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Intraperitoneal Infection of Wild-Type Mice with Synthetically Generated Mammalian Prion
Xinhe Wang1, Gillian McGovern2, Yi Zhang3
1Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, United States of America; Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio, United States of America.
Abstract:
The prion hypothesis postulates that the infectious agent in transmissible spongiform encephalopathies (TSEs) is an unorthodox protein conformation based agent. Recent successes in generating mammalian prions in vitro with bacterially expressed recombinant prion protein provide strong support for the hypothesis. However, whether the pathogenic properties of synthetically generated prion (rec-Prion) recapitulate those of naturally occurring prions remains unresolved. Using end-point titration assay, we showed that the in vitro prepared rec-Prions have infectious titers of around 104 LD50/μg. In addition, intraperitoneal (i.p.) inoculation of wild-type mice with rec-Prion caused prion disease with an average survival time of 210-220 days post inoculation. Detailed pathological analyses revealed that the nature of rec-Prion induced lesions, including spongiform change, disease specific prion protein accumulation (PrP-d) and the PrP-d dissemination amongst lymphoid and peripheral nervous system tissues, the route and mechanisms of neuroinvasion were all typical of classical rodent prions. Our results revealed that, similar to naturally occurring prions, the rec-Prion has a titratable infectivity and is capable of causing prion disease via routes other than direct intra-cerebral challenge. More importantly, our results established that the rec-Prion caused disease is pathogenically and pathologically identical to naturally occurring contagious TSEs, supporting the concept that a conformationally altered protein agent is responsible for the infectivity in TSEs.
Insights
Synthetically generated prions (rec-Prions) mimic natural prion diseases in mice. This study confirms that these in vitro prions are infectious and cause pathology identical to transmissible spongiform encephalopathies (TSEs).
Area of Science:
- Neuroscience
- Infectious Diseases
- Biochemistry
Background:
- Transmissible spongiform encephalopathies (TSEs) are linked to the prion hypothesis, suggesting an unconventional protein-based infectious agent.
- In vitro generation of mammalian prions using recombinant prion protein supports this hypothesis.
- Key questions remain regarding whether synthetically generated prions (rec-Prions) exhibit pathogenic properties identical to naturally occurring prions.
Purpose of the Study:
- To determine if in vitro-generated rec-Prions recapitulate the pathogenic and pathological characteristics of naturally occurring prions.
- To assess the infectivity and disease-causing potential of rec-Prions in a mammalian model.
Main Methods:
- End-point titration assays were used to quantify the infectious titer of rec-Prions.
- Wild-type mice were inoculated intraperitoneally with rec-Prions.
- Detailed pathological analyses were performed on affected mice to examine lesion characteristics, prion protein accumulation, and neuroinvasion pathways.
Main Results:
- In vitro-prepared rec-Prions demonstrated infectious titers of approximately 10^4 LD50/μg.
- Intraperitoneal inoculation of mice with rec-Prions resulted in prion disease with survival times of 210-220 days.
- Pathological examination revealed rec-Prion-induced lesions, including spongiform changes and prion protein accumulation, consistent with classical rodent prion diseases. Neuroinvasion pathways were also typical.
Conclusions:
- Rec-Prions possess titratable infectivity and can cause prion disease through non-cerebral routes, similar to natural prions.
- The disease induced by rec-Prions is pathologically and pathogenically indistinguishable from naturally occurring transmissible spongiform encephalopathies.
- These findings strongly support the prion hypothesis that a conformationally altered protein agent is responsible for TSE infectivity.
