Role of the Lymphoreticular System in Prion Neuroinvasion from the Oral and Nasal Mucosa

ABSTRACT Prion neuroinvasion from peripheral tissues involves agent replication in the lymphoreticular system (LRS) prior to entry into the nervous system. This study investigated the role of the LRS in prion neuroinvasion from the oral and nasal mucosa in wild-type and immunodeficient mice and in hamsters infected with the HY and DY strains of the transmissible mink encephalopathy (TME) agent. Following inoculation at neural sites, all hosts were susceptible to prion disease and had evidence of prion infection in the brain, but infection of the LRS was found only in scrapie-infected wild-type mice and HY TME-infected hamsters. In the LRS replication-deficient models, prion neuroinvasion was not observed following intraperitoneal or oral inoculation. However, immunodeficient mice, which have impaired follicular dendritic cells, were susceptible to scrapie following intratongue and intranasal inoculation despite the absence of PrPSc in the tongue or the nasal cavity. For DY TME, hamsters were susceptible following intratongue but not intranasal inoculation and PrPSc was limited to nerve fibers of the tongue. These findings indicate that neuroinvasion from the tongue and nasal cavity can be independent of LRS infection but neuroinvasion was partially dependent on the strain of the prion agent and/or the host species. The paucity of PrPSc deposition in the oral and nasal mucosa from LRS replication-deficient hosts following neuroinvasion from these tissues suggests an infection of nerve fibers that is below the threshold of PrPSc detection and/or the transport of the prion agent along cranial nerves without agent replication.

Prion Interference Is Due to a Reduction in Strain-Specific PrPSc Levels

ABSTRACT When two prion strains infect a single host, one strain can interfere with the ability of the other to cause disease but it is not known whether prion replication of the second strain is also diminished. To further investigate strain interference, we infected hamsters in the sciatic nerve with the long-incubation-period transmissible mink encephalopathy (TME) agent DY TME prior to superinfection of hamsters with the short-incubation-period HY TME agent. Increases in the interval between TME agent inoculations resulted in an extension of the incubation period of HY TME or a complete block of the ability of the HY TME agent to cause disease. The sciatic nerve route of inoculation gave the two TME strains access to the same population of neurons, allowing for the potential of prion interference in the lumbar spinal cord. The ability of the DY TME agent to extend the incubation period of HY TME corresponds with detection of DY TME PrPSc, the abnormal isoform of the prion protein, in the lumbar spinal cord. The increased incubation period of HY TME or the inability of the HY TME agent to cause disease in the coinfected animals corresponds with a reduction in the abundance of HY TME PrPSc in the lumbar spinal cord. When the two strains were not directed to the same populations of neurons within the lumbar spinal cord, interference between HY TME and DY TME did not occur. This suggests that DY TME agent replication interferes with HY TME agent replication when the two strains infect a common population of neurons.

Microglial Activation Varies in Different Models of Creutzfeldt-Jakob Disease

ABSTRACT Progressive changes in host mRNA expression can illuminate crucial pathogenetic pathways in infectious disease. We examined general and specific approaches to mRNA expression in three rodent models of Creutzfeldt-Jakob disease (CJD). Each of these models displays distinctive neuropathology. Although mRNAs for the chemokine receptor CCR5, the lysosomal protease cathepsin S, and the pleiotropic cytokine transforming growth factor β1 (TGF-β1) were progressively upregulated in rodent CJD, the temporal patterns and peak magnitudes of each of these transcripts varied substantially among models. Cathepsin S and TGF-β1 were elevated more than 15-fold in mice and rats infected with two different CJD strains, but not in CJD-infected hamsters. In rats, an early activation of microglial transcripts preceded obvious deposits of prion protein (PrP) amyloid. However, in each of the three CJD models, the upregulation of CCR5, cathepsin S, and TGF-β1 was variable with respect to the onset of PrP pathology. These results show glial cell involvement varies as a consequence of the agent strain and species infected. Although neurons are generally assumed to be the primary sites for agent replication and abnormal PrP formation, microglia may be targeted by some agent strains. In such instances, microglia can both process PrP to become amyloid and can enhance neuronal destruction. Because microglia can participate in agent clearance, they may also act as chronic reservoirs of infectivity. Finally, the results here strongly suggest that TGF-β1 can be an essential signal for amyloid deposition.

Scrapie-associated PrP accumulation and agent replication: effects of sulphated glycosaminoglycan analogues

An abnormally protease-resistant and apparently neuropathogenic form of PrP accumulates in the brains of hosts with scrapie and related transmissible spongiform encephalopathies. Studies with scrapieinfected neuroblastom a cells have highlighted dramatic differences in the metabolism of the normal (protease-sensitive) and scrapie-associated (protease-resistant) isoforms of PrP. Furthermore, this model has been useful in identifying inhibitors of protease-resistant PrP accumulation and scrapie agent replication which are valuable as potential therapeutic agents and as probes of the mechanism of protease-resistant PrP formation. These inhibitors include the amyloid stain Congo red and certain sulphated glycans which are glycosaminoglycans themselves or glycosaminoglycan analogues. The relative potencies of various sulphated glycans correlate with their previously determ ined anti-scrapie activities in vivo , suggesting that the prophylactic effects of sulphated polyanions is due to inhibition of protease-resistant PrP accumulation. These and other observations suggest that an interaction of PrP with endogenous sulphated glycosaminoglycans or proteoglycans is important in protease-resistant PrP accumulation, and raise the possibility that therapies for transmissible spongiform encephalopathies and other amyloidoses could be based on blocking (pre)am yloid-glycosaminoglycan interactions.