Immune system replication blockade prevents prion spread
MedWire News: Prion replication is blocked in the spleen when expression of cellular prion protein (PrPC) is switched off in follicular dendritic cells (FDC) in lymphoid tissue, suggest study findings.
Prion diseases are infectious neurologic disorders considered to be caused by abnormally folded infectious proteins, PrPSc, which accumulate first in FDC within lymphoid tissues, before spreading to the brain. The findings of the current study confirm that FDC are essential sites of prion replication in lymphoid tissue.
"This study is the first to demonstrate that the specific ablation of a cellular protein only on FDC, without apparent consequences for FDC status and function, blocks the replication of an important pathogen in the spleen," say Neil Mabbott (University of Edinburgh, UK) and co-authors.
To establish the role of FDC in prion pathogenesis, the researchers created transgenic mice in which PrPC expression was switched "on" or "off" only in FDC.
When FDC expressed PrPC, prions were able to replicate on the surface of these cells, thus sustaining prion replication in the spleen. Furthermore, prion replication was blocked in the spleen when PrPC expression was specifically ablated only on FDC.
In addition, the team found that the effects of Prnp-ablation on prion replication in the spleen were specific to FDC, and had no effect on prion neuropathogenesis when the infection was established directly in the CNS.
In the absence of PrPC expression on FDC, the PrPSc from the initial inoculums appeared to be scavenged by macrophages resident within the B cell follicles.
"Our data confirm that FDC express high levels of PrPC and do not simply acquire it from other host cells," say Mabbott and team in the journal, Public Library of Science Pathogens.
The results are of importance as previous studies have shown that treatments which impair the status or immune complex-trapping function of FDC reduce prion susceptibility after peripheral exposure. The finding that FDC Prnp ablation blocked prion replication in the spleen without affecting FDC status suggests that it may be possible to prevent neuroinvasion by modulation of PrPC expression on FDC.
In an associated press release, Mabbott said: "If we can find a way of stopping this protein from being expressed by specific immune cells then we could potentially block the spread of the disease to the brain."
He added: "We also want to understand how cells are infected with [variant Creutzfeldt-Jakob disease] in the first place, so that we can look at ways of stopping this from happening and find ways to diagnose the disease at its early stages."
By Ingrid Grasmo