Influence of Polymorphisms in the Prion Protein Gene on the Pathogenesis and Neuropathological Phenotype of Sheep Scrapie after Oral Infection

González, Lorenzo; Pitarch, José Luis; Martin, Stuart; Thurston, Lisa; Simmons, Hugh; Acín, Cristina; Jeffrey, Martin

doi:10.1016/j.jcpa.2013.10.001

Cited by 31 publications

(37 citation statements)

References 40 publications

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“…With regard to the goats carrying mutations at PRNP gene codons 154 and 211, their IHC profile was slightly different due to the presence of plaque-like PrP Sc deposition in the diencephalic portion of the brain. It is believed that the IHC PrP Sc deposition profile results from a composite interaction of various factors, among which is the PRNP host genotype (24,25). Considering that the same experimental conditions, including the infection source, were used in our study, this finding provides further evidence that minimal amino acid differences in the host PRNP genotype drive the neuropathological phenotype.…”

Section: Discussionsupporting

confidence: 59%

“…One approach to defining the phenotype of TSE cases is the evaluation of the neuroanatomical distribution and magnitude of given IHC PrP Sc patterns in the natural host (24,25). By this means, we found that IHC phenotype in our goats was similar to that observed in wild-type sheep, and it was highly retained in the experimentally infected goat as well as in naturally exposed ones and their progeny when they expressed the same PRNP genotype.…”

Section: Discussionmentioning

confidence: 60%

See 1 more Smart Citation

Genetic and Pathological Follow-Up Study of Goats Experimentally and Naturally Exposed to a Sheep Scrapie Isolate

Maestrale

Cancedda

Pintus

et al. 2015

J Virol

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Thirty-seven goats carrying different prion protein genotypes (PRNP) were orally infected with a classical scrapie brain homogenate from wild-type (ARQ/ARQ) sheep and then mated to obtain 2 additional generations of offspring, which were kept in the same environment and allowed to be naturally exposed to scrapie. Occurrence of clinical or subclinical scrapie was observed in the experimentally infected goats (F 0 ) and in only one (F 1b ) of the naturally exposed offspring groups. In both groups (F 0 and F 1b ), goats carrying the R154H, H154H, R211Q, and P168Q-P240P dimorphisms died of scrapie after a longer incubation period than wild-type, G37V, Q168Q-P240P, and S240P goats. In contrast, D145D and Q222K goats were resistant to infection. The immunobiochemical signature of the scrapie isolate and its pathological aspects observed in the sheep donors were substantially maintained over 2 goat generations, i.e., after experimental and natural transmission. This demonstrates that the prion protein gene sequence, which is shared by sheep and goats, is more powerful than any possible but unknown species-related factors in determining scrapie phenotypes. With regard to genetics, our study confirms that the K222 mutation protects goats even against ovine scrapie isolates, and for the first time, a possible association of D145 mutation with scrapie resistance is shown. In addition, it is possible that the sole diverse frequencies of these genetic variants might, at least in part, shape the prevalence of scrapie among naturally exposed progenies in affected herds. IMPORTANCEThis study was aimed at investigating the genetic and pathological features characterizing sheep-to-goat transmission of scrapie. We show that in goats with different prion protein gene mutations, the K222 genetic variant is associated with scrapie resistance after natural and experimental exposure to ovine prion infectivity. In addition, we observed for the first time a protective effect of the D145 goat variant against scrapie. Importantly, our results demonstrate that the phenotypic characteristic of the wild-type sheep scrapie isolate is substantially preserved in goats carrying different susceptible PRNP gene variants, thus indicating that the prion protein gene sequence, which is shared by sheep and goats, plays a fundamental role in determining scrapie phenotypes.

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 60%

Genetic and Pathological Follow-Up Study of Goats Experimentally and Naturally Exposed to a Sheep Scrapie Isolate

Maestrale

Cancedda

Pintus

et al. 2015

J Virol

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“…One study reports the occurrence of three ARQ/ARR-positive sheep to scrapie, 1086 days after the infection by detecting prion in the lymphoreticular tissue. Gonzalez et al (2014) believe that the susceptibility of ARQ/ARR sheep is linked to a combination of factors, such as the dose of infection and the age. Another study reported by Toungue et al (2006) showed that during the periods 1998-2002, in the national scrapie plan of Great Britain, ARQ/ARR ovines with a frequency of 0.34 % were found, indicating that the resistance of ARQ/ARR scrapie sheep is not absolute.…”

Section: Discussionmentioning

confidence: 99%

Report of outbreaks of classical scrapie in Dorper sheep and associated prion protein gene polymorphisms in affected flocks

Andrade

Oliveira

Leal

et al. 2015

Trop Anim Health Prod

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Scrapie is an infectious neurodegenerative disease affecting sheep and goats, related with conformational alteration of an isoform of the prion protein that leads to deposition and aggregation in the host's central nervous system. Occurrence of the natural disease can be influenced by host genetic factors, such as a single nucleotide polymorphism of the prion protein gene. This study reports three scrapie-affected Dorper flocks located on three different farms in Brazil. The objective of this study was to analyze these three flocks using scrapie diagnostics, combining histology, immunohistochemistry, genotyping, and western blot assays. For immunohistochemistry, 192 sheep were selected and 308 sheep blood samples were taken for genotyping. A total of 22 sheep were scrapie positive by immunohistochemistry. Of these, four presented clinical signs and had scrapie immunoreactivity at the obex in western blot assays. The sheep without clinical signs were positive in lymphoid organs, such as the third eyelid and rectal mucosa. The major genotypes found on the flocks were ARQ/ARQ, ARQ/ARR, and ARQ/VRQ for codons 136, 154, and 171. Most of the sheep were considered to be at moderate to high risk, based on risk groups for developing scrapie. Some blood samples were sequenced, and polymorphisms were identified in other codons, such as 127, 142, and 143. Our data demonstrate the importance of preclinical scrapie diagnosis in Brazilian sheep, as most of the affected sheep showed no clinical signs, and emphasize the relevance of genotyping other Dorper sheep to determine the genotypic profile of the breed.

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“…However, that study involved experimental scrapie sources and not enough sheep were included to assess the effect of the PrP genotype on the IHC characteristics. Subsequently studies have indicated that there is an association between PRNP genotype and IHC patterns [61][62][63] . It has been proposed that, at least under natural conditions, sheep may be exposed to various strains and specific PRNP genotypes may allow certain strains to propagate preferentially.…”

Section: Classical Scrapiementioning

confidence: 99%

Pathology of Animal Transmissible Spongiform Encephalopathies (TSEs)

Spiropoulos

Simmons

2017

Food Safety

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Pathology is the study of the structural and functional changes produced by diseases or − more specifically − the lesions they cause. To achieve this pathologists employ various approaches. These include description of lesions that are visible to the naked eye which are the subject of anatomic pathology and changes at the cellular level that are visible under the microscope, the subject of histopathology. Changes at the molecular level which are identified by probes that target specific molecules − mainly proteins that are detected using immunohistochemistry (IHC). As transmissible spongiform encephalopathies (TSEs) do not cause visible lesions anatomic pathology is not applicable to their study. For decades the application of histopathology to detect vacuoles or plaques was the only means of confirming TSE disease. The subsequent discovery of the cellular prion protein (PrP C ) and its pathogenic isoform, PrP Sc , which is a ubiquitous marker of TSEs, led to the production of anti-PrP antibodies, and enabled the development of PrP Sc detection techniques such as immunohistochemistry, Histoblot and PETblot that have evolved in parallel with similar biochemical methods such as Western blot and ELISA. These methods offer greater sensitivity than histopathology in TSE diagnosis and crucially they can be applied to analyze various phenotypic aspects of single TSE sources increasing the amount of data and offering higher discriminatory power. The above principles are applied to diagnose and define TSE phenotypes which form the basis of strain characterisation.

show abstract

Influence of Polymorphisms in the Prion Protein Gene on the Pathogenesis and Neuropathological Phenotype of Sheep Scrapie after Oral Infection

Cited by 31 publications

References 40 publications

Genetic and Pathological Follow-Up Study of Goats Experimentally and Naturally Exposed to a Sheep Scrapie Isolate

Genetic and Pathological Follow-Up Study of Goats Experimentally and Naturally Exposed to a Sheep Scrapie Isolate

Report of outbreaks of classical scrapie in Dorper sheep and associated prion protein gene polymorphisms in affected flocks

Pathology of Animal Transmissible Spongiform Encephalopathies (TSEs)

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