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

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DOI

https://doi.org/10.1371/journal.ppat.1012370

Language of the publication
English
Date
2024-07-08
Type
Article
Author(s)
  • Chang, Sheng Chun
  • Arifin, Maria Immaculata
  • Tahir, Waqas
  • McDonald, Keegan John
  • Zeng, Doris
  • Schatzl, Hermann M.
  • Hannaoui, Samia
  • Gilch, Sabine
Publisher
Public Library of Science

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.

Subject

  • Animal diseases

Keywords

  • Bovine spongiform encephalopathies,
  • Chronic wasting disease,
  • Cervidae--Diseases,
  • Communicable diseases--Transmission

Rights

Pagination

1-19

Peer review

Yes

Identifiers

ISSN
1553-7374

Article

Journal title
PLoS Pathogens
Journal volume
20
Journal issue
7
Article number
e1012370
Accepted date
2024-06-25
Submitted date
2024-03-26

Citation(s)

Chang, S. C., Arifin, M. I., Tahir, W., McDonald, K. J., Zeng, D., Schatzl, H. M., Hannaoui, S., & Gilch, S. (2024). Extraneural infection route restricts prion conformational variability and attenuates the impact of quaternary structure on infectivity. PLoS Pathogens, 20(7), Article e1012370. https://doi.org/10.1371/journal.ppat.1012370

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