Resistance of Neonatal Mice to Scrapie Is Associated with Inefficient Infection of the Immature Spleen

Abstract

Previous studies demonstrated that neonatal mice up to about a week old are less susceptible than adult mice to infection by intraperitoneal inoculation with mouse-passaged scrapie. In peripherally inoculated adult mice, scrapie replicates in lymphoid tissues such as the spleen before invading the central nervous system. Here, we investigated scrapie susceptibility in neonatal mice in more detail, concentrating on spleen involvement. First, we demonstrated that neonatal mice are about 10 times less susceptible than adults to intraperitoneal scrapie inoculation. Then we injected mice intraperitoneally with a scrapie dose that produced disease in all mice inoculated at 10 days or older but in only about a third of neonatally inoculated mice. In this experiment, spleens collected 70 days after scrapie injection of mice 10 days old or older almost all contained pathological prion protein, PrP Sc , and those that were bioassayed all contained high infectivity levels. In contrast, at this early stage, only two of six spleens from neonatally inoculated mice had detectable, low infectivity levels; no PrP Sc was detected, even in the two spleens. Therefore, neonatal mice have an impaired ability to replicate scrapie in their spleens, suggesting that replication sites are absent or sparse at birth but mature within 10 days. The increase in susceptibility with age correlated with the first immunocytochemical detection of the normal cellular form of prion protein, PrP c , on maturing follicular dendritic cell networks. As lymphoid tissues are more mature at birth in sheep, cattle, and humans than in mice, our results suggest that in utero infection with scrapie-like agents is theoretically possible in these species.

Prion pathogenesis and secondary lymphoid organs (SLO)

“…A similar effect of host age on susceptibility to peripheral infection with RML scrapie prions has also been reported 98 . Data also show that the underdeveloped or reduced functional status of FDC in neonatal mice likewise coincides with impaired prion neuroinvasion following peripheral exposure 99 , 100 . Whether a similar correlation is observed in natural prion infections remains to be determined?…”

Susceptibility of Young Sheep to Oral Infection with Bovine Spongiform Encephalopathy Decreases Significantly after Weaning

“…Alternatively, once TSE infection is transported across the gut wall, it could take a route via the lymphoreticular system (LRS) prior to invasion of the central nervous system. In the LRS the importance of follicular dendritic cells (FDCs) in the dissemination of infectivity has been elegantly demonstrated in mice (9,29). Lambs, however, have different immune system status from neonatal mice and are well endowed with FDCs in their lymphoid tissues before birth (25), so this is unlikely to be important in our unweaned sheep.…”

The Effects of Host Age on the Transport of Complement-Bound Complexes to the Spleen and the Pathogenesis of Intravenous Scrapie Infection

“…Data from experimental mouse models show that the underdeveloped or reduced functional status of FDCs in either very young (neonatal) or aged mice significantly impairs TSE neuroinvasion following intraperitoneal (i.p.) or oral exposure (4,21,42). This implies that the pathogenesis of many acquired TSE infections which accumulate in lymphoid tissues prior to neuroinvasion, including natural sheep scrapie, CWD, and vCJD, may likewise be much less efficient in the aged.…”