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

• Published in: PLoS pathogens Vol. 20; no. 7; p. e1012370
• Main Authors: Chang, Sheng Chun, Arifin, Maria Immaculata, Tahir, Waqas, McDonald, Keegan John, Zeng, Doris, Schatzl, Hermann M, Hannaoui, Samia, Gilch, Sabine
• Format: Journal Article
• Language: English
• Published: San Francisco Public Library of Science 08.07.2024; Public Library of Science (PLoS)
• Subjects: Animal models; Animals; Biological properties; Biology and Life Sciences; Brain; Brain research; Cervidae; Chronic infection; Chronic wasting disease; Computer and Information Sciences; Conformation; Deer; Disease; Disease transmission; Diseases; Health aspects; Infections; Infectivity; Inoculation; Inoculum; Invasiveness; Medicine and Health Sciences; Neuropathology; Particle size; Pathogenesis; Prion protein; Prions; Protein folding; Protein structure; Proteins; Quaternary structure; Research and Analysis Methods; Spinal cord; Stability; Statistical analysis; Structure; Transmissible spongiform encephalopathy; Variability; United States; Canada
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1012370

Prions can exist as different strains that consist of conformational variants of the misfolded, pathogenic prion protein isoform PrP Sc . 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 PrP Sc . In brains of mice infected intraperitoneally with either inoculum, PrP Sc propagated with identical conformational stability and fewer PrP Sc deposits in most brain regions than intracerebrally inoculated animals. For either inoculum, PrP Sc 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 PrP Sc quaternary structure on infection and reduces conformational variability of PrP Sc propagated in the brain. These findings provide new insights into the evolution of stable CWD strains in natural, extraneural transmissions.