Follicular dendritic cell dedifferentiation reduces scrapie susceptibility following inoculation via the skin

Abstract

Summary Transmissible spongiform encephalopathies (TSEs) are a group of subacute infectious neurodegenerative diseases that are characterized by the accumulation in affected tissues of PrPSc, an abnormal isoform of the host prion protein (PrPc). Following peripheral exposure, TSE infectivity and PrPSc usually accumulate in lymphoid tissues prior to neuroinvasion. Studies in mice have shown that exposure through scarified skin is an effective means of TSE transmission. Following inoculation via the skin, a functional immune system is critical for the transmission of TSEs to the brain, but until now, it has not been known which components of the immune system are required for efficient neuroinvasion. Temporary dedifferentiation of follicular dendritic cells (FDCs) by treatment with an inhibitor of the lymphotoxin‐β receptor signalling pathway (LTβR‐Ig) 3 days before or 14 days after inoculation via the skin, blocked the early accumulation of PrPSc and TSE infectivity within the draining lymph node. Furthermore, in the temporary absence of FDCs before inoculation, disease susceptibility was reduced and survival time significantly extended. Treatment with LTβR‐Ig 14 days after TSE inoculation also significantly extended the disease incubation period. However, treatment 42 days after inoculation did not affect disease susceptibility or survival time, suggesting that the infection may have already have spread to the nervous system. Together these data show that FDCs are essential for the accumulation of PrPSc and infectivity within lymphoid tissues and subsequent neuroinvasion following TSE exposure via the skin.

Pathogenesis of Chronic Wasting Disease in Cervidized Transgenic Mice

“…In these tissues, PrP RES was observed within likely follicular dendritic cells, cells that have been shown to be important enablers of prion disease propagation and neuroinvasion. 21,[37][38][39][40][41][42][43] Detection of splenic PrP RES at a time point (60 dpi) preceding PrP RES detection in the brain (120 dpi) suggests that splenic-mediated neuroinvasion plays a role in Tg[CerPrP] mice, as has been theorized for scrapie prion transit via nerve fibers associated with follicular dendritic cell-rich splenic germinal centers as conduits to the thoracic spinal cord. 44,45 Although splenic-mediated neuroinvasion remains the most likely possibility, we cannot exclude the possibility of hematogenous neuroinvasion, a phenomenon that, although little investigated, finds support in the literature and in the detection of infectious prions in blood.…”

Role of the GALT in Scrapie Agent Neuroinvasion from the Intestine

“…This conclusion is congruent with data from an epidemiological, mathematical, and pathological study, which suggested that for sheep, cattle, and humans, there was an association between development of lymphoid tissues in the gastrointestinal tract and susceptibility to natural TSE infection (40). The precise role that FDCs play in TSE pathogenesis awaits definitive demonstration, but they appear to amplify the levels of the TSE agent above the threshold required to achieve neuroinvasion (11)(12)(13)(14). When and how the TSE agent spreads from the FDCs within PPs to the peripheral nervous system is likewise unknown.…”

“…FDCs are a distinct lineage from migratory bone marrow-derived dendritic cells because they are considered to derive from stromal precursor cells, are nonphagocytic, and are nonmigratory (10). In mouse scrapie models, mature FDCs are critical for scrapie agent accumulation in lymphoid tissues, and in their absence, neuroinvasion is significantly impaired (11)(12)(13)(14). From the lymphoid tissues, translocation to the CNS occurs via the peripheral nervous system (15,16).…”

Fatal Neurological Disease in Scrapie-Infected Mice Induced for Experimental Autoimmune Encephalomyelitis

“…PrP Sc , a protease-resistant isoform of the host protein PrP C , was shown repeatedly to mark the presence of prions and is believed to be the only component of these infectious agents (30,40). Prions invade the nervous system by a mechanism believed to involve mostly transmigration of infected lymphoid cells as well as retrograde transport in ascending peripheral tracts (3,29,35,36,39,41). Once prions enter the brain, replication of infectivity and PrP Sc accumulation occur faster than those in the lymphoid system, subsequently leading to the death of the affected organism (15,20,42).…”