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Journal of Virology, September 2007, p. 9942-9949, Vol. 81, No. 18
0022-538X/07/$08.00+0     doi:10.1128/JVI.00780-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Fatal Neurological Disease in Scrapie-Infected Mice Induced for Experimental Autoimmune Encephalomyelitis

Yael Friedman-Levi,^1, Haim Ovadia,^1, Romana Hoftberger,^2, Ofira Einstein,¹ Oded Abramsky,¹ Herbert Budka,² and Ruth Gabizon^1*

Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah University Hospital, Jerusalem, Israel,¹ Institute of Neurology, Medical University of Vienna, Vienna, Austria²

Received 11 April 2007/ Accepted 25 June 2007

During the years or decades of prion disease incubation, at-risk individuals are certain to encounter diverse pathological insults, such as viral and bacterial infections, autoimmune diseases, or inflammatory processes. Whether prion disease incubation time and clinical signs or otherwise the pathology of intercurrent diseases can be affected by the coinfection process is unknown. To investigate this possibility, mice infected with the scrapie agent at both high and low titers were subsequently induced for experimental autoimmune encephalomyelitis, an immune system-mediated model of central nervous system (CNS) inflammation. We show here that coinduced mice died from a progressive neurological disease long before control mice succumbed to classical scrapie. To investigate the mechanism of the coinduced syndrome, we evaluated biochemical and pathological markers of both diseases. Brain and spleen PrP^Sc levels in the dying coinduced mice were comparable to those observed in asymptomatic scrapie-infected animals, suggesting that coinduced disease is not an accelerated form of scrapie. In contrast, inflammatory markers, such as demyelination, immune cell infiltrates, and gliosis, were markedly increased in coinduced mouse spinal cords. Activated astrocytes were especially elevated in the medulla oblongata. Furthermore, PrP^sc depositions were found in demyelinated white matter areas in coinduced mouse spinal cords, suggesting the presence of activated infected immune cells that infiltrate into the CNS to facilitate the process of prion neuroinvasion. We hypothesize that inflammatory processes affecting the CNS may have severe clinical implications in subjects incubating prion diseases.

Published ahead of print on 11 July 2007.

Y.F.-L., H.O., and R.H. contributed equally to this work.