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- Title
Extraneural infection route restricts prion conformational variability and attenuates the impact of quaternary structure on infectivity.
- Authors
Chang, Sheng Chun; Arifin, Maria Immaculata; Tahir, Waqas; McDonald, Keegan John; Zeng, Doris; Schatzl, Hermann M.; Hannaoui, Samia; Gilch, Sabine
- 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. Author summary: Chronic wasting disease (CWD) is a prion disease spreading among wild and farmed cervids. Several strains of CWD prions have been identified that propagate stably upon intracerebral passage in experimental models. Understanding the emergence and adaptation of prion strains is critical for risk assessment of CWD cross-species transmission. We capitalize on our new gene-targeted mouse models of CWD that recapitulate key features of CWD pathogenesis in cervids. We infected these mice with whole of fractionated brain homogenates of deer containing previously characterized, distinct CWD strains by inoculation either into the brain or intraperitoneally. We found that the biochemical properties and pathological hallmarks of prions generated in central nervous system tissues of those mice differed, depending on route of inoculation. Furthermore, mouse survival times upon inoculation with fractionated brain homogenates were less variable upon intraperitoneal compared to intracerebral inoculation. Our findings shed new light on the impact of extraneural infection routes that mirror natural transmission and unravel peripheral infection as a selective barrier that restricts the conformational diversity of prions in the brain.
- Subjects
QUATERNARY structure; CHRONIC wasting disease; PRIONS; PRION diseases; WHITE-tailed deer; NEURAL transmission
- Publication
PLoS Pathogens, 2024, Vol 20, Issue 7, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1012370