Estimating chronic wasting disease susceptibility in cervids using real-time quaking-induced conversion

Area of Science:

• Veterinary Medicine
• Neuroscience
• Biochemistry

Background:

• Prion disease susceptibility in mammals is largely determined by the host's cellular prion protein (PrP^C) sequence.
• In sheep, specific PrP^C amino acid variations (136, 154, 171) define scrapie susceptibility, informing breeding programs.
• Chronic wasting disease (CWD) resistance in cervids is linked to specific alleles, but absolute resistance has not been identified.

Purpose of the Study:

• To develop an in vitro model for predicting cervid prion disease susceptibility using various PrP^C alleles.
• To compare the amplification rates and amyloid extension efficiencies of CWD isolates in different cervid PrP^C substrates.
• To evaluate if in vitro conversion characteristics correlate with in vivo susceptibility and to test hypotheses about additive resistance from multiple genetic changes.

Main Methods:

• Utilized real-time quaking-induced conversion (RT-QuIC) assays.
• Compared amplification rates and amyloid extension efficiencies of eight distinct CWD isolates.
• Tested recombinant cervid PrP^C substrates representing various natural and hypothetical alleles.

Main Results:

• In vitro prion conversion metrics demonstrated a strong correlation with in vivo susceptibility.
• Alleles with multiple resistance-associated amino acid substitutions did not necessarily show additive resistance.
• The whitetail deer QGAK PrP^C substrate exhibited the slowest amplification rate, indicating potential for high resistance.

Conclusions:

• In vitro prion conversion assays are reliable tools for predicting prion disease susceptibility in cervids.
• Understanding PrP^C allele variations is crucial for managing CWD.
• The whitetail deer QGAK allele warrants further in vivo investigation for its potential resistance mechanisms.