Study of CWD Deer and Elk Prion Disease in Nonhuman Primates and transgenic mice

National Institute Of Allergy And Infectious Diseases

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Abstract

To study the possibility of cross-species transmission of Chronic Wasting Disease (CWD), two species of nonhuman primates, squirrel monkeys and cynomolgus macaques, were infected orally or intracerebrally with brain material derived from CWD-affected deer or elk. All of the squirrel monkeys developed clinical neurological signs and were confirmed by biochemical and pathological testing of brain to have a prion disease. In contrast, experiments done in cynomolgus macaques, which are genetically closer to humans than are squirrel monkeys, were not susceptible to CWD by either route of inoculation. In FY19-22 we tested CWD transmission via intracerebral inoculation into transgenic mice (tg66 and tgRM) that over-expressed human prion protein. In FY22-23 we identified 4 tg66 mice out of a group of 88 mice screened by the ultrasensitive RT-QuIC assay that produced inconsistent positive RT-QuIC reactions. We were uncertain if these were false positive reactions, residual input inoculum or indicative of subclinical infections suggestive of cross species transmission of CWD to humans. Additional experiments were performed to understand the nature of the prion seeding activity in this model, and showed that the tissues giving inconsistent results were not infectious to additional recipient tg66 mice. The failure of CWD prions to cause disease in tg66 after two sequential passages suggested that a strong species barrier prevented CWD infection of mice expressing human prion protein. These results reinforced our earlier conclusions that humans are unlikely to be susceptible to cervid CWD. In FY23-24 we are characterizing CWD samples using mouse bioassay, neuropathology and biochemical properties of CWD prions to better understand the variety of CWD strains present in the United States. Samples have been collected from many different geographical locations, and represent isolates from over three decades. In FY25 we have started characterization of four additional deer CWD isolates and two new elk isolates. The deer isolates are from animals with unique prion gene polymorphisms that may change the misfolding characteristics of the prion protein. The two elk isolates are from Wyoming and represent an elk with a unique clinical progression and an elk with typical CWD. ===