Positioning of follicular dendritic cells within the spleen controls prion neuroinvasion.
Peripheral infection is the natural route of transmission in most prion diseases. Peripheral prion infection is followed by rapid prion replication in lymphoid organs, neuroinvasion and progressive neurological disease. Both immune cells and nerves are involved in pathogenesis, 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.
Prinz
Marco
M
Institute of Neuropathology, University Hospital of Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland.
Heikenwalder
Mathias
M
Junt
Tobias
T
Schwarz
Petra
P
Glatzel
Markus
M
Heppner
Frank L
FL
Fu
Yang-Xin
YX
Lipp
Martin
M
Aguzzi
Adriano
A
D000818:Animals; D016026:Bone Marrow Transplantation; D002678:Chimera / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D017353:Gene Deletion; D007700:Kinetics; D053259:Lymphotoxin beta Receptor; D051379:Mice; D018345:Mice, Knockout; D011328:Prions / Q000276:immunology / Q000378:metabolism*; D054380:Receptors, CXCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D012608:Scrapie / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013154:Spleen / Q000276:immunology* / Q000294:innervation / Q000378:metabolism / Q000473:pathology; D013564:Sympathetic Nervous System / Q000276:immunology / Q000378:metabolism / Q000473:pathology
C513179:CXCR5 protein, mouse; C505697:LTBR protein, human; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D011328:Prions; D054380:Receptors, CXCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D018124:Receptors, Tumor Necrosis Factor