Comparative study of age-dependent susceptibility to the transmissible spongiform encephalopathies

Abstract

The age distribution of the naturally occurring transmissible spongiform encephalopathies (TSEs) or prion diseases, including scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle and variant Creutzfeldt-Jakob disease in humans (vCJD) may be explained by age-dependent susceptibility to infection. Epidemiological studies have shown that exposure to BSE-contaminated meat and meat products alone cannot fully account for the young age distribution of vCJD cases, and that changes in susceptibility may also play a role. Oral exposure has been implicated as the most likely route of natural transmission of TSEs. Peyer's patches (PPs), part of the gut-associated lymphoid tissue (GALT), may represent a portal of entry for orally transmitted prions and appear to be the most likely sites of prion accumulation in the gastrointestinal tract. The main aim of this project was to determine whether the observed age-susceptibility relationship of scrapie, BSE and vCJD could be explained by the development of PPs in the gut. Statistical analyses were performed on an experimental scrapie dataset to determine whether there was an effect of age at exposure on scrapie outcome and incubation period of the disease, taking into consideration other potentially important factors related to susceptibility. PP tissue was quantified in the distal ileum of NPU Cheviot sheep, and data on measures of PP development in cattle and humans were extracted from previous studies. Anatomical PP data and estimates of age-related risks of infection, derived from mathematical models, were used to determine a potential link between age-related risk of natural TSE infection and the development of PP tissue in the three species. Because follicular dendritic cells (FDCs) have been implicated as the likely sites of prion replication in lymphoid tissues, immunocytochemistry was carried out to investigate the ontogeny of PrP-associated FDCs in ileal PP tissue in both mice and sheep. Results showed that age at exposure to the TSE agent is a potentially important factor in determining disease outcome as well as the incubation period of disease. Younger sheep were found to have shorter incubation periods than older animals following subcutaneous inoculation of the infectious agent, a finding which may be attributed to the development of peripheral nerves and which warrants further investigation. For sheep, cattle and humans, measures of PP development peaked in adolescent years followed by a decline, thereafter. There was a significant correlation between measures of PP development and estimated risks of natural TSE infection, with the two age-related distributions peaking in the same age group for all three species. Immunocytochemistry studies showed that PrP-associated FDCs can first be detected in 7 day-old mice, and provided further evidence for the presence of mature FDC networks in GALT of postnatal sheep. These findings imply that, in the absence of FDCs, mice younger than 7 days old may be less susceptible to oral scrapie challenge. The presence of FDCs in newborn sheep suggests that these animals may be susceptible to TSE infection in early postnatal life particularly at lambing when an infected placenta could act as a source of scrapie infection to the young lamb. Age-dependent susceptibility to oral TSE infection in mice and sheep may offer a convenient experimental framework with which to explore the reasons for age-dependent susceptibility to TSE infection in humans.