Lymphotoxin-dependent prion replication in inflammatory stromal cells of granulomas.
Prior to invading the nervous system, prions frequently colonize lymphoid organs and sites of inflammatory lymphoneogenesis, where they colocalize with Mfge8+ follicular dendritic cells (FDCs). Here, we report that soft-tissue granulomas, a frequent feature of chronic inflammation, expressed the cellular prion protein (PrPC, encoded by Prnp) and the lymphotoxin receptor (LTbetaR), even though they lacked FDCs and did not display lymphoneogenesis. After intraperitoneal prion inoculation, granulomas of Prnp(+/+) mice, but not Prnp(-/-) granulomas or unaffected Prnp(+/+) skin, accumulated prion infectivity and disease-associated prion protein. Bone-marrow transfers between Prnp(+/+) and Prnp(-/-) mice and administration of lymphotoxin signaling antagonists indicated that prion replication required radioresistant PrPC-expressing cells and LTbetaR signaling. Granulomatous PrPC was mainly expressed by stromal LTbetaR+ mesenchymal cells that were absent from unaffected subcutis. Hence, granulomas can act as clinically silent reservoirs of prion infectivity. Furthermore, lymphotoxin-dependent prion replication can occur in inflammatory stromal cells that are distinct from FDCs.
Heikenwalder
Mathias
M
Institute of Neuropathology, Department of Pathology, University Hospital of Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland.
Kurrer
Michael O
MO
Margalith
Ilan
I
Kranich
Jan
J
Zeller
Nicolas
N
Haybaeck
Johannes
J
Polymenidou
Magdalini
M
Matter
Matthias
M
Bremer
Juliane
J
Jackson
Walker S
WS
Lindquist
Susan
S
Sigurdson
Christina J
CJ
Aguzzi
Adriano
A
D000818:Animals; D020566:Dendritic Cells, Follicular / Q000276:immunology* / Q000378:metabolism; D006099:Granuloma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D053259:Lymphotoxin beta Receptor / Q000276:immunology* / Q000378:metabolism; D008233:Lymphotoxin-alpha / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism
D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D000072002:Prion Proteins; D011328:Prions; C512657:Prnp protein, mouse