Transmission of cervid prions to humanized mice demonstrates the zoonotic potential of CWD

Abstract

Prions cause infectious and fatal neurodegenerative diseases in mammals. Chronic wasting disease (CWD), a prion disease of cervids, spreads efficiently among wild and farmed animals. Potential transmission to humans of CWD is a growing concern due to its increasing prevalence. Here, we provide evidence for a zoonotic potential of CWD prions, and its probable signature using mice expressing human prion protein (PrP) as an infection model. Inoculation of these mice with deer CWD isolates resulted in atypical clinical manifestation with prion seeding activity and efficient transmissible infectivity in the brain and, remarkably, in feces, but without classical neuropathological or Western blot appearances of prion diseases. Intriguingly, the protease-resistant PrP in the brain resembled that found in a familial human prion disease and was transmissible upon second passage. Our results suggest that CWD might infect humans, although the transmission barrier is likely higher compared to zoonotic transmission of cattle prions. Notably, our data suggest a different clinical presentation, prion signature, and tissue tropism, which causes challenges for detection by current diagnostic assays. Furthermore, the presence of infectious prions in feces is concerning because if this occurs in humans, it is a source for human-to-human transmission. These findings have strong implications for public health and CWD management.

Second passage experiments of chronic wasting disease in transgenic mice overexpressing human prion protein

“…It is unclear how representative the PMCA replication process is compared to natural conditions. A second very recent study has reported clinical disease in several CWD-inoculated tg650 mice [ 19 ]. Of concern, these clinical mice did not have consistent positive confirmatory tests for prion disease including immunohistochemistry, immunoblot, and RT-QuIC.…”

“…Transgenic mice genetically engineered to express human prion protein have proved to be an excellent tool for studying prion disease transmission. To date, eight groups including ours have tested the susceptibility of human prion protein-expressing mice to CWD infection [ 12 – 19 ]. Seven groups have reported no strong evidence for CWD transmission to humanized mice [ 12 – 18 ].…”

“…Seven groups have reported no strong evidence for CWD transmission to humanized mice [ 12 – 18 ]. A recent publication by Hannaoui et al reported bioassay evidence for transmission, but initial classification of prion infection was based heavily on clinical signs rather than consistent biochemical confirmation of prion infection [ 19 ].…”

Vaccines for prion diseases: a realistic goal?

“…CWD transmission studies in transgenic mouse models expressing PrPs from various species including ovine, bovine, and human showed low or absent ability of CWD prions to cross relevant species barriers (Tamgüney et al 2009b ; Wilson et al 2012 ; Kurt et al 2015 ; Wadsworth et al 2022 ). Interestingly, a more recent study found atypical disease and fecal prion shedding in transgenic mice expressing human PrP when infected with deer prions, indicating zoonotic potential of CWD (Hannaoui et al 2022 ). In addition, transmission of CWD into non-human primates via the oral route (Marsh et al 2005 ; Race et al 2009 , 2018 ) and efficient in vitro conversion of human PrP by CWD prions (Barria et al 2011 ; Wang et al 2021 ) should also not be ignored.…”

PMCA for ultrasensitive detection of prions and to study disease biology

“…Thus, answering the question of whether or not CWD prions can infect humans is highly relevant. Conventional rodent infection studies from independent labs have reported failed attempts to transmit CWD prions to transgenic mice that overexpress human PrP (Kong et al 2005 ; Tamgüney et al 2006 ; Sandberg et al 2010 ; Wilson et al 2012 ; Kurt et al 2015 ; Race et al 2019 ; Wadsworth et al 2021 ) with the exception of a recent study (Hannaoui et al 2022 ). Using non-human primates, the Bartz group reported two squirrel monkeys that were intracerebrally challenged with CWD prions developed prion diseases and reached terminal stages in 31 and 34 months after infection (Marsh et al 2005 ).…”