Epidemiological mechanisms of genetic resistance to kuru

Abstract

Transmissible spongiform encephalopathies (TSEs), such as kuru, are invariably fatal neurodegenerative conditions caused by a malformation of the prion protein. Heterozygosity of codon 129 of the prion protein gene has been associated with increased host resistance to TSEs, although the mechanism by which this resistance is achieved has not been determined. To evaluate the epidemiological mechanism of human resistance to kuru, we developed a model that combines the dynamics of kuru transmission and the population genetics of human resistance. We fitted our model to kuru data from the epidemic that occurred in Papua New Guinea over the last hundred years. To elucidate the epidemiological mechanism of human resistance, we estimated the incubation period and transmission rate of kuru for codon 129 heterozygotes and homozygotes using kuru incidence data and human genotype frequency data from 1957 to 2004. Our results indicate that human resistance arises from a combination of both a longer incubation period and reduced susceptibility to infection. This work provides evidence for balancing selection acting on a human population and the mechanistic basis for the heterozygote resistance to kuru.

Keywords: dynamic model; incubation period; prion; reproductive ratio; transmissibility; transmissible spongiform encephalopathy.

Figure 1.

Comparison of predicted and actual kuru mortality. Recorded kuru mortality [29,30] is indicated by crosses. The black line shows the mortality predicted using the best-fit estimates of transmission and virulence rates. The credible intervals, calculated using Markov chain Monte Carlo, are given in grey. Transmission was assumed to stop in 1959 after the ban on cannibalism was implemented. (Online version in colour.)

Figure 2.

Mortality predictions from the suite of eight transmission models incorporating the population genetics of human resistance, after fitting each model to the kuru incidence data indicated by crosses [29,30]. Changing the transmission and/or incubation rates of the heterozygotes relative to the homozygotes can have a substantial impact on the predicted mortality rate of heterozygotes, but little impact on the overall predicted kuru incidence. (a) Model T: black lines show the predicted kuru mortality from varying β_MV and β_MM such that the predicted incidence is very similar to the best-fit model. (b) Model Ti: the fraction of kuru mortality attributable to heterozygotes with the same values of β_MV and β_MM used in (a) such that β_MV < β_MM. (c) Model Tii: the fraction of kuru mortality attributable to heterozygotes with the same values of β_MV and β_MM used in (a) such that β_MV > β_MM. (d) Model I: predicted kuru mortality from varying υ_MV and υ_MM. (e) Model Ii:  the same values of υ_MV and υ_MM used in (d) such that υ_MV < υ_MM. (f) Model Iii: the same values of υ_MV and υ_MM used in (d) such that υ_MV > υ_MM. (g,j) Model B: predicted kuru mortality from varying β_MV, β_MM, υ_MV and υ_MM. (h) Model Bi: the same values of β_MV, β_MM, υ_MV and υ_MM used in (g) and (j) such that β_MV < β_MM and υ_MV < υ_MM. (i) Model Bii: the same values of β_MV, β_MM, υ_MV and υ_MM used in (g) and (j) such that β_MV < β_MM and υ_MV > υ_MM. (k) Model Biii: the same values of β_MV, β_MM, υ_MV and υ_MM used in (g) and (j) such that β_MV > β_MM and υ_MV < υ_MM. (l) Model Biv: the same values of β_MV, β_MM, υ_MV and υ_MM used in (g) and (j) such that β_MV > β_MM and υ_MV > υ_MM. (Online version in colour.)