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Journal of Virology, September 2000, p. 8614-8622, Vol. 74, No. 18
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Follicular Dendritic Cells and Dissemination of Creutzfeldt-Jakob Disease

Laura Manuelidis,1,* Igor Zaitsev,1 Pandelakis Koni,2,dagger Zhi Yun Lu,1 Richard A. Flavell,2,3 and William Fritch1

Section of Neuropathology,1 Section of Immunobiology,2 and Howard Hughes Medical Institute,3 Yale University School of Medicine, New Haven, Connecticut 06520

Received 1 May 2000/Accepted 12 June 2000

The contribution of immune system cells to the propagation of transmissible encephalopathies is not well understood. To determine how follicular dendritic cells (FDC) may act, we challenged lymphotoxin beta  null and wild-type (wt) controls with a Creutzfeldt-Jakob disease (CJD) agent. There was only a small difference in incubation time to clinical disease even after peripheral challenge with low infectious doses (31 in a total of 410 days). Brain pathology with extensive microglial infiltration, identified by keratan sulfate, as well as astrocytic hypertrophy, was also equivalent in all groups despite the fact that null mice had neither FDC nor splenic metallophilic macrophages that filter particulate antigen. Because FDC accumulate pathologic prion protein (PrP) in infected but not wt mice, we studied the cellular distribution of PrP by confocal microscopy. The majority of pathologic PrP collected on the plasma membrane of FDC, as identified by the Ca+2-binding protein S100A. This surface distribution suggested that agent aggregated with pathologic PrP might spread by cell-to-cell contacts. While several types of leukocytes may be involved in agent dissemination, cells of myeloid lineage were found to be infectious. Moreover, perivascular tracks of microglia and abnormal PrP after intraperitoneal inoculation were consistent with hematogenous spread. In summary, FDC are not required for CJD agent spread from the periphery, although FDC may enhance spread through surface accumulation of pathologic PrP. While it is still not clear where the infectious agent replicates, macrophages can sequester appreciable levels of infectivity and hence act as reservoirs for prolonged latent infection.

* Corresponding author. Mailing address: Section of Neuropathology, Yale University School of Medicine, 310 Cedar St., New Haven, CT 06510. Phone: (203) 785-4442. Fax: (203) 785-6381. E-mail: laura.manuelidis{at}yale.edu.

dagger Present address: Medical College of Georgia, Augusta, GA 30912.

Journal of Virology, September 2000, p. 8614-8622, Vol. 74, No. 18
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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