Entry versus Blockade of Brain Infection following Oral or Intraperitoneal Scrapie Administration: Role of Prion Protein Expression in Peripheral Nerves and Spleen

Abstract

Naturally occurring transmissible spongiform encephalopathy (TSE) diseases such as bovine spongiform encephalopathy in cattle are probably transmitted by oral or other peripheral routes of infection. While prion protein (PrP) is required for susceptibility, the mechanism of spread of infection to the brain is not clear. Two prominent possibilities include hematogenous spread by leukocytes and neural spread by axonal transport. In the present experiments, following oral or intraperitoneal infection of transgenic mice with hamster scrapie strain 263K, hamster PrP expression in peripheral nerves was sufficient for successful infection of the brain, and cells of the spleen were not required either as a site of amplification or as transporters of infectivity. The role of tissue-specific PrP expression of foreign PrP in interference with scrapie infection was also studied in these transgenic mice. Peripheral expression of heterologous PrP completely protected the majority of mice from clinical disease after oral or intraperitoneal scrapie infection. Such extensive protection has not been seen in earlier studies on interference, and these results suggested that gene therapy with mutant PrP may be effective in preventing TSE diseases.

Test for Detection of Disease-Associated Prion Aggregate in the Blood of Infected but Asymptomatic Animals

“…However, the mechanisms by which PrP Sc enters the CNS are not completely understood (2,7,24,42). It is believed that PrP Sc is imported into the CNS either by follicular dendritic cells (10,18) or by neurons (17,30). Irrespective of the pathway, diseaseassociated PrP Sc aggregates are detectable in the brains of some mice at 1 week after an intraperitoneal inoculation by AS-FACTT.…”

Lymph nodal prion replication and neuroinvasion in mice devoid of follicular dendritic cells

“…Lymphoinvasion most likely plays an important role in the pathogenesis of vCJD, because prion infectivity can be detected in tonsils of virtually every vCJD patient (29,30). After lymphoinvasion, neuroinvasion occurs via autonomic nerves (31)(32)(33)(34)(35), but the nexus between germinal centers and nerves is still elusive. By virtue of their mobility, macrophages may represent a plausible candidate for transport of prion infectivity from germinal centers to sympathetic nerve terminals.…”

Rodent models for prion diseases

“…-mapping PrP regions involved in or required for PrP conversion and prion replication [36,37,44,56,57,63,78,80]; -studies on the physiological role of PrP C and the contributions of individual molecular regions to these functions [65]; -studies on molecular aspects of species barrier effects by mutation of single or limited numbers of positions within the PrP [20,41,51,76,77,82]; -modelling of familial forms of human prion diseases [3,4,60]; -analysis of the cell specificity of prion propagation [48,71,72]; -analysis of the role of PrP glycosylation [22,64]; -studies on the mechanisms of prion spread [11,12]; -studies on the neuropathological roles of PrP C and of PrP D in prion disease [39]; -studies on the function of PrP Doppel [34].…”