Emergence of multiple prion strains from single isolates of ovine scrapie

Abstract

The infectious agent associated with prion diseases such as ovine scrapie shows strain diversity. Ovine prion strains have typically been identified by their transmission properties in wild-type mice. However, strain typing of ovine scrapie isolates in wild-type mice may not reveal properties of the infectious prion agent as they exist in the original host. This could be circumvented if ovine scrapie isolates are passaged in ovine prion protein (PrP)-transgenic mice. This study used incubation time, lesion profile, immunohistochemistry of the disease-associated PrP (PrP Sc ) and molecular profile to compare the range of ovine prion strains that emerged from sheep scrapie isolates following serial passage in wild-type and ovine PrP transgenic mice. It was found that a diverse range of ovine prion strains emerged from homozygous ARQ and VRQ scrapie isolates passaged in wild-type and ovine PrP transgenic mice. However, strain-specific PrP Sc deposition and PrP27-30 molecular profile patterns were identified in ovine PrP transgenic mice that were not detected in wild-type mice. Significantly, it was established that the individual mouse brain selected for transmission during prion strain typing had a significant influence on strain definition. Serial passage of short-and long-incubation-time animals from the same group of scrapieinoculated mice revealed different prion strain phenotypes. These observations are consistent with the possibility that some scrapie isolates contain more than one prion strain.

Disease phenotype in sheep after infection with cloned murine scrapie strains

“…When a new disease phenotype is seen following passage, it has been difficult therefore to differentiate between host and strain effects, and in particular to know whether there has been strain mutation or adaptation or whether the new host has selected from a mixture of pre-existing strains in the donor. [38][39][40] Our results confirm that not all the pathological features of cloned murine strains are transferred to the sheep host, in which phenotypic variability appears to be dependant of host factors such as Prnp genotype or breed. Although not definitive as the inocula were cloned this phenotypic variability would not appear to be due to the existence of a mixture of strains in the infectious material given to sheep.…”

Mechanisms of prion-induced neurodegeneration

“…The molecular mechanisms of TSE phenotypic heterogeneity are not fully understood, although polymorphisms in the host PRNP gene influence the phenotypic differences and individual susceptibility to certain forms of the disease ( Refs 24,25,26,27,28,29,30,31). These polymorphisms also partially explain the origin of biochemically distinct PrP TSE conformers substantiating the existence of prion strains in humans ( Refs 32,33,34) and animals ( Refs 35,36,37).…”

Scientific Opinion on a request for a review of a scientific publication concerning the zoonotic potential of ovine scrapie prions

“…However, successful attempts have been made to apply some of these new techniques to wild type mice (Beck et al, 2010a(Beck et al, , 2012aCorda et al, 2012;van Keulen et al, 2014). With the introduction of transgenic mouse lines there has been no standardised designation of strains although at least two approaches have been suggested: one based on the immunohistochemical characteristics of PrP Sc in coronal sections of mice (Thackray et al, 2011(Thackray et al, , 2012, and the other based on a combination of incubation period and Western blot (Laferriere et al, 2013). However, most strains characterised in transgenic mice are designated according to the reference code of the ovine source from which they have been isolated.…”

“…Based on strain typing studies in mice it is well documented that more than one TSE strain is responsible for Classical scrapie in sheep Bruce, 2003;Thackray et al, 2011Thackray et al, , 2012Beck et al, 2012a;Cassard et al, 2014). However, the exact number of Classical scrapie strains is unknown despite characterisation of several scrapie isolates in both wild type and transgenic mouse models.…”

“…Therefore they retain little resemblance to the properties of the agent in the sheep, and cannot be considered to comprehensively represent the field situation. Since the BSE epidemic, further characterisation of naturally occurring Classical scrapie cases that were detected after 1985 was initiated to identify strain variation in natural Classical scrapie using both wild type and transgenic mouse models (Bruce, 2002;Bruce et al, 2002;Beck et al, 2012a;Thackray et al, 2011Thackray et al, , 2012Cassard et al, 2014). Remarkably, the studies conducted in wild type mice after 1985 revealed novel strains in addition to the 20 that were known historically, suggesting that there may be evolution of Classical scrapie strains (Bruce et al, 2002;Beck et al, 2012a).…”