Abstract
This study investigated the role of prion infection of the olfactory mucosa in the shedding of prion infectivity into nasal secretions. Prion infection with the HY strain of the transmissible mink encephalopathy (TME) agent resulted in a prominent infection of the olfactory bulb and the olfactory sensory epithelium including the olfactory receptor neurons (ORNs) and vomeronasal receptor neurons (VRNs), whose axons comprise the two olfactory cranial nerves. A distinct glycoform of the disease-specific isoform of the prion protein, PrPSc, was found in the olfactory mucosa compared to the olfactory bulb, but the total amount of HY TME infectivity in the nasal turbinates was within 100-fold of the titer in the olfactory bulb. PrPSc co-localized with olfactory marker protein in the soma and dendrites of ORNs and VRNs and also with adenylyl cyclase III, which is present in the sensory cilia of ORNs that project into the lumen of the nasal airway. Nasal lavages from HY TME-infected hamsters contained prion titers as high as 103.9 median lethal doses per ml, which would be up to 500-fold more infectious in undiluted nasal fluids. These findings were confirmed using the rapid PrPSc amplification QuIC assay, indicating that nasal swabs have the potential to be used for prion diagnostics. These studies demonstrate that prion infection in the olfactory epithelium is likely due to retrograde spread from the olfactory bulb along the olfactory and vomeronasal axons to the soma, dendrites, and cilia of these peripheral neurons. Since prions can replicate to high levels in neurons, we propose that ORNs can release prion infectivity into nasal fluids. The continual turnover and replacement of mature ORNs throughout the adult lifespan may also contribute to prion shedding from the nasal passage and could play a role in transmission of natural prion diseases in domestic and free-ranging ruminants.
Highlights
Recent evidence indicates that natural prion diseases such as scrapie in sheep and chronic wasting disease in cervids, which cause a progressive fatal neurodegeneration, can be highly contagious [1,2]
To test for the presence of olfactory receptor neurons (ORNs) in the olfactory bulb and olfactory mucosa of Syrian golden hamsters, tissue lysates from the cerebellum-brainstem, olfactory bulb, and olfactory mucosa after extraction from the nasal turbinates were assayed for olfactory marker protein (OMP) by western blot (Figure 1A)
These findings demonstrate high levels of PrPC in the olfactory bulb and a distinct PrPC polypeptide pattern in the olfactory mucosa compared to the olfactory bulb and brain
Summary
Recent evidence indicates that natural prion diseases such as scrapie in sheep and chronic wasting disease in cervids, which cause a progressive fatal neurodegeneration, can be highly contagious [1,2]. The culling and testing of two endemically infected flocks revealed that 58% of sheep were positive for the abnormal isoform of the prion protein, PrPSc, despite a very low number of clinical scrapie cases [11] These infection rates indicate that a relatively high percent of certain sheep breeds and North American deer in endemic areas can have a subclinical prion infection, but that typically only a small percent of animals exhibit symptoms of disease at a given time. These studies suggest that these prion diseases have the potential to be highly contagious under certain conditions, which are not completely understood (e.g., animal density, number of contacts, prion protein genotype, etc). Despite these recents developments in identifying a high prevalence of infection for scrapie and CWD in domestic and free-ranging ruminants, the mode(s) of prion transmission among hosts is not well understood
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