. Pathol. 124, 280–289 (2001).
infected cattle-brain homogenate (0.05 g).
7. Kao, R. R. et al. Science 295, 332–335 (2002).
in the dorsal motor nucleus of the vagus of a sheep that is 8. Hope, J. et al. J. Gen. Virol. 81, 851 (2000).
homozygous for the ARR allele (see text) and has been infected 9. Jeffrey, M. et al. J. Comp. Pathol. 125, 271–284 (2001).
sheep of three different breeds (Suffolk, with bovine spongiform encephalopathy (BSE). a, Intraneuronal
10. Bossers, A., de Vries, R. & Smits, M. A. J. Virol. 74,
Cheviot and Poll Dorset) and six different and neuropil-associated accumulations are revealed by the R145 PrP genotypes (VRQ/VRQ, VRQ/ARQ, 11. Ryder, S. J., Hawkins, S. A., Dawson, M. & Wells, G. A. J. Comp. antibody; b, the antibody P4 reveals neuropil-associated (but not
Pathol. 122, 131–143 (2000).
VRQ/ARR, ARQ/ARQ, ARQ/ARR and intraneuronal) extracellular accumulation. This pattern of labelling 12. Jeffrey, M. et al. J. Comp. Pathol. 127, 264–273 (2002).
can distinguish BSE from scrapie in sheep.
Competing financial interests: declared none.
NATURE | VOL 423 | 29 MAY 2003 | www.nature.com/nature 2003 Nature Publishing Group

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