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Journal of Virology, June 2000, p. 5432-5440, Vol. 74, No. 12
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Opposite Effects of Dextran Sulfate 500, the Polyene Antibiotic MS-8209, and Congo Red on Accumulation of the Protease-Resistant Isoform of PrP in the Spleens of Mice Inoculated Intraperitoneally with the Scrapie Agent

Vincent Beringue,1,* Karim T. Adjou,1 François Lamoury,1 Thomas Maignien,1 Jean-Philippe Deslys,1 Richard Race,2 and Dominique Dormont1

CEA, Service de Neurovirologie, DRM/DSV, CRSSA, Fontenay aux Roses, France,1 and Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana2

Received 20 December 1999/Accepted 21 March 2000

The mode and the site of action of the major antiscrapie drugs have been studied by investigating their effects on the abnormal protease-resistant isoform of PrP (PrPres) and on its accumulation in mouse spleen. Day-by-day PrPres accumulation in the spleen and in other peripheral organs was first monitored to describe the early steps of scrapie pathogenesis. Three phases were identified: the detection of scrapie inoculum on the day of scrapie infection, a clearance phase, and then the peripheral accumulation of PrPres. In a second step, the effects of the polyene antibiotic MS-8209, the polyanion dextran sulfate 500 (DS500), and Congo red were assessed on these phases, after the drugs were coincubated with scrapie inoculum. Highly different mechanisms and sites of action were apparent. MS-8209 had a weak effect on the accumulation of PrPres in spleen, suggesting another site of intervention for this drug. DS500 delayed the beginning of the clearance phase but then blocked PrPres synthesis for a long period of time, probably because of its immunological effects on the spleen. Surprisingly, Congo red suppressed the clearance phase of scrapie inoculum and then increased transiently accumulation of PrPres in spleen. We showed in vitro that this effect was related to a direct enhancement of the protease resistance of PrPres by the drug.

* Corresponding author. Present address: Neuroimmunology Group/Department of Neurogenetics, Imperial College School of Medicine at St Mary's, Norfolk Place, London W2 1PG, United Kingdom. Phone: 44 171 594 3825. Fax: 44 171 706 3272. E-mail: v.beringue{at}ic.ac.uk.

Journal of Virology, June 2000, p. 5432-5440, Vol. 74, No. 12
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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