Extraneural infection route restricts prion conformational variability and attenuates the impact of quaternary structure on infectivity

PLoS Pathog. 2024 Jul 8;20(7):e1012370. doi: 10.1371/journal.ppat.1012370. eCollection 2024 Jul.

Abstract

Prions can exist as different strains that consist of conformational variants of the misfolded, pathogenic prion protein isoform PrPSc. Defined by stably transmissible biological and biochemical properties, strains have been identified in a spectrum of prion diseases, including chronic wasting disease (CWD) of wild and farmed cervids. CWD is highly contagious and spreads via direct and indirect transmission involving extraneural sites of infection, peripheral replication and neuroinvasion of prions. Here, we investigated the impact of infection route on CWD prion conformational selection and propagation. We used gene-targeted mouse models expressing deer PrP for intracerebral or intraperitoneal inoculation with fractionated or unfractionated brain homogenates from white-tailed deer, harboring CWD strains Wisc-1 or 116AG. Upon intracerebral inoculation, Wisc-1 and 116AG-inoculated mice differed in conformational stability of PrPSc. In brains of mice infected intraperitoneally with either inoculum, PrPSc propagated with identical conformational stability and fewer PrPSc deposits in most brain regions than intracerebrally inoculated animals. For either inoculum, PrPSc conformational stability in brain and spinal cord was similar upon intracerebral infection but significantly higher in spinal cords of intraperitoneally infected animals. Inoculation with fractionated brain homogenates resulted in lower variance of survival times upon intraperitoneal compared to intracerebral infection. In summary, we demonstrate that extraneural infection mitigates the impact of PrPSc quaternary structure on infection and reduces conformational variability of PrPSc propagated in the brain. These findings provide new insights into the evolution of stable CWD strains in natural, extraneural transmissions.

MeSH terms

  • Animals
  • Brain* / metabolism
  • Brain* / pathology
  • Deer*
  • Mice
  • Mice, Transgenic
  • PrPSc Proteins* / metabolism
  • Prion Diseases / metabolism
  • Prion Diseases / pathology
  • Prion Diseases / transmission
  • Prions / metabolism
  • Prions / pathogenicity
  • Protein Conformation
  • Wasting Disease, Chronic* / transmission

Substances

  • PrPSc Proteins
  • Prions

Grants and funding

This study was funded by the Alberta Prion Research Institute (grant #201800003 to SG and grant #201600023 to HMS) and the Natural Sciences and Engineering Council of Canada (NSERC; RGPIN-2019-05309 to SG). SG was supported through the Canada Research Chairs program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.