Sympathetic Innervation of Lymphoreticular Organs Is Rate Limiting for Prion Neuroinvasion

Abstract

Transmissible spongiform encephalopathies are commonly propagated by extracerebral inoculation of the infectious agent. Indirect evidence suggests that entry into the central nervous system occurs via the peripheral nervous system. Here we have investigated the role of the sympathetic nervous system in prion neuroinvasion. Following intraperitoneal prion inoculation, chemical or immunological sympathectomy delayed or prevented scrapie. Prion titers in spinal cords were drastically reduced at early time points after inoculation. Instead, keratin 14-NGF transgenic mice, whose lymphoid organs are hyperinnervated by sympathetic nerves, showed reduction in scrapie incubation time and, unexpectedly, much higher titers of prion infectivity in spleens. We conclude that sympathetic innervation of lymphoid organs is rate limiting for prion neuroinvasion and that splenic sympathetic nerves may act as extracerebral prion reservoirs.

Peripheral prion pursuit

“…However, more indirect paths also exist and may represent the more significant route from the gut to the brain. Thus, following intraperitoneal delivery of prions, disease can be delayed by sympathectomy or can be accelerated by sympathetic hyperinnervation of lymphoreticular organs (9). …”

Follicular Dendritic Cell Dedifferentiation by Treatment with an Inhibitor of the Lymphotoxin Pathway Dramatically Reduces Scrapie Susceptibility

“…Studies of mouse scrapie models have shown that mature FDCs are critical for replication in lymphoid tissues and, in their absence, neuroinvasion after peripheral challenge is significantly impaired (6, 17, 31, 37-39, 46, 51). From the lymphoid tissues infectivity spreads to the CNS via peripheral nerves (21).…”

“…The extended survival time in LT␤R-treated mice could simply be related to the time required for FDC networks to restore and initiate replication of the inocula. This would delay the subsequent transfer of infectivity via peripheral nerves into the CNS (21). However, LT␤R treatment also significantly reduced disease susceptibility, suggesting a substantial portion of the inoculum is destroyed, for example, by macrophages (4,9).…”

Five Questions on Prion Diseases

“…After replication and accumulation in lymphoid organs, prions invade the nervous system through sympathetic and parasympathetic nerves [11], [12]. The spread pathways of prions were determined by identifying the location and temporal sequence of pathological accumulation of PrP after oral challenge [11].…”

“…The spread pathways of prions were determined by identifying the location and temporal sequence of pathological accumulation of PrP after oral challenge [11]. Upon i.p inoculation, permanent or transient sympathectomy chemically or immunologically delays or even prevents scrapie, whereas sympathetic hyperinnervation accelerates prion pathogenesis [12]. Hence innervation of lymphoid organs is rate-limiting for prion neuroinvasion.…”