Downloaded from www.microbiologyresearch.org by IP: 54.224.135.207 On: Thu, 14 Apr 2016 03:54:59 Journal of General Virology (2000), 81, 2813–2821. Printed in Great Britain ................................................................................................................................................................................................................................................................................... PrP C expression in the peripheral nervous system is a determinant of prion neuroinvasion Markus Glatzel and Adriano Aguzzi Institute of Neuropathology, University Hospital Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland Transmissible spongiform encephalopathies are often propagated by extracerebral inoculation. The mechanism of spread from peripheral portals of entry to the central nervous system (neuroinvasion) is complex : while lymphatic organs typically show early accumulation of prions, and B-cells and follicular dendritic cells are required for efficient neuroinvasion, actual entry into the central nervous system occurs probably via peripheral nerves and may utilize a PrP C - dependent mechanism. This study shows that transgenic mice overexpressing PrP C undergo rapid and efficient neuroinvasion upon intranerval and footpad inoculation of prions. These mice exhibited deposition of the pathological isoform of the prion protein (PrP Sc ) and infectivity in specific portions of the central and peripheral sensory pathways, but almost no splenic PrP Sc accumulation. In contrast, wild-type mice always accumulated splenic PrP Sc , and had widespread deposition of PrP Sc throughout the central nervous system even when prions were injected directly into the sciatic nerve. These results indicate that a lympho-neural sequence of spread occurs in wild-type mice even upon intranerval inoculation, while overexpression of PrP C leads to substantial predilection of intranerval over lymphoreticular spread. The rate of transport of infectivity in peripheral nerves was ca. 07 mm per day, and prion infectivity titres of sciatic nerves were much higher in tga20 than in wild-type mice, suggesting that overexpression of PrP C modulates the capacity for intranerval transport. Introduction Prion diseases are transmissible fatal neurodegenerative diseases. Although the infectious agent is most efficiently propagated through intracerebral inoculation, peripheral in- fection is the natural route of transmission in most prion diseases. Oral administration is most probably involved in kuru, BSE and the new variant of Creutzfeldt–Jakob disease, while parenteral administration of growth hormone and gonadotropins has resulted in iatrogenic Creutzfeldt–Jakob disease. In all these instances transport of the infectious agent from the site of entry into the body to the central nervous system (CNS) is of crucial importance (Hill et al., 1997 ; Scott et al., 1999). A large body of evidence indicates that both the lymphoreticular system (LRS) and the peripheral nervous system (PNS) are involved in scrapie neuroinvasion (Baldauf et al., 1997; Kimberlin & Walker, 1988; Klein et al., 1997; Lasmezas et al., 1996). Transport along the PNS was suggested by experiments showing that intranerval (i.n.) injection of Author for correspondence : Adriano Aguzzi. Fax 41 1 2554402. e-mail Adrianopathol.unizh.ch infectivity could bypass the need for extraneural replication of the agent (Kimberlin et al., 1983 b). Also, the first pathological lesions and replication of infectivity after peripheral adminis- tration of the scrapie agent occur in spinal cord and medulla oblongata : these sites are consistent with entry via peripheral nerves like the vagal or splanchnic nerves (Beekes et al., 1998 ; Cole & Kimberlin, 1985). The LRS clearly plays an important role in the transport of the scrapie agent. In several animal models, including hamsters and mice, lymphoid organs such as the spleen are early sites of accumulation and replication of the agent following intra- peritoneal (i.p.) inoculation (Eklund et al., 1967; Kimberlin & Walker, 1986, 1989). Although B-lymphocytes are required for efficient neuroinvasion of the agent, they do not need to express PrP C . It appears that their role in neuroinvasion consists – at least in part – of lymphotoxin β-mediated induction of follicular dendritic cell maturation (Montrasio et al., 2000 ; Klein et al., 1998). In order to replicate prions within lymphatic tissues follicular dendritic cells may need to express PrP C (Brown et al., 1999). Although various components of the immune system play a pivotal role in scrapie neuroinvasion, there is substantial 0001-7152  2000 SGM CIBD