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Scrapie infections initiated at varying doses: an analysis of 117 titration experiments
1Institute for Animal Health, Newbury, Berkshire, UK.
Abstract:
An analysis of 117 titration experiments in the murine scrapie model is presented. The experiments encompass 30 years' work and a wide range of experimental conditions. To check that the experimental designs were reasonably consistent over time, comparisons were made of size, duration, source of inoculum, etc., in each experiment. These comparisons revealed no systematic trends that would render invalid comparisons across experiments. For 114 of the experiments it was possible to calculate the dose at which half of the challenged animals were infected (the ID50). These 114 experiments were then combined on the basis of relative dose (i.e. tenfold dilution relative to the ID50). This created a data set in which over 4000 animals were challenged with doses of scrapie ranging from four orders of magnitude below to five orders of magnitude above the ID50. Analysis of this data reveals that mean incubation periods rise linearly with logarithmic decreases in dose. A one unit increase in relative dose (i.e. a tenfold increase in actual dose) will, on average, decrease the incubation period by 25 days. At ID50 the average incubation period in this data set is 300 days. Within a single dose, in a single experimental model, incubation periods have a distribution close to normal. Variability in incubation period also rises linearly as dose decreases. There is no age or sex effect upon the probability of infection, but female mice have incubation periods that are, on average, nine days shorter than their male counterparts and young mice have incubation periods that are longer by seven days. Although many of these patterns are apparent in the results of single titration curves, they can be more rigorously investigated by considering the outcome for thousands of mice.
Insights
This study analyzed 117 titration experiments in mice, revealing that lower doses of scrapie increase incubation periods. A tenfold dose increase shortens incubation by 25 days, with the average at the infectious dose 50 (ID50) being 300 days.
Area of Science:
- Neuroscience
- Infectious Diseases
- Prion Research
Background:
- Scrapie is a fatal neurodegenerative disease affecting sheep and goats.
- Understanding the dose-response relationship in prion diseases is crucial for disease modeling and control.
- Previous studies on scrapie titration have varied in experimental conditions and sample size.
Purpose of the Study:
- To analyze a large dataset of scrapie titration experiments to establish a robust dose-incubation period relationship.
- To investigate the influence of dose on the variability of incubation periods in the murine scrapie model.
- To identify potential effects of age and sex on scrapie incubation and infection probability.
Main Methods:
- Meta-analysis of 117 titration experiments in the murine scrapie model spanning 30 years.
- Calculation of the infectious dose 50 (ID50) for 114 experiments.
- Normalization of data by relative dose (tenfold dilutions relative to ID50) for over 4000 challenged animals.
- Statistical analysis to determine the relationship between dose, incubation period, and variability.
Main Results:
- Mean incubation periods increase linearly with logarithmic decreases in scrapie dose.
- A tenfold increase in dose reduces incubation period by an average of 25 days.
- Incubation period at ID50 is approximately 300 days; variability increases as dose decreases.
- No significant effect of age or sex on infection probability, but females and younger mice show slightly altered incubation periods.
Conclusions:
- A clear, quantifiable inverse relationship exists between scrapie dose and incubation period in mice.
- The murine scrapie model demonstrates predictable dose-response dynamics, valuable for studying prion disease pathogenesis.
- This comprehensive analysis provides a foundation for refining prion disease models and understanding disease progression based on exposure levels.