Adaptation and Selection of Prion Protein Strain Conformations following Interspecies Transmission of Transmissible Mink Encephalopathy

Abstract

Interspecies transmission of the transmissible spongiform encephalopathies (TSEs), or prion diseases, can result in the adaptation and selection of TSE strains with an expanded host range and increased virulence such as in the case of bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease. To investigate TSE strain adaptation, we serially passaged a biological clone of transmissible mink encephalopathy (TME) into Syrian golden hamsters and examined the selection of distinct strain phenotypes and conformations of the disease-specific isoform of the prion protein (PrP Sc ). The long-incubation-period drowsy (DY) TME strain was the predominate strain, based on the presence of its strain-specific PrP Sc following interspecies passage. Additional serial passages in hamsters resulted in the selection of the hyper (HY) TME PrP Sc strain-dependent conformation and its short incubation period phenotype unless the passages were performed with a low-dose inoculum (e.g., 10؊5 dilution), in which case the DY TME clinical phenotype continued to predominate. For both TME strains, the PrP Sc strain pattern preceded stabilization of the TME strain phenotype. These findings demonstrate that interspecies transmission of a single cloned TSE strain resulted in adaptation of at least two strain-associated PrP Sc conformations that underwent selection until one type of PrP Sc conformation and strain phenotype became predominant. To examine TME strain selection in the absence of host adaptation, hamsters were coinfected with hamster-adapted HY and DY TME. DY TME was able to interfere with the selection of the short-incubation HY TME phenotype. Coinfection could result in the DY TME phenotype and PrP Sc conformation on first passage, but on subsequent passages, the disease pattern converted to HY TME. These findings indicate that during TSE strain adaptation, there is selection of a strain-specific PrP Sc conformation that can determine the TSE strain phenotype.

De novo generation of a transmissible spongiform encephalopathy by mouse transgenesis

“…This barrier appeared to be bidirectional, as tg1020 mice experienced long, highly variable incubation periods upon inoculation with RML mouse prions. The incubation time and its variability decreased by Ϸ50% on second passage in tg1020 mice, as would be expected from strain adaptation (25,33,34).…”

Prion agent diversity and species barrier

“…DY but not HY retained pathogenicity for mink through at least four passages in hamsters, suggesting the possibility that it was the major if not the sole mink pathogen component in the original source [24]. When the Stetsonville isolate was biologically cloned by three transmissions at endpoint dilutions in mink, so as to isolate a single strain from a potential mixture before transmission to hamsters, both HY and DY PrP res patterns were again detected on first passage and both strains could be stably propagated on serial passage [11]. At the molecular level, this suggests that mink PrP Sc has the ability to convert hamster PrP C into more than one stable hamster PrP Sc conformation.…”

A prion disease of cervids: Chronic wasting disease

“…Therefore, two different strains could be passaged from a single mule deer CWD isolate, a rapid and a slowly replicating strain with differing disease phenotypes [70]. Alternatively, these strains could have been generated upon interspecies transmission [6].…”

“…However, strain features including histologic profile, target organs, and glycoform patterns will not necessarily remain the same upon crossing species barriers [5,6,8,57]. The PrP Sc form is cleaved by proteinase-K (PK) at different sites depending on the conformation of the protein and may aid determination of whether the PrP Sc conformation is similar.…”