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J. Biol. Chem., Vol. 282, Issue 49, 35878-35886, December 7, 2007

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High Titers of Transmissible Spongiform Encephalopathy Infectivity Associated with Extremely Low Levels of PrP^Sc in Vivo^*

Rona M. Barron¹², Susan L. Campbell¹³, Declan King, Anne Bellon, Karen E. Chapman^¶, R. Anthony Williamson, and Jean C. Manson

From the Neuropathogenesis Unit, Roslin Institute, Ogston Building, West Mains Road, Edinburgh EH9 3JF, Scotland, United Kingdom, the Department of Immunology, Scripps Research Institute, La Jolla, California 92037, and the ^¶Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, United Kingdom

Diagnosis of transmissible spongiform encephalopathy (TSE) disease in humans and ruminants relies on the detection in post-mortem brain tissue of the protease-resistant form of the host glycoprotein PrP. The presence of this abnormal isoform (PrP^Sc) in tissues is taken as indicative of the presence of TSE infectivity. Here we demonstrate conclusively that high titers of TSE infectivity can be present in brain tissue of animals that show clinical and vacuolar signs of TSE disease but contain low or undetectable levels of PrP^Sc. This work questions the correlation between PrP^Sc level and the titer of infectivity and shows that tissues containing little or no proteinase K-resistant PrP can be infectious and harbor high titers of TSE infectivity. Reliance on protease-resistant PrP^Sc as a sole measure of infectivity may therefore in some instances significantly underestimate biological properties of diagnostic samples, thereby undermining efforts to contain and eradicate TSEs.

Received for publication, May 25, 2007 , and in revised form, September 24, 2007.

^* This work was supported by United Kingdom Department for Environment, Food, and Rural Affairs Grant SE1437. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3 and Table S1.

¹ Both authors contributed equally to this work.

³ Current address: Medical Research Council Clinical Sciences Centre, Imperial College, Hammersmith Campus, Du Cane Road, London W12 0NN, United Kingdom.

² To whom correspondence should be addressed. Tel.: 44-131-667-5204; Fax: 44-131-668-3872; E-mail: rona.barron{at}bbsrc.ac.uk.

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