Evidence for Co-infection of Ovine Prion Strains in Classical Scrapie Isolates

Thackray, Alana M.; Lockey, Richard; Beck, Katy E.; Spiropoulos, John; Bujdoso, Raymond

doi:10.1016/j.jcpa.2012.01.009

Cited by 24 publications

(28 citation statements)

References 64 publications

(73 reference statements)

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“…Conventional ovine prion strain typing is carried out by serial transmission studies in either wild-type or PrP transgenic mice [41,[65][66][67][68]. This view is re-enforced by our ability to generate PK-resistant ovine PrP Sc by PMCA using prion-exposed VRQ(GPI) head homogenate as seed and tg338 (ovine VRQ PrP transgenic) mouse brain homogenate as a substrate.…”

Section: Figure 8 Transmissibility Of Prion-induced Toxicity In Prp Tmentioning

confidence: 99%

Prion-induced and spontaneous formation of transmissible toxicity in PrP transgenic Drosophila

Thackray

Zhang

et al. 2014

Biochemical Journal

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Prion diseases are fatal transmissible neurodegenerative diseases of various mammalian species. Central to these conditions is the conversion of the normal host prion protein PrP(C) into the abnormal prion conformer PrP(Sc). Mature PrP(C) is attached to the plasma membrane by a glycosylphosphatidylinositol anchor, whereas during biosynthesis and metabolism cytosolic and secreted forms of the protein may arise. The role of topological PrP(C) variants in the mechanism of prion formation and prion-induced neurotoxicity during prion disease remains undefined. In the present study we investigated whether Drosophila transgenic for ovine PrP targeted to the plasma membrane, to the cytosol or for secretion, could produce transmissible toxicity following exposure to exogenous ovine prions. Although all three topological variants of PrP were efficiently expressed in Drosophila, cytosolic PrP was conformationally distinct and required denaturation before recognition by immunobiochemical methods. Adult Drosophila transgenic for pan neuronally expressed ovine PrP targeted to the plasma membrane, to the cytosol or for secretion exhibited a decreased locomotor activity after exposure at the larval stage to ovine prions. Proteinase K-resistant PrP(Sc) was detected by protein misfolding cyclic amplification in prion-exposed Drosophila transgenic for membrane-targeted PrP. Significantly, head homogenate from all three variants of prion-exposed PrP transgenic Drosophila induced a decreased locomotor activity when transmitted to PrP recipient flies. Drosophila transgenic for PrP targeted for secretion exhibited a spontaneous locomotor defect in the absence of prion exposure that was transmissible in PrP transgenic flies. Our data are consistent with the formation of transmissible prions in PrP transgenic Drosophila.

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Section: Figure 8 Transmissibility Of Prion-induced Toxicity In Prp Tmentioning

confidence: 99%

Prion-induced and spontaneous formation of transmissible toxicity in PrP transgenic Drosophila

Thackray

Zhang

et al. 2014

Biochemical Journal

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“…On the basis of the transmission features in conventional mice (incubation periods, distribution of the lesions in the brain), early transmission experiments described a considerable diversity of the scrapie agents with up to 20 prion strains reportedly identified 8 . However, more recent strain typing in transgenic mouse lines that express ovine PrP has identified a more restricted range that comprises at least four phenotypically distinct scrapie strains 5,[9][10][11][12] . Despite converging evidence that scrapie is caused by a variety of prion strains, there is at this stage no comprehensive description of their diversity.…”

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confidence: 99%

Evidence for zoonotic potential of ovine scrapie prions

Torres²,

et al. 2014

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Although Bovine Spongiform Encephalopathy (BSE) is the cause of variant Creutzfeldt Jakob disease (vCJD) in humans, the zoonotic potential of scrapie prions remains unknown. Mice genetically engineered to overexpress the human prion protein (tgHu) have emerged as highly relevant models for gauging the capacity of prions to transmit to humans. These models can propagate human prions without any apparent transmission barrier and have been used used to confirm the zoonotic ability of BSE. Here we show that a panel of sheep scrapie prions transmit to several tgHu mice models with an efficiency comparable to that of cattle BSE. The serial transmission of different scrapie isolates in these mice led to the propagation of prions that are phenotypically identical to those causing sporadic CJD (sCJD) in humans. These results demonstrate that scrapie prions have a zoonotic potential and raise new questions about the possible link between animal and human prions.

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“…Passage of sheep scrapie to wild-type or transgenic mice expressing ovine PrP C results in the isolation of distinct prion strains (33)(34)(35). This suggests that more than one strain of sheep scrapie is present in the inoculum.…”

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Incongruity between Prion Conversion and Incubation Period following Coinfection

Langenfeld

Shikiya

Kincaid

et al. 2016

J Virol

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When multiple prion strains are inoculated into the same host, they can interfere with each other. Strains with long incubation periods can suppress conversion of strains with short incubation periods; however, nothing is known about the conversion of the long-incubation-period strain during strain interference. To investigate this, we inoculated hamsters in the sciatic nerve with long-incubation-period strain 139H prior to superinfection with the short-incubation-period hyper (HY) strain of transmissible mink encephalopathy (TME). First, we found that 139H is transported along the same neuroanatomical tracks as HY TME, adding to the growing body of evidence indicating that PrP Sc favors retrograde transneuronal transport. In contrast to a previous report, we found that 139H interferes with HY TME infection, which is likely due to both strains targeting the same population of neurons following sciatic nerve inoculation. Under conditions where 139H blocked HY TME from causing disease, the strainspecific properties of PrP Sc corresponded with the strain that caused disease, consistent with our previous findings. In the groups of animals where incubation periods were not altered, we found that the animals contained a mixture of 139H and HY TME PrP Sc . This finding expands the definition of strain interference to include conditions where PrP Sc formation is altered yet disease outcome is unaltered. Overall, these results contradict the premise that prion strains are static entities and instead suggest that strain mixtures are dynamic regardless of incubation period or clinical outcome of disease. IMPORTANCEPrions can exist as a mixture of strains in naturally infected animals, where they are able to interfere with the conversion of each other and to extend incubation periods. Little is known, however, about the dynamics of strain conversion under conditions where incubation periods are not affected. We found that inoculation of the same animal with two strains can result in the alteration of conversion of both strains under conditions where the resulting disease was consistent with infection with only a single strain. These data challenge the idea that prion strains are static and suggests that strain mixtures are more dynamic than previously appreciated. This observation has significant implications for prion adaptation. P rion diseases are transmissible neurodegenerative diseases of animals, including humans, with no known effective treatment. Prion diseases of animals include scrapie of sheep and goats, chronic wasting disease of cervids, bovine spongiform encephalopathy of cattle, and transmissible mink encephalopathy (TME) of ranch-raised mink. Prion diseases of humans include kuru of the Fore people of Papua New Guinea, Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia (1-8). Human prion diseases are unique in biology in that they can have infectious, familial, or sporadic etiologies. Interestingly, brain material from all three etiologies is infecti...

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Evidence for Co-infection of Ovine Prion Strains in Classical Scrapie Isolates

Cited by 24 publications

References 64 publications

Prion-induced and spontaneous formation of transmissible toxicity in PrP transgenic Drosophila

Prion-induced and spontaneous formation of transmissible toxicity in PrP transgenic Drosophila

Evidence for zoonotic potential of ovine scrapie prions

Incongruity between Prion Conversion and Incubation Period following Coinfection

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