Chronic lymphocytic inflammation specifies the organ tropism of prions.
Prions typically accumulate in nervous and lymphoid tissues. Because proinflammatory cytokines and immune cells are required for lymphoid prion replication, we tested whether inflammatory conditions affect prion pathogenesis. We administered prions to mice with five inflammatory diseases of the kidney, pancreas, or liver. In all cases, chronic lymphocytic inflammation enabled prion accumulation in otherwise prion-free organs. Inflammatory foci consistently correlated with lymphotoxin up-regulation and ectopic induction of FDC-M1+ cells expressing the normal cellular prion protein PrPC. By contrast, inflamed organs of mice lacking lymphotoxin-alpha or its receptor did not accumulate the abnormal isoform PrPSc, nor did they display infectivity upon prion inoculation. By expanding the tissue distribution of prions, chronic inflammatory conditions may act as modifiers of natural and iatrogenic prion transmission.
Heikenwalder
Mathias
M
Institute of Neuropathology, University Hospital of Zürich, CH-8091 Zürich, Switzerland.
Zeller
Nicolas
N
Seeger
Harald
H
Prinz
Marco
M
Klöhn
Peter-Christian
PC
Schwarz
Petra
P
Ruddle
Nancy H
NH
Weissmann
Charles
C
Aguzzi
Adriano
A
D000818:Animals; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000378:metabolism; D006505:Hepatitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism; D007668:Kidney / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008214:Lymphocytes / Q000276:immunology*; D008233:Lymphotoxin-alpha / Q000378:metabolism; D053308:Lymphotoxin-beta; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009393:Nephritis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010179:Pancreas / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010195:Pancreatitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018621:PrPC Proteins / Q000378:metabolism; D018620:PrPSc Proteins / Q000032:analysis / Q000378:metabolism*; D012608:Scrapie / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D014018:Tissue Distribution
C515479:Ccl21c protein, mouse; D054421:Chemokine CCL21; D019742:Chemokines, CC; C505887:Ltb protein, mouse; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D008565:Membrane Proteins; D018621:PrPC Proteins; D018620:PrPSc Proteins