title: Lymphotoxin-dependent prion replication in inflammatory stromal cells of granulomas.
abstract: 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.
authors.affiliation: Institute of Neuropathology, Department of Pathology, University Hospital of Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwalder
authors.forename: Michael O
authors.initials: MO
authors.lastname: Kurrer
authors.forename: Ilan
authors.initials: I
authors.lastname: Margalith
authors.forename: Jan
authors.initials: J
authors.lastname: Kranich
authors.forename: Nicolas
authors.initials: N
authors.lastname: Zeller
authors.forename: Johannes
authors.initials: J
authors.lastname: Haybaeck
authors.forename: Magdalini
authors.initials: M
authors.lastname: Polymenidou
authors.forename: Matthias
authors.initials: M
authors.lastname: Matter
authors.forename: Juliane
authors.initials: J
authors.lastname: Bremer
authors.forename: Walker S
authors.initials: WS
authors.lastname: Jackson
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Sigurdson
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
mesh_terms: 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
chemical_list: D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D000072002:Prion Proteins; D011328:Prions; C512657:Prnp protein, mouse