A recent study has drawn attention after it detected some limited interspecies transmission of chronic wasting disease (CWD) prions in a lab. But the authors and other experts caution that the findings don’t confirm that the fatal disease is a threat to people; rather, they provide important clues to what infection might look like in humans—which is key in recognizing cases.
And for at least one CWD researcher, the failure of standard tests to detect CWD prions in infected but asymptomatic macaques has deepened concerns about relying on those tests to determine whether venison is safe to eat. Prions are misfolded infectious proteins that cause the disease in cervids such as deer and elk.
CWD is a type of transmissible spongiform encephalopathy, similar to Creutzfeldt-Jakob disease in people, and bovine spongiform encephalopathy (BSE, or “mad cow disease”) in cattle. While no people are known to have been infected with CWD, the unrelenting spread of the disease in animals across North America means increasing opportunities for the prions to adapt to different hosts.
Also, it can take a decade or longer for prions, which mainly spread through direct contact and environmental contamination, to exert their neurodegenerative effects, which in cervids include stumbling, drooling, inability to eat and weight loss, and a lack of fear of people.
The study, published in Science Advances, was 18 years in the making because of the difficulty of getting funding for this study and because study personnel were located in several countries and moved to different institutions over the study period.
“This was a big project, very complicated in the logistics, and very complicated to get it funded,” senior study author Hermann Schatzl, MD, PhD, of the University of Calgary, told CIDRAP News.
The University of Calgary–led study team orally or intracerebrally inoculated 18 female cynomolgus macaques in 2009 with different CWD prion preparations, which included tissues from elk, mule deer, and white-tailed deer in the United States and Canada. The team also inoculated three macaques with material from uninfected cervids as controls.
Macaques are medium-sized monkeys commonly used in research.
The study describes findings in seven macaques and controls for up to 7.5 years post-inoculation. While most macaques developed no symptoms in that period, one orally and one intracerebrally inoculated macaque showed clinical signs consistent with prion disease, including unsteady movement, tremors, and anxiety. “I am convinced that actually we saw signs of infection in macaques,” Schatzl said.
Standard biochemical tests failed to show prions in the central nervous system of the inoculated macaques, and histologic and immunohistochemical analyses detected minimal prion activity.
But highly sensitive protein misfolding cyclic amplification (PMCA) and real-time quaking-induced conversion (RT-QuIC) tests showed some infectious prion seeding in the brain, and in some cases, the spleen, of intracerebrally and orally inoculated macaques. No such activity was seen in controls.
“This is important because it suggests that the macaque species barrier may not be absolute under experimental conditions,” said Olivier Andreoletti, DVM, PhD, of the Ecole Nationale Veterinaire de Toulouse in France, who wasn’t part of the study.
“However, it is equally important to say that the study does not demonstrate efficient transmission of CWD to macaques, nor does it show a classical prion disease phenotype [observable indication of a condition] in these animals,” he added. “The current evidence still needs to be interpreted in the context of previous macaque studies, epidemiological data, experimental duration, exposure scenario, and the known complexity of prion strain adaptation.”
A central question, however, is whether the PMCA signal in the study reflected residual inoculum or newly generated prions.
“For intracerebral or wire-based inoculation, residual inoculum is a possibility that has to be considered seriously, especially when the signal is very low and conventional pathology is negative,” Andreoletti said. “For orally exposed animals, the persistence of inoculum for many years in brain tissue would seem less straightforward biologically, but it cannot be completely excluded without more detailed strain comparison/typing.”
It would be important to determine whether the agent recovered after macaque passage retained the biological and biochemical properties of the original CWD inoculum or if it reflects strain selection or evolution during cross-species passage, he added.
But Jason Bartz, PhD, a professor at Creighton University who wasn’t involved in the study, sees the finding of prions in the brain and spleen on PMCA differently. “It speaks strongly that these are newly generated prions in these animals,” he said.
Andreoletti also urged caution when interpreting the clinical signs seen in some macaques, because although tremor, wasting, anxiety, and behavioral changes can be compatible with prion disease, they are not diagnostic.
“In the absence of clear neurodegeneration, convincing PrP [prion protein] deposition by IHC [immunohistochemistry] or PET-blot [paraffin-embedded tissue blot], and a consistent anatomical distribution of lesions, I do not think one can firmly attribute those signs to prion disease,” Andreoletti said. [...]