Examining PRNP gene frequencies and ‘resistance’ to chronic wasting disease
Multiple studies have demonstrated that various alleles of the cervid prion protein (PRNP) gene affect chronic wasting disease (CWD) progression.
Why this matters: Specific genetic differences in the cervid prion protein gene have been linked to disease ‘resistance’ and there is some evidence that gene frequencies in wild populations with high CWD prevalence are shifting towards these ‘resistant’ genotypes. It has been argued that this shift may eventually control CWD in the wild. A thorough examination of published science, however, suggests the situation may be more complex.
In white-tailed deer (Odocoileus virginianus), a putative ‘resistance’ allele encodes serine at amino acid 96 (96S) of the prion protein instead of the more common glycine (96G). Similarly, in mule deer (O. hemionus), a putative ‘resistance’ allele encodes phenylalanine at amino acid 225 (225F) instead of serine (225S). CWD has been found at lower abundance in heterozygous white-tailed deer with the 96S allele (96GS) and heterozygous mule deer with the 225F allele (225SF); CWD in homozygous 96S or 225F deer is rare (Johnson et al. 2006, Jewell et al. 2005). In experimental challenge studies all deer with 96S or 225F alleles (heterozygous or homozygous) contract CWD (Johnson et al. 2011, Wolfe et al. 2014, Plummer et al. 2017), but the presence of 96S or 225F, respectively, extends the incubation period. Although a prolonged incubation period may allow additional time for CWD+ deer to reproduce, it also increases opportunities for disease transmission and may allow disease prevalence to rise to a new equilibrium within endemic regions.
To increase our understanding of the potential impacts of disease-modifying alleles on CWD, the USGS National Wildlife Health Center and the Wisconsin Department of Natural Resources are examining PRNP gene frequencies in white-tailed deer to assess whether the relative abundance of Wisconsin deer expressing 96S has changed since the beginning of the epizootic. However, even if populations are shifting to higher frequencies of 96S or 225F, the resulting CWD epizootic trajectory may not be improved. Genetic resistance that can prevent infection by specific strains of pathogens must be distinguished from resistance that can prevent infection by all strains of that pathogen. In the context of CWD, the disease-modifying properties of 96S or 225F must be evaluated within a broader paradigm not only of the strains of CWD in circulation today, but also those that could arise in the future. For example, white-tailed deer with histidine at PRNP allele 95 give rise to a new emergent strain of CWD (termed H95+) when they are infected with the “wild-type” strain of CWD currently spreading in white-tailed deer. This H95+ CWD strain is likely to have very high attack rates in 96S deer (Duque Velasquez et al. 2015, Duque Velasquez et al. 2020). Similarly, serial passage of CWD in 225F mule-deer could stabilize a new strain adapted to 225F mule deer. Emergent strains of CWD prions may also have expanded host ranges and enhanced zoonotic potential (Herbst et al. 2017).
If the putative ‘resistance’ to CWD can be demonstrated, it should likely be considered temporary. As was observed with COVID-19, the evolutionary pattern of host resistance followed by pathogen adaptation is typical for infectious diseases and there are no known reasons to except CWD from this paradigm. The only known genetic modification that can induce general resistance to all prion strains are mutations that ablate expression of the mammalian prion protein. The resistance of cervids or other mammals to prion disease is a continuum of vulnerability that reflects both the host’s prion protein sequence and the specific prion strain that it is exposed to.
Expanding Distribution of Chronic Wasting Disease
Application of a systems approach for management of chronic wasting disease
Chronic Wasting Disease
Multiple studies have demonstrated that various alleles of the cervid prion protein (PRNP) gene affect chronic wasting disease (CWD) progression.
Why this matters: Specific genetic differences in the cervid prion protein gene have been linked to disease ‘resistance’ and there is some evidence that gene frequencies in wild populations with high CWD prevalence are shifting towards these ‘resistant’ genotypes. It has been argued that this shift may eventually control CWD in the wild. A thorough examination of published science, however, suggests the situation may be more complex.
In white-tailed deer (Odocoileus virginianus), a putative ‘resistance’ allele encodes serine at amino acid 96 (96S) of the prion protein instead of the more common glycine (96G). Similarly, in mule deer (O. hemionus), a putative ‘resistance’ allele encodes phenylalanine at amino acid 225 (225F) instead of serine (225S). CWD has been found at lower abundance in heterozygous white-tailed deer with the 96S allele (96GS) and heterozygous mule deer with the 225F allele (225SF); CWD in homozygous 96S or 225F deer is rare (Johnson et al. 2006, Jewell et al. 2005). In experimental challenge studies all deer with 96S or 225F alleles (heterozygous or homozygous) contract CWD (Johnson et al. 2011, Wolfe et al. 2014, Plummer et al. 2017), but the presence of 96S or 225F, respectively, extends the incubation period. Although a prolonged incubation period may allow additional time for CWD+ deer to reproduce, it also increases opportunities for disease transmission and may allow disease prevalence to rise to a new equilibrium within endemic regions.
To increase our understanding of the potential impacts of disease-modifying alleles on CWD, the USGS National Wildlife Health Center and the Wisconsin Department of Natural Resources are examining PRNP gene frequencies in white-tailed deer to assess whether the relative abundance of Wisconsin deer expressing 96S has changed since the beginning of the epizootic. However, even if populations are shifting to higher frequencies of 96S or 225F, the resulting CWD epizootic trajectory may not be improved. Genetic resistance that can prevent infection by specific strains of pathogens must be distinguished from resistance that can prevent infection by all strains of that pathogen. In the context of CWD, the disease-modifying properties of 96S or 225F must be evaluated within a broader paradigm not only of the strains of CWD in circulation today, but also those that could arise in the future. For example, white-tailed deer with histidine at PRNP allele 95 give rise to a new emergent strain of CWD (termed H95+) when they are infected with the “wild-type” strain of CWD currently spreading in white-tailed deer. This H95+ CWD strain is likely to have very high attack rates in 96S deer (Duque Velasquez et al. 2015, Duque Velasquez et al. 2020). Similarly, serial passage of CWD in 225F mule-deer could stabilize a new strain adapted to 225F mule deer. Emergent strains of CWD prions may also have expanded host ranges and enhanced zoonotic potential (Herbst et al. 2017).
If the putative ‘resistance’ to CWD can be demonstrated, it should likely be considered temporary. As was observed with COVID-19, the evolutionary pattern of host resistance followed by pathogen adaptation is typical for infectious diseases and there are no known reasons to except CWD from this paradigm. The only known genetic modification that can induce general resistance to all prion strains are mutations that ablate expression of the mammalian prion protein. The resistance of cervids or other mammals to prion disease is a continuum of vulnerability that reflects both the host’s prion protein sequence and the specific prion strain that it is exposed to.