Sympathetic innervation of lymphoreticular organs is rate limiting for prion neuroinvasion

Transmissible spongiform encephalopathies are commonly propagated by extrac erebral inoculation of the infectious agent. Indirect evidence suggests tha t entry into the central nervous system occurs via the peripheral nervous s ystem. Here we have investigated the role of the sympathetic nervous system in prion neuroinvasion. Following intraperitoneal prion inoculation, chemi cal or immunological sympathectomy delayed or prevented scrapie. Prion tite rs in spinal cords were drastically reduced at early time points after inoc ulation. Instead, keratin 14-NGF transgenic mice, whose lymphoid organs are hyperinnervated by sympathetic nerves, showed reduction in scrapie incubat ion time and, unexpectedly, much higher titers of prion infectivity in sple ens. We conclude that sympathetic innervation of lymphoid organs is rate li miting for prion neuroinvasion and that splenic sympathetic nerves may act as extracerebral prion reservoirs.