PRP-EXPRESSING TISSUE REQUIRED FOR TRANSFER OF SCRAPIE INFECTIVITY FROM SPLEEN TO BRAIN

Much available evidence points to a pathological isoform of the prion protein PrP being the infectious agent that causes transmissible spong iform encephalopathies, but the mechanisms controlling the neurotropis m of prions are still unclear. We have previously shown that mice that do not express PrP (Prnp(o/o) mice) are resistant to infection by pri ons(1,2), and that if a Prnp(+/+) neurograft is introduced into such a nimals and these are infected intracerebrally with scrapie, the graft but not the surrounding tissue shows scrapie pathology(3). Here we sho w that PrP-expressing neurografts in Prnp(o/o) mice do not develop scr apie histopathology after intraperitoneal or intravenous inoculation w ith scrapie prions. Prion titres were undetectable in spleens of inocu lated Prnp(o/o) mice, but were restored to wild-type levels upon recon stitution of the host lymphohaemopoietic system with PrP-expressing ce lls. Surprisingly, however, i.p. or i.v. inoculation failed to produce scrapie pathology in the neurografts of 27 out of 28 reconstituted an imals, in contrast to intracerebral inoculation. We conclude that tran sfer of infectivity from the spleen to the central nervous system is c rucially dependent on the expression of PrP in a tissue compartment th at cannot be reconstituted by bone marrow transfer. Thus the requireme nt for the normal isoform of PrP in peripheral tissues represents a bo ttleneck for the spread of prions from peripheral sites to the central nervous system.