New Zealand sheep with scrapie-susceptible PrP genotypes succumb to experimental challenge with a sheep-passaged scrapie isolate (SSBP/1)

Houston, E. Fiona; Halliday, S.; Jeffrey, Martin; Goldmann, Wilfred; Hunter, Nora

doi:10.1099/0022-1317-83-5-1247

Cited by 55 publications

(59 citation statements)

References 21 publications

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“…Cheviot sheep of the ARQ/ARQ genotype were sourced from the Defra flock of New Zealand (scrapie-free) origin (27) and were housed indoors in concrete pens in the sheep unit at The Institute for Animal Health, Compton, United Kingdom. Prior to arrival at Compton, some ewes were implanted with ARQ/ARQ embryos so that the resulting lambs could be inoculated soon after birth.…”

Section: Methodsmentioning

confidence: 99%

Susceptibility of Young Sheep to Oral Infection with Bovine Spongiform Encephalopathy Decreases Significantly after Weaning

Hunter

Houston

Foster

et al. 2012

J Virol

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bBovine spongiform encephalopathy (BSE) is a transmissible spongiform encephalopathy (TSE) (or prion disease) that is readily transmissible to sheep by experimental infection and has the shortest incubation period in animals with the ARQ/ARQ PRNP genotype (at codons 136, 154, and 171). Because it is possible that sheep in the United Kingdom could have been infected with BSE by being fed contaminated meat and bone meal supplements at the same time as cattle, there is considerable interest in the responses of sheep to BSE inoculation. Epidemiological evidence suggests that very young individuals are more susceptible to TSE infection; however, this has never been properly tested in sheep. In the present study, low doses of BSE were fed to lambs of a range of ages (ϳ24 h, 2 to 3 weeks, 3 months, and 6 months) and adult sheep. The incidence of clinical BSE disease after inoculation was high in unweaned lambs (ϳ24 h and 2 to 3 weeks old) but much lower in older weaned animals The incubation period was also found to be influenced by the genotype at codon 141 of the PRNP gene, as lambs that were LF heterozygotes had a longer mean incubation period than those that were homozygotes of either type. The results suggest that sheep in the United Kingdom would have been at high risk of BSE infection only if neonatal animals had inadvertently ingested contaminated supplementary foodstuffs.T ransmissible spongiform encephalopathies (TSEs) are prion diseases that affect many mammals and are associated with the presence of the protein PrP Sc , a protease-resistant form of a normal host protein, PrP C . PrP Sc is believed to form all or part of the infectious agent (44). The natural sheep TSE is scrapie; however, sheep can also be experimentally infected with bovine spongiform encephalopathy (BSE) by several routes, including intracerebral, oral (17), and intravenous (28). The manifestation of clinical signs of BSE following inoculation depends upon a number of factors, the most important being the PRNP genotype. In the Neuropathogenesis Unit, Edinburgh, United Kingdom (NPU), Cheviot sheep, animals homozygous for the ARQ PRNP gene allele (codons 136, 154, and 171 indicated in order) are most susceptible (23). However, for reasons that are currently unknown, a various number of adult ARQ/ARQ sheep will survive a challenge with BSE (16). Understanding this aspect of resistance is of fundamental importance. One potential influence on disease outcome following infection with any TSE is the age at which the individual is challenged. Because of the etiology of scrapie, which suggests that in sheep the risk for infection is very high during the perinatal period, many sheep challenge studies, including the study described in reference 3, have used young lambs rather than adult sheep as infection models. In addition, epidemiological studies in cattle (15) have suggested that in general, younger individuals are more susceptible to infection with BSE, and studies in human beings have shown that more individuals at relatively young ages have b...

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Section: Methodsmentioning

confidence: 99%

Susceptibility of Young Sheep to Oral Infection with Bovine Spongiform Encephalopathy Decreases Significantly after Weaning

Hunter

Houston

Foster

et al. 2012

J Virol

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“…Our results are also consistent with those of a number of other studies. In sheep, the relationship between the length of the incubation period and the PrP genotype has been shown experimentally (Goldmann et al, 1994;Houston et al, 2002). The results of Houston et al (2002) indicate differences in average incubation period among different genotypes for Cheviot and Dorset animals that were infected …”

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confidence: 99%

Polygenic variation and transmission factors involved in the resistance/susceptibility to scrapie in a Romanov flock

Díaz

Vitezica

Rupp

et al. 2005

Journal of General Virology

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Data from 4049 Romanov sheep belonging to a flock affected by natural scrapie were analysed by using survival-analysis techniques. Failure time was defined as the period of time between first exposure to infection and the date that animals left the flock with scrapie signs. Four hundred and forty-seven sheep were identified as 'scrapie animals'. Several models, including level of exposure as a time-dependent effect, PrP genotype, sex, age at first exposure, litter size and factors related to vertical transmission, were tested. The best model was extended to a sire-dam frailty model, in order to estimate the polygenic variation in addition to that in the Prnp gene. A combined effect of rearing type and the dam's disease status was detected. Thus, only sheep with a low degree of exposure to infection as lambs (lambs reared artificially and born out of a healthy dam) showed less risk than others. Animals first exposed to infection at older ages seemed to be less susceptible to scrapie. In this Romanov population, new genotypes (AHQ/AHQ, AHQ/VRQ, ARR/VRQ and ARR/ARQ) were associated with risk, suggesting the effect of genotypes on the incubation period of animals. Polygenic variance was responsible for 21 % of the total genetic variability that was related to susceptibility to scrapie. Therefore, the genetic susceptibility to scrapie may be explained by the joint effect of point mutations at the Prnp major gene and a number of genes that modulate its effect. INTRODUCTIONTransmissible spongiform encephalopathies (TSEs), or prion diseases, are a group of fatal degenerative disorders of the central nervous system. They comprise a group of diseases that affect many species. TSEs are characterized by the accumulation of an abnormal isoform of the cellular prion protein, named PrP Sc . Scrapie is a TSE affecting sheep and goats. TSE in sheep, as in mice and humans, is controlled genetically (Hunter et al., 1989;Hunter, 1997;Prusiner & Scott, 1997;Elsen et al., 1999). Susceptibility to scrapie, which may be evaluated by mortality rate and incubation period, is mainly controlled by polymorphisms in the Prnp gene. Several point mutations located at codons 136 (T, A, V), 154 (R, H) and 171 (R, Q, H, K) of the gene have been associated with natural scrapie (e.g. Hunter, 1997). The ARR allele is associated with resistance and VRQ is associated with susceptibility (e.g. Hunter et al., 1996;Elsen et al., 1999). However, there are alleles, such as ARQ, ARH and AHQ, that behave differently depending on the breed (e.g. Hunter, 1997;Thorgeirsdottir et al., 1999). It has also been demonstrated that there is an interaction between the genotype of the host and the scrapie strain (Goldmann et al., 1994;O'Rourke et al., 1997; Barron et al., 2003). In the mouse, the incubation period of the disease has been associated with the PrP genotype (Moore et al., 1998) and with the prion strain inoculated (Bruce et al., 1991). However, polymorphism of the Prnp gene does not explain the total variation in incubation period that is observed, indicati...

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“…The effect of the PrP genotype on scrapie survival time in sheep has been shown experimentally (Goldmann et al, 1994;Houston et al, 2002) and from field data (Elsen et al, 1999). The mean incubation time for the ARQ/VRQ genotype was significantly greater than in the other two genotypes and the standard deviation for ARQ/---group was twice the standard deviation for the VRQ/VRQ genotype.…”

Section: Discussionmentioning

confidence: 98%

Mapping of quantitative trait loci affecting classical scrapie incubation time in a population comprising several generations of scrapie-infected sheep

Moréno

Moazami‐Goudarzi

Briand

et al. 2009

Journal of General Virology

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Although susceptibility to scrapie is largely controlled by the PrP gene, the role of other genes that affect scrapie resistance in sheep is now confirmed. Following the detection of quantitative trait loci (QTL) on chromosomes 6 and 18 in a half-sib family with an ARQ/VRQ susceptible PrP genotype, the whole pedigree of a naturally infected flock was investigated to confirm these QTL regions in different PrP genotypes. The present study has allowed us to confirm the QTL on chromosome 18, and to demonstrate the QTL effects in several PrP genotypes. INTRODUCTIONScrapie is a transmissible spongiform encephalopathy (TSE), and host resistance is largely controlled by the PrP gene encoding the PrP protein (Goldmann et al., 1990;Palmer et al., 1991). Recently, some loci that modulate susceptibility to TSEs, other than the PrP gene, have been detected in mice (Lloyd et al., 2001(Lloyd et al., , 2002Manolakou et al., 2001;Moreno et al., 2003;Stephenson et al., 2000) and cattle (HernandezSanchez et al., 2002; Zhang et al., 2004). In sheep, Diaz et al. (2005) have shown that the PrP gene explains only part of the total genetic variance of the survival time in a Romanov sheep flock naturally infected by scrapie. Moreno et al. (2008) detected two quantitative trait loci (QTL) regions (at the 5 % chromosome-wide level) affecting scrapie incubation time, on chromosomes 6 and 18, in one half-sib family of 67 scrapie-affected animals.In this article, our aim was to confirm QTL previously detected by Moreno et al. (2008) by using additional data from the sheep population from the INRA Langlade farm and to verify their presence in the PrP genotypes with different scrapie susceptibilities. RESULTSThe significant fixed effects affecting incubation time were the PrP genotype (P,0.001), rearing (P,0.006), litter size (P,0.01), the PrP genotype of dam (P,0.05) and the interaction between season and birth year (P,0.001). The significance of the PrP genotype is mainly due to the greater estimated mean of incubation time for the ARQ/ VRQ genotype compared with the other genotypes (Table 1). However, the standard deviation of the ARQ/ VRQ population was similar to that of the ARQ/ARQ population, but twice that of the VRQ/VRQ population. Because heterogeneous variances were observed between VRQ/VRQ and ARQ/---sub-populations, the variance component analyses were repeated for these two genotype groups separately.The heritabilities of scrapie incubation time estimated in the total population and in sub-populations are shown in Table 2. These heritabilities suggest that, in addition to the PrP effects, a proportion of the between-animal variability is due to genetic effects. However, the estimated values were somewhat (albeit not significantly, P.0.05) higher in the two sub-populations than in the total dataset, particularly when the QTL effect was not fitted.The data provided no evidence of a QTL on chromosome 6, with the likelihood ratio test (LRT) value being close to zero at all tested locations. However, a significant QTL was identified o...

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New Zealand sheep with scrapie-susceptible PrP genotypes succumb to experimental challenge with a sheep-passaged scrapie isolate (SSBP/1)

Cited by 55 publications

References 21 publications

Susceptibility of Young Sheep to Oral Infection with Bovine Spongiform Encephalopathy Decreases Significantly after Weaning

Susceptibility of Young Sheep to Oral Infection with Bovine Spongiform Encephalopathy Decreases Significantly after Weaning

Polygenic variation and transmission factors involved in the resistance/susceptibility to scrapie in a Romanov flock

Mapping of quantitative trait loci affecting classical scrapie incubation time in a population comprising several generations of scrapie-infected sheep

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