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Antimicrobial Agents and Chemotherapy, November 2007, p. 4141-4147, Vol. 51, No. 11
0066-4804/07/$08.00+0     doi:10.1128/AAC.00524-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Antiprion Activity of Cholesterol Esterification Modulators: a Comparative Study Using Ex Vivo Sheep Fibroblasts and Lymphocytes and Mouse Neuroblastoma Cell Lines{triangledown}

Alessandra Pani,1* Claudia Norfo,2 Claudia Abete,2 Claudia Mulas,2 Marirosa Putzolu,2 Sergio Laconi,2 Christina Doriana Orrù,1 M. Dolores Cannas,1 Sarah Vascellari,1 Paolo La Colla,1 and Sandra Dessì2

General Microbiology and Virology and Microbial Biotechnologies Section,1 Experimental Pathology Section, Department of Biomedical Sciences and Technologies, University of Cagliari, Monserrato, Italy2

Received 20 April 2007/ Returned for modification 15 June 2007/ Accepted 14 August 2007

Our studies on the role of cholesterol homeostasis in the pathogenesis of scrapie revealed abnormal accumulation of cholesterol esters in ex vivo peripheral blood mononuclear cells (PBMCs) and skin fibroblasts from healthy and scrapie-affected sheep carrying a scrapie-susceptible genotype compared to sheep with a resistant genotype. Similar alterations were observed in mouse neuroblastoma N2a cell lines persistently infected with mouse-adapted 22L and RML strains of scrapie that showed up to threefold-higher cholesterol ester levels than parental N2a cells. We now report that proteinase K-resistant prion protein (PrPres)-producing cell populations of subclones from scrapie-infected cell lines were characterized by higher cholesterol ester levels than clone populations not producing PrPres. Treatments with a number of drugs known to interfere with different steps of cholesterol metabolism strongly reduced the accumulation of cholesterol esters in ex vivo PBMCs and skin fibroblasts from scrapie-affected sheep but had significantly less or no effect in their respective scrapie-resistant or uninfected counterparts. In scrapie-infected N2a cells, inhibition of cholesterol esters was associated with selective antiprion activity. Effective antiprion concentrations of cholesterol modulators (50% effective concentration [EC50] range, 1.4 to 40 µM) were comparable to those of antiprion reference compounds (EC50 range, 0.6 to 10 µM). These data confirm our hypothesis that abnormal accumulation of cholesterol esters may represent a biological marker of susceptibility to prion infection/replication and a novel molecular target of potential clinical importance.

* Corresponding author. Mailing address: Università di Cagliari, Dipartimento di Scienze e Tecnologie Biomediche, Cittadella Universitaria, 09042-Monserrato (CA), Italy. Phone: 39070 6754209. Fax: 39070 6754210. E-mail: pania{at}unica.it

{triangledown} Published ahead of print on 20 August 2007.

Antimicrobial Agents and Chemotherapy, November 2007, p. 4141-4147, Vol. 51, No. 11
0066-4804/07/$08.00+0     doi:10.1128/AAC.00524-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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