Journal of Virology, November 2002, p. 10905-10913, Vol. 76, No. 21
0022-538X/02/$04.00+0 DOI: 10.1128/JVI.76.21.10905-10913.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.
Microglia from Creutzfeldt-Jakob Disease-Infected Brains Are Infectious and Show Specific mRNA Activation Profiles
Christopher A. Baker, Daniel Martin, and Laura Manuelidis*
Section of Neuropathology, Yale University School of Medicine, New Haven, Connecticut 06510
Received 25 February 2002/
Accepted 16 July 2002
Neurons are often assumed to be the principal sites for replication of the infectious agents causing Creutzfeldt-Jakob disease (CJD), scrapie, and bovine spongiform encephalopathy because they express high levels of normal and pathological prion protein (PrP). However, isolated brain cell types have not been evaluated for either infection or gene expression. Microglia purified from CJD-infected mice showed infectivity comparable to that of starting brain homogenate but expressed
50-fold less PrP. CJD-infected microglia also displayed morphological changes indicative of cellular activation. To determine the molecular pathways of activation, we evaluated pertinent transcripts, including those linked to inflammation. Semiquantitative reverse transcription-PCR showed a >4-fold increase in cathepsin S, an enzyme important in antigen presentation, the cytokine interleukin-1ß, and the chemokine B-lymphocyte chemoattractant. The profile of microglial changes induced by the CJD agent differed substantially from activation induced by bacterial lipopolysaccharide or by ß-amyloid, a structure comparable to pathological PrP. These microglial studies emphasize migratory hematopoietic cells in the dispersion, and possibly replication, of the CJD agent. The low PrP levels in these highly infectious and activated cells further support the concept that pathological PrP is the result of infection rather than the infectious agent itself. Because microglia develop a specific pattern of responses to the CJD agent, microglial markers may be exploited in the diagnosis of these spongiform encephalopathies.
* Corresponding author. Mailing address: Section of Neuropathology, Yale University School of Medicine, 333 Cedar St., FMB 11, New Haven, CT 06510. Phone: (203) 785-4442. Fax: (203) 785-6381. E-mail: laura.manuelidis{at}yale.edu.
Journal of Virology, November 2002, p. 10905-10913, Vol. 76, No. 21
0022-538X/02/$04.00+0 DOI: 10.1128/JVI.76.21.10905-10913.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.
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Copyright © 2002 by the American Society for Microbiology. All rights reserved.