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Lymphotoxin-dependent prion replication in inflammatory stromal cells of granulomas


Heikenwalder, M; Kurrer, M O; Margalith, I; Kranich, J; Zeller, N; Haybaeck, J; Polymenidou, M; Matter, M; Bremer, J; Jackson, W S; Lindquist, S; Sigurdson, C J; Aguzzi, A (2008). Lymphotoxin-dependent prion replication in inflammatory stromal cells of granulomas. Immunity, 29(6):998-1008.

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 (PrP(C), 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 PrP(C)-expressing cells and LTbetaR signaling. Granulomatous PrP(C) 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.

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 (PrP(C), 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 PrP(C)-expressing cells and LTbetaR signaling. Granulomatous PrP(C) 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2008
Deposited On:21 Jan 2009 21:20
Last Modified:05 Apr 2016 12:46
Publisher:Elsevier
ISSN:1074-7613
Publisher DOI:10.1016/j.immuni.2008.10.014
PubMed ID:19100703
Permanent URL: http://doi.org/10.5167/uzh-9281

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