Rapid Prion Neuroinvasion following Tongue Infection

Abstract

Food-borne transmission of prions can lead to infection of the gastrointestinal tract and neuroinvasion via the splanchnic and vagus nerves. Here we report that the transmission of transmissible mink encephalopathy (TME) is 100,000-fold more efficient by inoculation of prions into the tongues of hamsters than by oral ingestion. The incubation period following TME agent (hereinafter referred to as TME) inoculation into the lingual muscles was the shortest among the five nonneuronal routes of inoculation, including another intramuscular route. Deposition of the abnormal isoform of the prion protein, PrP Sc , was first detected in the tongue and submandibular lymph node at 1 to 2 weeks following inoculation of the tongue with TME. PrP Sc deposits in the tongue were associated with individual axons, and the initial appearance of TME in the brain stem was found in the hypoglossal nucleus at 2 weeks postinfection. At later time points, PrP Sc was localized to brain cell groups that directly project to the hypoglossal nucleus, indicating the transneuronal spread of TME. TME PrP Sc entry into the brain stem preceded PrP Sc detection in the rostral cervical spinal cord. These results demonstrate that TME can replicate in both the tongue and regional lymph nodes but indicate that the faster route of brain invasion is via retrograde axonal transport within the hypoglossal nerve to the hypoglossal nucleus. Topical application of TME to a superficial wound on the surface of the tongue resulted in a higher incidence of disease and a shorter incubation period than with oral TME ingestion. Therefore, abrasions of the tongue in livestock and humans may predispose a host to oral prion infection of the tongue-associated cranial nerves. In a related study, PrP Sc was detected in tongues following the intracerebral inoculation of six hamster-adapted prion strains, which demonstrates that prions can also travel from the brain to the tongue in the anterograde direction along the tongue-associated cranial nerves. These findings suggest that food products containing ruminant or cervid tongue may be a potential source of prion infection for humans.Prion diseases are fatal neurodegenerative diseases of humans, livestock, and cervids. The majority of prion diseases have an infectious etiology, and food-borne infection has been linked to the transmission of transmissible mink encephalopathy (TME), bovine spongiform encephalopathy (BSE), and kuru in humans (21,23,58). Indirect evidence suggests that oral infection is involved in the transmission of other prion diseases, such as scrapie in sheep, chronic wasting disease (CWD) in deer and elk, and variant Creutzfeldt-Jakob disease in humans (2,13,26,47,52). The experimental ingestion of high doses of scrapie agent (hereinafter referred to as scrapie) has been used to determine the sites of scrapie replication in peripheral tissues and the routes by which the disease spreads to the peripheral and central nervous systems (24,33,36,38,54).The disease-specific isoform of the prion protein, PrP Sc ...

Investigation of PrPres in dental tissues in variant CJD

“…Both infectivity and PrP res have both been detected in dental tissues (including salivary gland and tongue) in experimental models of prion diseases; 20,21,27,28 however, these studies have generally employed models where levels of infectivity both in the nervous system and in other tissues are likely to be higher than those encountered in human prion diseases. 29 Accordingly, the relevance of these studies to human diseases can be questioned, but there is a need for more sensitive and specific means of detection of PrP res in human tissues and fluids, which might also allow the development of screening tests for asymptomatic carriers who are incubating variant CJD.…”

“…Recent studies on animal models have also suggested that the tongue and gingiva might represent site of transmission for prion diseases. 20,21 A case control study on variant CJD has not yet identified any significant difference between cases and controls in terms of the history of dental surgery and other surgical procedures (Dr H. Ward, personal communication). Our findings will help inform the ongoing risk assessment for exposure of surgical instruments to infectivity in variant CJD.…”

“…17,18 Infectivity in dental tissues has been described in a rodent model of scrapie, 20 and experimental inoculation of infected brain homogenate into the tongue and into dental pulp appears to be an efficient route of neuroinvasion. 21 However, PrP res was undetectable in dental pulp samples from patients with sporadic CJD. 22 Here we use Western blot, PET blot and immunohistochemical analysis of a range of oral…”

Risque de transmission des prions lors de la prise en charge d’un patient suspect de maladie de Creutzfeldt-Jakob sporadique

“…Cette étude suggère qu'il y a une diffusion de l'agent infectieux des tissus buccaux vers le système nerveux central par l'intermédiaire du nerf trijumeau [10]. D'autres études réa-lisées chez l'animal [11,12] ont confirmé l'infectiosité des tissus buccaux (langue, glandes salivaires) après inoculation d'une souche de PrP Sc . L'inoculation par injection linguale chez le hamster a permis le développement de la maladie : la PrP Sc a été localisée dans certaines cellules du cerveau (noyau de l'hypoglosse) confirmant la propagation transneuronale du prion.…”

Propagation of scrapie in peripheral nerves after footpad infection in normal and neurotoxin exposed hamsters

“…The endemic appearance of Kuru in Papua New Guinea is due to endocannibalistic rites [1]. Nevertheless, in vivo experiments showed successful transmission of TSE-disease not only by oral, intracerebral, intravenous or intraperitoneal application of infectivity but also by subcutaneous injection, through defect mucosa [5,12] or, even very effectively, by scarification of the intact skin [48].…”