Lymph nodal prion replication and neuroinvasion in mice devoid of follicular dendritic cells

Marco Prinz, Fabio Montrasio, Michael A Klein, Petra Schwarz, Josef Priller, Bernhard Odermatt, Klaus Pfeffer, Adriano Aguzzi

Research output: Contribution to journalArticlepeer-review


Variant Creutzfeldt-Jakob disease and scrapie are typically initiated by extracerebral exposure to prions, and exhibit early prion accumulation in germinal centers. Follicular dendritic cells (FDCs), whose development and maintenance in germinal centers depends on tumor necrosis factor (TNF) and lymphotoxin (LT) signaling, are thought to be indispensable for extraneural prion pathogenesis. Here, we administered prions intraperitoneally to mice deficient for TNF and LT signaling components. LT alpha(-/-), LT beta(-/-), LT betaR(-/-), and LT alpha(-/-) x TNFalpha(-/-) mice resisted infection and contained no infectivity in spleens and lymph nodes (when present). However, TNFR1(-/-), TNFR2(-/-), and some TNFalpha(-/-) mice developed scrapie similarly to wild-type mice. High prion titers were detected in lymph nodes, but not spleens, of TNFR1(-/-) and TNF alpha(-/-) mice despite absence of FDCs and germinal centers. Transfer of TNFR1(-/-) fetal liver cells into lethally irradiated Prnp(0/0) mice restored infectivity mainly in lymph nodes. Prion protein (PrP) colocalized with a minority of macrophages in tumor necrosis factor receptor (TNFR) 1(-/-) lymph nodes. Therefore, prion pathogenesis can be restricted to lymphoreticular subcompartments, and mature follicular dendritic cells are dispensable for this process. Macrophage subsets are plausible candidates for lymphoreticular prion pathogenesis and neuroinvasion in the absence of FDCs, and may represent a novel target for postexposure prophylaxis.

Original languageEnglish
Pages (from-to)919-24
Number of pages6
JournalProceedings of the National Academy of Sciences (PNAS)
Issue number2
Publication statusPublished - 22 Jan 2002


  • Animals
  • Antigens, CD
  • Chimera
  • Dendritic Cells, Follicular
  • Humans
  • Lymph Nodes
  • Lymphotoxin beta Receptor
  • Lymphotoxin-alpha
  • Lymphotoxin-beta
  • Membrane Proteins
  • Mice
  • Mice, Knockout
  • Prion Diseases
  • Prions
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor-alpha
  • Journal Article
  • Research Support, Non-U.S. Gov't


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