General overview of prion and prion diseases

Prions are 'self-replicating' basic proteins of small molecular weight. Prions form a new class of infectious agents responsible for a number of slow degenerative central nervous system diseases of humans and other animal species. The transmissible spongiform encephalopathies (TSEs) are a group of progressive neurological prion diseases, including scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) in cattle and Creutzfeldt-Jakob disease (CJD) in humans.

Public awareness of prion diseases have been raised after an outbreak of BSE occurred among cattle in many European countries and scientific evidence indicated the foodborne transmission of BSE to humans. 

The disease is transmitted to humans via meats contaminated with the brain or spinal cords of infected carcasses.
http://www.cdc.gov/ncidod/dvrd/prions/

Summary Data

Diringer et al. (1998) inoculated outbred Syrian hamsters orally with graded doses of scrapie agent. The infectious agent was prepared from the brains of scrapied hamsters at the terminal stage of disease.

Jacquemot et al. (2005) exposed C57BL/6 mice to mouse-adapted scrapie strain C506M3 via the intraperitoneal route. The inoculum was a brain homogenate at 10% (wt/vol) in 5% glucose solution from a mouse with scrapie at the terminal stage of disease.

Taylor et al. (1995) injected Weanling RIII/FaDk-ro mice with pooled BSE-infected brain. They measured the titer of infectivity by bioassay in mice. The infectious agent was prepared from the brains of 861cattle with suspected BSE obtained between August and November 1990 from five veterinary centers throughout England.

Recommended Model

It is recommended that experiment 250 should be used as the best dose response model. The exposure was oral route which is a better representation of an actual release scenario.

Exponential and betapoisson model.jpg

ID Exposure Route # of Doses Agent Strain Dose Units Host type Μodel LD50/ID50 Optimized parameters Response type Reference
250 oral 5.00 scrapie strain 263k LD50 i.c. hamsters beta-Poisson 1.04E+05 a = 1.76E+00 N50 = 1.04E+05 death
Jacquemot, C. ., Cuche, C. ., Dormont, D. ., & Lazarini, F. . (2005). High Incidence of Scrapie Induced by Repeated Injections of Subinfectious Prion Doses. Journal of Virology, 79(14). https://doi.org/10.1128/JVI.79.14.8904-8908.2005
251 intraperitoneal 3.00 scrapie strain C506M3 LD50 i.c. mice exponential 2.89E+04 k = 2.4E-05 death
Taylor, D. M., Woodgate, S. L., & Atkinson, M. J. (1995). Inactivation of the bovine spongiform encephalopathy agent by rendering procedures. Veterinary Record, 137(24). Retrieved from https://pubmed.ncbi.nlm.nih.gov/8746849/
252 unknown type of injection 4.00 BSE agent ID50 unit mice exponential 1 k = 6.93E-01 infection
John, D. T., & Hoppe, K. L. (1990). Susceptibility of Wild Mammals to Infection with Naegleria fowleri. The Journal of Parasitology, 76, 6.
Highest quality
Exposure Route:
oral
# of Doses:
5.00
Agent Strain:
scrapie strain 263k
Dose Units:
LD50 i.c.
Host type:
hamsters
Μodel:
beta-Poisson
LD50/ID50:
1.04E+05
Optimized parameters: a = 1.76E+00 N50 = 1.04E+05
Response type:
death

hamsters/scrapie strain 263K model data 
Dose Dead Survived Total
200 0 40 40
2000 1 79 80
2E+04 9 71 80
2E+05 58 22 80
2E+06 29 1 30

 

Goodness of fit and model selection
Model Deviance Δ Degrees 
of freedom
χ20.95,1 
p-value
χ20.95,m-k 
p-value
Exponential 14.5 12.6 4 3.84 
0.000382
9.49 
0.00576
Beta Poisson 1.92 3 7.81 
0.589
Beta-Poisson fits better than exponential; cannot reject good fit for beta-Poisson.

 

Optimized parameters for the beta-Poisson model, from 10000 bootstrap iterations
Parameter MLE estimate Percentiles
0.5% 2.5% 5% 95% 97.5% 99.5%
α 1.76E+00 7.48E-01 8.76E-01 9.66E-01 1.44E+04 1.73E+04 2.08E+04
N50 1.04E+05 7.05E+04 7.83E+04 8.22E+04 1.34E+05 1.40E+05 1.55E+05

 

Parameter scatter plot for beta Poisson model ellipses signify the 0.9, 0.95 and 0.99 confidence of the parameters.

beta Poisson model plot, with confidence bounds around optimized model

Exposure Route:
intraperitoneal
# of Doses:
3.00
Agent Strain:
scrapie strain C506M3
Dose Units:
LD50 i.c.
Host type:
mice
Μodel:
exponential
LD50/ID50:
2.89E+04
Optimized parameters: k = 2.4E-05
Response type:
death

mice/ scrapie strain C506M3 model data 
Dose Dead Survived Total
125 0 11 11
1250 1 9 10
12500 2 8 10

 

Goodness of fit and model selection
Model Deviance Δ Degrees 
of freedom
χ20.95,1 
p-value
χ20.95,m-k 
p-value
Exponential 1.34 0.99 2 3.84 
0.32
5.99 
0.512
Beta Poisson 0.35 1 3.84 
0.554
Exponential is preferred to beta-Poisson; cannot reject good fit for exponential.

 

Optimized k parameter for the exponential model, from 10000 bootstrap iterations
Parameter MLE estimate Percentiles
0.5% 2.5% 5% 95% 97.5% 99.5%
k 2.4E-05 1.00E-13 1.00E-13 7.23E-06 5.47E-05 5.81E-05 7.44E-05
ID50/LD50/ETC* 2.89E+04 9.32E+03 1.19E+04 1.27E+04 9.58E+04 6.92E+12 6.92E+12
*Not a parameter of the exponential model; however, it facilitates comparison with other models.

 

Parameter histogram for exponential model (uncertainty of the parameter)

Exponential model plot, with confidence bounds around optimized model

Exposure Route:
unknown type of injection
# of Doses:
4.00
Agent Strain:
BSE agent
Dose Units:
ID50 unit
Host type:
mice
Μodel:
exponential
LD50/ID50:
1
Optimized parameters: k = 6.93E-01
Response type:
infection

mice/BSE agent model data 
Dose Infected Non-infected Total
0.0186 0 13 13
0.186 4 12 16
1.86 9 5 14
18.6 13 0 13

 

Goodness of fit and model selection
Model Deviance Δ Degrees 
of freedom
χ20.95,1 
p-value
χ20.95,m-k 
p-value
Exponential 2.78 0.763 3 3.84 
0.382
7.81 
0.427
Beta Poisson 2.01 2 5.99 
0.365
Exponential is preferred to beta-Poisson; cannot reject good fit for exponential.

 

Optimized k parameter for the exponential model, from 10000 bootstrap iterations
Parameter MLE estimate Percentiles
0.5% 2.5% 5% 95% 97.5% 99.5%
k 6.93E-01 3.03E-01 3.69E-01 4.16E-01 1.14E+00 1.32E+00 1.70E+00
ID50/LD50/ETC* 1E+00 4.08E-01 5.27E-01 6.08E-01 1.67E+00 1.88E+00 2.29E+00
*Not a parameter of the exponential model; however, it facilitates comparison with other models.

 

Parameter histogram for exponential model (uncertainty of the parameter)

Exponential model plot, with confidence bounds around optimized model

References

  • Gale, P. . (2006). The infectivity of transmissible spongiform encephalopathy agent at low doses: the importance of phospholipid. Journal of Applied Microbiology, 101, 261–274.
  • Will, R. G., Ironside, J. ., Zeidler, M. ., Estibeiro, K. ., Cousens, S. ., Smith, P. ., … Hofman, A. . (1996). A new variant of Creutzfeldt-Jakob disease in the UK. The Lancet, 347, 921–925.
  • Smith, P. G., & Bradley, R. . (2003). Bovine spongiform encephalopathy (BSE) and its epidemiology. British Medical Bulletin, 66, 185–198.
  • Diringer, H. ., Roehmel, J. ., & Beekes, M. . (1998). Effect of repeated oral infection of hamsters with scrapie. Journal of General Virology, 79. Retrieved from http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.541.3587&rep=rep1&type=pdf
  • Jacquemot, C. ., Cuche, C. ., Dormont, D. ., & Lazarini, F. . (2005). High Incidence of Scrapie Induced by Repeated Injections of Subinfectious Prion Doses. Journal of Virology, 79(14). https://doi.org/10.1128/JVI.79.14.8904-8908.2005
  • Taylor, D. M., Woodgate, S. L., & Atkinson, M. J. (1995). Inactivation of the bovine spongiform encephalopathy agent by rendering procedures. Veterinary Record, 137(24). Retrieved from https://pubmed.ncbi.nlm.nih.gov/8746849/