Abstract
The agent responsible for prion diseases is a misfolded form of a normal protein (PrPC). The prion hypothesis stipulates that PrPC must be present for the disease to manifest. Cervid populations across the world are infected with chronic wasting disease, a horizontally-transmissible prion disease that is likely spread via oral exposure to infectious prions (PrPCWD). Though PrPCWD has been identified in many tissues, there has been little effort to characterize the overall PrPC expression in cervids and its relationship to PrPCWD accumulation. We used immunohistochemistry (IHC), western blot and enzyme-linked immunosorbent assay to describe PrPC expression in naïve white-tailed deer. We used real-time, quaking-induced conversion (RT-QuIC) to detect prion seeding activity in CWD-infected deer. We assessed tissues comprising the alimentary tract, alimentary-associated lymphoid tissue and systemic lymphoid tissue from 5 naïve deer. PrPC was expressed in all tissues, though expression was often very low compared to the level in the CNS. IHC identified specific cell types wherein PrPC expression is very high. To compare the distribution of PrPC to PrPCWD, we examined 5 deer with advanced CWD infection. Using RT-QuIC, we detected prion seeding activity in all 21 tissues. In 3 subclinical deer sacrificed 4 months post-inoculation, we detected PrPCWD consistently in alimentary-associated lymphoid tissue, irregularly in alimentary tract tissues, and not at all in the brain. Contrary to our hypothesis that PrPC levels dictate prion accumulation, PrPC expression was higher in the lower gastrointestinal tissues than in the alimentary-associated lymphoid system and was higher in salivary glands than in the oropharyngeal lymphoid tissue. These data suggest that PrPC expression is not the sole driver of prion accumulation and that alimentary tract tissues accumulate prions before centrifugal spread from the brain occurs.
Highlights
Chronic wasting disease (CWD) is spreading among deer, elk and other cervids in North America, the Republic of Korea, and, recently, Norway [1,2,3,4]
The prion hypothesis postulates that the normal prion protein, PrPC, must be present in an individual tissue for the disease to manifest, since it is absolutely necessary for the generation of pathogenic PrPCWD prions [43, 44]
Though the presence of PrPCWD has been demonstrated in many tissues in CWD-infected cervids, there has been no comprehensive description of PrPC expression in the natural host [6, 9,10,11, 29,30,31,32,33]
Summary
Chronic wasting disease (CWD) is spreading among deer, elk and other cervids in North America, the Republic of Korea, and, recently, Norway [1,2,3,4]. PrPC expression has been detected in the brain, intestine, lymphoid tissue, lung, heart, kidney, muscle, uterus, adrenal gland, salivary glands, stomachs and mammary glands [21, 22]. PrPC has been identified in the muscle, alimentary tract, skin and respiratory epithelium of mice [23, 24] and in the CNS, lymphoid tissue, heart, liver, lung, kidney, stomach and intestine of hamsters [25,26,27]. We conclude that prion replication occurs in alimentary tissues before centrifugal spread of PrPCWD from the brain. These results are an important step for understanding the pathogenesis of CWD and for understanding its facile horizontal transmission
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