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Pathogenesis of scrapie is faster when infection is intraspinal instead of intracerebral
R H Kimberlin1, S Cole, C A Walker
1AFRC & MRC Neuropathogenesis Unit, Edinburgh, U.K.
Abstract:
Previous studies of mice infected peripherally with 139A scrapie showed that scrapie agent initially replicates outside the CNS and that invasion of the CNS occurs several weeks later by neural spread of infection along visceral autonomic fibres to the mid-thoracic cord, and thence to brain. Direct intracerebral infection of brain bypasses the need for extraneural replication and gives shorter incubation periods than peripheral routes. However, it was also found that the duration of the scrapie replication phase in brain, before clinical disease develops, is actually shorter with peripheral routes than with the intracerebral route. We have now investigated this surprising observation using the intraspinal route to reproduce just the neural phase of scrapie pathogenesis seen after peripheral infection. In studies of three strains of scrapie (263K, 139A and ME7) in either hamsters or mice, we have fulfilled the prediction that incubation periods should be shorter after intraspinal infection than after intracerebral infection. Detailed studies of 139A scrapie showed that the shorter incubation period by the intraspinal route could be accounted for by the shorter duration of the scrapie replication phase in brain before clinical disease developed. As a consequence, the severity of the vacuolar lesions in brain at the clinical stage of all three scrapie models was less after intraspinal infection than after intracerebral infection but the severities of vacuolation after intraspinal and intraperitoneal infection were remarkably similar. We speculate that (a) the site of injection (or of invasion) of the central nervous system determines which neural pathways become accessible for the spread of scrapie infection, and that (b) the duration of the neural phase of scrapie pathogenesis is related to the complexity of the pathways between the site of invasion and the clinical target areas in which, it is suggested, scrapie must replicate for disease to develop.
Insights
Intraspinal infection with scrapie (a prion disease) leads to shorter incubation periods and less severe brain lesions compared to intracerebral infection. This suggests the invasion site influences disease progression and duration.
Area of Science:
- Neuroscience
- Prion Diseases
- Infectious Diseases
Background:
- Scrapie agent initially replicates outside the central nervous system (CNS) before invading it via neural pathways.
- Intracerebral infection bypasses extraneural replication, leading to shorter incubation periods than peripheral routes.
- Peripheral scrapie infection shows a shorter replication phase in the brain before clinical disease onset compared to intracerebral routes.
Purpose of the Study:
- To investigate the surprising observation of a shorter brain replication phase in peripheral scrapie infection.
- To reproduce the neural phase of scrapie pathogenesis using an intraspinal infection route.
- To compare incubation periods and lesion severity between intraspinal, intracerebral, and intraperitoneal scrapie infection routes.
Main Methods:
- Studied three strains of scrapie (263K, 139A, ME7) in hamsters and mice.
- Utilized intraspinal infection to mimic the neural phase of scrapie pathogenesis.
- Compared incubation periods, brain replication phase duration, and vacuolar lesion severity across different infection routes.
Main Results:
- Incubation periods were shorter after intraspinal infection than intracerebral infection across all scrapie strains and animal models.
- The shorter incubation period following intraspinal infection was attributed to a shorter scrapie replication phase in the brain.
- Vacuolar lesion severity in the brain was less pronounced after intraspinal infection compared to intracerebral infection, but similar to intraperitoneal infection.
Conclusions:
- The site of central nervous system invasion influences accessible neural pathways for scrapie spread.
- The duration of the neural phase of scrapie pathogenesis correlates with the complexity of neural pathways to target areas.
- Scrapie replication within specific brain areas is crucial for the development of clinical disease.