The Nasal Cavity Is a Route for Prion Infection in Hamsters

The prion diseases, or transmissible spongiform encephalopathies (TSEs), are a group of fatal neurodegenerative diseases that affect animals, including humans. These neurodegenerative diseases are notable for their ability to be transmitted from one animal to another and for their relatively long incubation periods. The natural route(s) of transmission have not been determined. The route of transmission that has been studied experimentally most extensively is the oral pathway. This route is thought to be responsible for the transmission of kuru, bovine spongiform encephalopathy (BSE), transmissible mink encephalopathy (TME), and variant Creutzfeldt-Jakob disease. Experimentally it has been shown that after ingesting food pellets containing infected brain homogenate prions gain access to the central nervous system (CNS) via the autonomic innervation of the gut (7, 27, 34, 36). The prion agent is transported retrogradely to the thoracic spinal cord and the medulla via the sympathetic and parasympathetic nerves, respectively (36). Once the prion agent enters the CNS, there is evidence that spread occurs via synaptically linked neurons (3, 7, 43). With the exception of BSE-contaminated meat and bone meal thought to be responsible for the outbreak of BSE in the United Kingdom (10) and the cannibalistic practices that spread kuru (18), the source of the prion agent that naturally spreads the TSE among the affected species is not known. Prions have been found in the urine of mice with chronic kidney infections, indicating that urine may be a vector for the spread of prion diseases in some cases (45). Recently, it was reported that infectious prions were found in the saliva and blood of deer with chronic wasting disease, thus indicating that these bodily fluids may be a source of infection in the wild (33). Other potential sources of infectivity that have varying levels of experimental support for their efficacy include placenta (42), decaying carcasses (39), and excreta (39). A recent in vitro study reported that soil can bind prions and maintain infectivity, thus potentially serving as a prion reservoir (25). Deer, elk, cattle, and sheep are susceptible to the TSE, and each of these species has a well-developed olfactory system that is used for reproductive purposes and to detect predators and food. Thus, it is likely that the nasal cavity of these species would be an initial site of contact with any material that harbors the infectious agent. We tested the hypothesis that the nasal cavity is a site of entry and neuroinvasion for the prion agent by placing a small amount of the hyper (HY) strain of TME agent just inferior to the nostrils of hamsters and observing these animals for the onset of clinical signs. This route was established to be more efficient for causing disease than oral inoculation. Subsequently, we carried out a pathogenesis study to identify the initial site(s) of deposition and subsequent spread of the prion disease-associated isoform of the prion protein (PrPd). Immunohistochemistry (IHC) was used to identify PrPd in the nasal cavity, submandibular lymph nodes, cervical lymph nodes, mesenteric lymph nodes, spleen, Peyer's patches, and tongue at 2-week intervals after extranasal (e.n.) exposure to the inoculum.