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Journal of Virology, June 1999, p. 5089-5097, Vol. 73, No. 6
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Microglial Activation Varies in Different Models of Creutzfeldt-Jakob Disease

Christopher A. Baker, Zhi Yun Lu, Igor Zaitsev, and Laura Manuelidis*

Section of Neuropathology, Yale School of Medicine, New Haven, Connecticut 06510

Received 7 December 1998/Accepted 10 March 1999

Progressive changes in host mRNA expression can illuminate crucial pathogenetic pathways in infectious disease. We examined general and specific approaches to mRNA expression in three rodent models of Creutzfeldt-Jakob disease (CJD). Each of these models displays distinctive neuropathology. Although mRNAs for the chemokine receptor CCR5, the lysosomal protease cathepsin S, and the pleiotropic cytokine transforming growth factor beta 1 (TGF-beta 1) were progressively upregulated in rodent CJD, the temporal patterns and peak magnitudes of each of these transcripts varied substantially among models. Cathepsin S and TGF-beta 1 were elevated more than 15-fold in mice and rats infected with two different CJD strains, but not in CJD-infected hamsters. In rats, an early activation of microglial transcripts preceded obvious deposits of prion protein (PrP) amyloid. However, in each of the three CJD models, the upregulation of CCR5, cathepsin S, and TGF-beta 1 was variable with respect to the onset of PrP pathology. These results show glial cell involvement varies as a consequence of the agent strain and species infected. Although neurons are generally assumed to be the primary sites for agent replication and abnormal PrP formation, microglia may be targeted by some agent strains. In such instances, microglia can both process PrP to become amyloid and can enhance neuronal destruction. Because microglia can participate in agent clearance, they may also act as chronic reservoirs of infectivity. Finally, the results here strongly suggest that TGF-beta 1 can be an essential signal for amyloid deposition.

* Corresponding author. Mailing address: Yale School of Medicine, 333 Cedar St., New Haven, CT 06510. Phone: (203) 785-4442. Fax: (203) 785-6381. E-mail: laura.manueldis{at}yale.edu.

Journal of Virology, June 1999, p. 5089-5097, Vol. 73, No. 6
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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