# Addressing the mechanisms of prion strain evolution and its effect on interspecies transmission

> **NIH NIH R01** · COLORADO STATE UNIVERSITY · 2021 · $513,616

## Abstract

Our broad, long-term objectives are to assess and manage the risk posed to humans from continually evolving
prions, specifically those causing chronic wasting disease (CWD), an uncontrollable contagious epidemic of
cervids of uncertain zoonotic potential. Understanding the properties of emergent CWD strains, their origins, how
they adapt and evolve, and their zoonotic threats are important goals. We propose four Specific Aims to address
the hypothesis that conformational conversion of host prion protein (PrPC) and adaptive selection of the resulting
infectious conformers (PrPSc) is influenced by variation at PrP residue 226, the singular primary structural
difference in PrP among susceptible cervid species. Since we further propose that strain selection in non-CNS
compartments influences CWD transmission, our expanded use of gene targeting (Gt) strategies for accurate
physiological PrP expression is a key component of this proposal. Aim I will characterize the properties of
emergent CWD strains. Our strategy builds upon evidence indicating that prion strains driving the current North
American CWD epidemic evolved from unstable emergent strains. Aim II will explore the origins of CWD by
addressing the hypothesis that atypical strains originated either from exposure to prions in sympatric species, or
from stochastic spontaneous conversion of cervid PrPC. We expect that iterative passaging and adaptation will
result in strains with properties consistent with established CWD. Aim III will explore the proposal that accurate
physiological PrP expression in Gt mice makes them uniquely suited to study strain adaptation. We expect that
different inoculation routes will select different strains, and that the properties of CWD prions in peripheral
compartments are different to those in the CNS. Our demonstration of novel emergent strains and their
demonstrated potential for adaptation increases uncertainties about CWD zoonosis. In Aim IV we employ newly
optimized Gt mice expressing human PrP that we expect will provide an improved application to explore human
prion disease pathogenesis, and an accurate means to assess the potential for zoonotic CWD transmission. Our
findings will aid in combating the incurable lethality and unpredictable epidemic and zoonotic potential of CWD
prions by understanding the means by which they propagate and exist as heritable strains with protean host
range properties that adapt and evolve under selective pressure.

## Key facts

- **NIH application ID:** 10185649
- **Project number:** 1R01NS121682-01
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** Glenn C Telling
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $513,616
- **Award type:** 1
- **Project period:** 2021-04-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10185649

## Citation

> US National Institutes of Health, RePORTER application 10185649, Addressing the mechanisms of prion strain evolution and its effect on interspecies transmission (1R01NS121682-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10185649. Licensed CC0.

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