INSIGHTS INTO THE MOLECULAR MECHANISMS UNDERLYING PROPAGATION AND ADAPTATION OF NOVEL EMERGENT CHRONIC WASTING DISEASE PRION STRAINS

Abstract

Prion diseases are a group of invariably fatal neurodegenerative disorders caused by the conformational misfolding of the cellular prion protein (PrPC), a membrane bound glycoprotein expressed abundantly in neurons and cells of the immune system, into an infectious form, PrPSc. The term “prion” was coined by Stanley Prusiner in 1982 to describe a proteinaceous infectious agent (PrPSc) devoid of nucleic acids and associated with several neurodegenerative diseases in humans and animals, including cattle, sheep, goats, mink, dromedary camels, and cervids. While most human prion diseases arise sporadically, familial forms are associated with point mutations or insertions in the coding sequence for PrPC. Others, such as human variant Creutzfeldt-Jakob disease (vCJD)—which has been linked to consumption of beef from cattle affected by bovine spongiform encephalopathy (BSE) or commonly known as “mad cow disease”—remain a compelling example of the zoonotic risk posed by prion diseases. Chronic wasting disease (CWD) is a prion disease that affects species of the Cervidae family, including deer, moose, elk, red deer, and reindeer. In North America, CWD has been reported in 36 US states and in five Canadian provinces. It is the only known prion disease affecting free ranging cervids, largely due to its efficient horizontal transmission and the remarkable environmental stability of infectious prions. The most recent body of research on CWD has shown that North American CWD is characterized by low strain diversity, high tropism for lymphoid tissues, and high capacity for contagious transmission. The emergence of CWD in Northern Europe in 2016, initially in reindeer and subsequently in moose and red deer, raised concerns about the possible introduction of North American CWD into Europe, as occurred in South Korea. However, studies by our group and others have demonstrated that Nordic CWD exhibits properties distinct from those of North American CWD, supporting a sporadic origin as the most plausible explanation for its emergence. Moreover, Nordic moose CWD in moose is non-lymphotropic, suggesting low risk of contagious transmission, though, this may not be the case for Norway reindeer CWD, which has been found to replicate in lymphoid tissues. With the development of a gene-targeted (Gt) mouse model by the Telling lab, which expresses physiologically regulated levels of cervid PrPC and recapitulates key features of CWD, including its lymphotropic properties, we are well-positioned to address, with greater precision, key questions regarding the strain diversity and properties of Nordic CWD. This model also facilitates investigation into the evolution and adaptation of prion strains and risks associated with the acquisition of properties that may enhance sympatric transmission, as well as the mechanisms by which unstable prion strains display unprecedented adaptation. This was demonstrated in a 2021 study by our research group, in which a non-lymphotropic Nordic moose strain unexpectedly evolved North American-like properties, including lymphotropism, following serial passage in the Gt mouse model. This dissertation will discuss in detail our use of gene-targeted mouse models to better understand 1) the unprecedented strain heterogeneity in Nordic moose CWD, 2) its potential for the evolution of greater contagious transmission potential through the acquisition of lymphotropic properties and 3) The effects of polymorphic variants of the cervid prion protein that are found exclusively in Nordic moose and how they may impact CWD pathogenesis and risk of spread to other cervid species. Nordic moose CWD is most likely of sporadic origin, with a unique strain heterogeneity with diverse mechanisms of infectious adaptation that could also draw parallels and differences with human neurodegenerative diseases of sporadic etiology.