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Lymphotoxin-dependent prion replication in inflammatory stromal cells of granulomas

Mathias Heikenwalder1, Michael O Kurrer, Ilan Margalith

  • 1Institute of Neuropathology, Department of Pathology, University Hospital of Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland.

Immunity
|December 23, 2008
PubMed

Insights

Chronic inflammation sites called granulomas can harbor infectious prions. These prion reservoirs replicate via cellular prion protein (PrPC) and lymphotoxin signaling in specific stromal cells, independent of FDCs.

Area of Science:

  • Prion biology
  • Immunology
  • Cellular biology

Background:

  • Prions often colonize lymphoid organs and sites of lymph node formation before invading the nervous system.
  • These sites typically involve Mfge8+ follicular dendritic cells (FDCs).
  • Chronic inflammation can lead to soft-tissue granulomas, but their role in prion disease was unclear.

Purpose of the Study:

  • To investigate whether soft-tissue granulomas serve as prion reservoirs.
  • To determine the cellular mechanisms and cell types involved in prion replication within granulomas.

Main Methods:

  • Analyzing prion protein (PrPC) and lymphotoxin receptor (LTbetaR) expression in granulomas.
  • Inoculating mice with prions and assessing prion accumulation in granulomas versus normal tissue.
  • Utilizing bone-marrow transfers and lymphotoxin signaling antagonists to identify key cellular components and pathways.

Main Results:

  • Granulomas expressed PrPC and LTbetaR, even without FDCs or lymph node formation.
  • Prion infectivity and disease-associated prion protein accumulated in granulomas of Prnp(+/+) mice but not Prnp(-/-) mice.
  • Prion replication required radioresistant PrPC-expressing cells and LTbetaR signaling, primarily in stromal mesenchymal cells.

Conclusions:

  • Soft-tissue granulomas can act as clinically silent reservoirs for prion infectivity.
  • Prion replication can occur in inflammatory stromal cells expressing PrPC and LTbetaR, independent of FDCs.
  • Lymphotoxin signaling is crucial for prion replication in these granuloma-associated stromal cells.

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