Experimental scrapie in 'plt' mice: an assessment of the role of dendritic-cell migration in the pathogenesis of prion diseases.
Peripherally acquired transmissible spongiform encephalopathies display strikingly long incubation periods, during which increasing amounts of prions can be detected in lymphoid tissues. While precise sites of peripheral accumulation have been described, the mechanisms of prion transport from mucosa and skin to lymphoid and nervous tissues remain unknown. Because of unique functional abilities, dendritic cells (DCs) have been suspected to participate in prion pathogenesis. In mice inoculated subcutaneously with scrapie-infected DCs, the incubation was shorter when cells were alive as compared with killed cells, suggesting that DC functions may facilitate prion neuroinvasion. However, early propagation in lymphoid tissues seemed not importantly affected by DC vitality. Mutant (plt) mice that have deficient CCL19/CCL21 expression and DC migration displayed similar infection of secondary lymphoid organs as normal mice, regardless of the route of inoculation and scrapie strain. Under certain conditions of transcutaneous inoculation, the incubation and duration of disease were moderately prolonged in plt mice. This was not related to a milder neuropathogenesis, since plt and normal mice were equally susceptible to intracerebral prion challenge. We conclude that peripheral spreading of prions appears poorly dependent on cell migration through the chemokine/receptor system CCL19/CCL21/CCR7, although DCs might be able to help prions reach sites of neuroinvasion.
Levavasseur
Etienne
E
Inserm UMR S 712, Hôpital St-Antoine, F-75012 Paris, France.|Université Pierre et Marie Curie-Paris 6, UMR S 712, Paris, France.
Metharom
Pat
P
Inserm UMR S 712, Hôpital St-Antoine, F-75012 Paris, France.|Université Pierre et Marie Curie-Paris 6, UMR S 712, Paris, France.
Dorban
Gauthier
G
CRPP, Faculty of Medicine, University of Liège, B-4020 Liège, Belgium.
Nakano
Hideki
H
Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Kakiuchi
Terutaka
T
Department of Immunology, Toho University School of Medicine, Tokyo, Japan.
Carnaud
Claude
C
Université Pierre et Marie Curie-Paris 6, UMR S 712, Paris, France.
Sarradin
Pierre
P
INRA, UR1282, Infectiologie Animale et Santé Publique, IASP, F-37380 Nouzilly, France.
Aucouturier
Pierre
P
Inserm UMR S 712, Hôpital St-Antoine, F-75012 Paris, France.|Université Pierre et Marie Curie-Paris 6, UMR S 712, Paris, France.
D000284:Administration, Oral; D000818:Animals; D002465:Cell Movement; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000172:deficiency / Q000235:genetics; D003713:Dendritic Cells / Q000737:chemistry / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008221:Lymphoid Tissue / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018620:PrPSc Proteins / Q000008:administration & dosage* / Q000378:metabolism; D012608:Scrapie / Q000276:immunology* / Q000503:physiopathology
C515461:Ccl19 protein, mouse; C515479:Ccl21c protein, mouse; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D019742:Chemokines, CC; D018620:PrPSc Proteins