Previous studies of peripherally injected mouse scrapie suggested that invasion of the CNS occurs initially in mid-thoracic cord by neural spread of infection from spleen and other visceral sites of extraneural replication. We now show that infection of the left sciatic nerve leads to direct spread of infection to brain (at a rate of approximately 1.0-2.0 mm/day), bypassing the need for extraneural replication and thus producing shorter incubation periods. However, the efficiency of intraneural infection is low. It can be increased by crush injury or by the injection of lysophosphatidyl choline, both of which temporarily increase the surface area of axolemma exposed to inoculum. Once infection is established, agent seems to spread throughout the nervous system but, at the clinical stage of disease, the titres in the PNS are much lower than in the CNS.

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PubMedDate not supplied

Scrapie infectivity, fibrils and low molecular weight protein.

The development of a short incubation model of scrapie (strain 263K), in golden hamsters has added impetus to the purification of the infectious agent. Our own attempts have been based on methods pioneered by Millson and developed by Prusiner. We present here results indicating that a purification factor of up to 10(4) with respect to protein may now be possible. Fractions from brain with high infectivity had a sedimentation range of 70-300S and contained an abundance of fibrils closely similar to the scrapie-associated fibrils (SAF) discovered by Merz et al.. Material of molecular weight (Mr) 26,000, which is probably protein, appears to be a major constituent of the fibrils. The association between infectivity and fibrils raises two possibilities: the fibrils are an infectious form of the scrapie agent or they are a pathological response to scrapie infection.

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PubMedDate not supplied

Pathogenesis of mouse scrapie: dynamics of vacuolation in brain and spinal cord after intraperitoneal infection.

At the late clinical stage of scrapie in mice, the severity and distribution of vacuolation in the brain (the lesion profile) is largely determined by the strain of agent and the genotype of the mouse: under controlled conditions, lesion profiles can be used to distinguish between scrapie strains. This paper describes the sequential development of lesions in brain at much earlier times and includes a study of spinal cord. Mice (CW) were infected intraperitoneally with 139A scrapie. Grey matter vacuolation first occurred in thoracic cord, developing later in lumbar and cervical cords, and then in various brain regions in a caudal to rostral sequence. This pattern closely matches the sequential spread of infection from mid-thoracic cord to much of the CNS that was previously found in this scrapie model. Further studies of grey matter in spinal cord suggest that agent entered the mid-thoracic region via sympathetic fibres. Vacuolation in white matter mirrored the grey matter pattern within an area but always occurred later. The severity of grey matter vacuolation in the four areas of the CNS where it developed early, reached plateau levels before the clinical stage of scrapie, but the severity was still increasing at the clinical stage in areas where vacuolation had started late. Hence the severity of lesions in a particular area may sometimes be limited by the time available for them to develop before the host dies. It appears that the distribution of vacuolation in this particular scrapie model is initially influenced by that of the infectious agent and only later does it reflect the distribution of vacuolation target areas shown by the characteristic lesion profile.

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PubMedDate not supplied

Scrapie: how much do we really understand?

Biological studies have produced convincing evidence for different scrapie strains, some of which undergo mutation. This argues strongly in favour of the infectious scrapie agent having a genome. The length of incubation period is influenced by the strain of agent but is also under strict host control. In mice, this control is exerted by a gene called Sinc which affects the overall rate of agent replication in the CNS. After peripheral infection, invasion of the CNS from lymphoreticular sites of agent replication is a key step in pathogenesis. Evidence from one scrapie model indicates spread of infection along autonomic nerves to the thoracic spinal cord and then to other parts of the CNS. Other studies have shown that infection can spread in neurons. There are close relationships between the presence of replicating agent and the development of vacuolation, and also of cerebral amyloid when it occurs. We can, therefore, begin to understand the patterns of lesion development in the brain in terms of the targeting of infection and its replication at certain sites. Structures known as SAF (Scrapie Associated Fibrils) have been discovered in extracts of scrapie brain (but not uninfected brain) and a glycoprotein (PrP 27-30: SAF protein) is a major constituent of purified SAF. The glycoprotein is coded by a single gene which is present in several species and expressed in uninfected brain. The normal protein seems to be modified in scrapie infected brain so that it accumulates as SAF. The modified protein may also be deposited as extracellular amyloid because there appear to be common epitopes between SAF and scrapie amyloid. The biochemical nature of the scrapie agent remains in doubt and the association between infectivity and purified SAF may arise fortuitously from the fact that scrapie agent is 'sticky'.

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PubMedDate not supplied

Transmissible mink encephalopathy (TME) in Chinese hamsters: identification of two strains of TME and comparisons with scrapie.

TME from a single source was transmitted by intracerebral injection to Chinese hamsters, producing clinical disease in all seven animals after incubation periods of over 600 days. The brain from each of the primary cases was used to establish separate intracerebral passage-lines of TME and this led to the isolation of two different strains of agent, designated 333K and 333W. These strains were easily distinguished by the incubation periods they produced (about 130 and 230 days, respectively) under standard conditions of infection, and by the characteristic profiles of vacuolation seen in different regions of the brain. Comparisons were made with a strain of scrapie passaged in Chinese hamsters, designated 34W, which could be distinguished from both strains of TME. Nevertheless the properties of the scrapie and TME strains overlapped, with one of the TME strains (333K) resembling the 34W strain of scrapie in Chinese hamsters more closely than the other TME strain (333W). These similarities strengthen the view that TME and scrapie are caused by a similar type of infectious agent. The very large 'species barrier effect' on transmitting TME to Chinese hamsters was in marked contrast to the minimal effect seen with scrapie and an explanation for this is suggested. Two interesting pathological features of the study were (a) the severe loss of pyramidal cells produced in the hippocampus by the 34W strain of scrapie, and (b) the focal, symmetrical vacuolation of the thalamus caused by 333K TME.

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