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, PrP(Sc), 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. PrP(Sc) 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 10(3.9) 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 PrP(Sc) 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.