1. Institute of Neuropathology, University Hospital of Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland
2. Institute of Experimental Immunology, University Hospital of Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland
3. Department of Pathology and Committee on Immunology, The University of Chicago, 5841 S. Maryland, Chicago, Illinois 60637, USA
4. Department of Molecular Tumor Genetics and Immunogenetics, Max Delbrück Center for Molecular Medicine (MDC), Robert-Rössle-Strasse 10, 13092 Berlin, Germany
5. These authors contributed equally to this work
6. Present address: Institute of Neuropathology, Georg-August-University Göttingen, Göttingen, Germany

Correspondence to: Adriano Aguzzi¹ Email: adriano@pathol.unizh.ch

Abstract

Peripheral infection is the natural route of transmission in most prion diseases¹. Peripheral prion infection is followed by rapid prion replication in lymphoid organs, neuroinvasion² and progressive neurological disease. Both immune cells and nerves are involved in pathogenesis^{3, 4}, but the mechanisms of prion transfer from the immune to the nervous system are unknown. Here we show that ablation of the chemokine receptor CXCR5 juxtaposes follicular dendritic cells (FDCs) to major splenic nerves, and accelerates the transfer of intraperitoneally administered prions into the spinal cord. Neuroinvasion velocity correlated exclusively with the relative locations of FDCs and nerves: transfer of CXCR5^-/- bone marrow to wild-type mice induced perineural FDCs and enhanced neuroinvasion, whereas reciprocal transfer to CXCR5^-/- mice abolished them and restored normal efficiency of neuroinvasion. Suppression of lymphotoxin signalling depleted FDCs, abolished splenic infectivity, and suppressed acceleration of pathogenesis in CXCR5^-/- mice. This suggests that prion neuroimmune transition occurs between FDCs and sympathetic nerves, and relative positioning of FDCs and nerves controls the efficiency of peripheral prion infection.