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Experimental verification of a traceback phenomenon in prion infection


Kobayashi, A; Sakuma, N; Matsuura, Y; Mohri, S; Aguzzi, A; Kitamoto, T (2010). Experimental verification of a traceback phenomenon in prion infection. Journal of Virology, 84(7):3230-3238.

Abstract

The clinicopathological phenotypes of sporadic Creutzfeldt-Jakob disease (sCJD) correlate with the allelotypes (M or V) of the polymorphic codon 129 of the human prion protein (PrP) gene and the electrophoretic mobility patterns of abnormal prion protein (PrP(Sc)). Transmission of sCJD prions to mice expressing human PrP with a heterologous genotype (referred to as cross-sequence transmission) results in prolonged incubation periods. We previously reported that cross-sequence transmission can generate a new prion strain with unique transmissibility designated as a traceback phenomenon. To verify experimentally the traceback of sCJD-VV2 prions, we inoculated sCJD-VV2 prions into mice expressing human PrP with the 129M/M genotype. These 129M/M mice showed altered neuropathology and a novel PrP(Sc) type after a long incubation period. We then passaged the brain homogenate from the 129M/M mouse inoculated with sCJD-VV2 prions into further 129M/M or 129V/V mice. Despite cross-sequence transmission, 129V/V mice were highly susceptible to these prions compared to the 129M/M mice. The neuropathology and PrP(Sc) type of the 129V/V mice inoculated with the 129M/M mouse-passaged sCJD-VV2 prions were identical to those of the 129V/V mice inoculated with sCJD-VV2 prions. Moreover, we generated for the first time type 2 PrP(Sc)-specific antibody in addition to type 1 PrP(Sc)-specific antibody and discovered that drastic changes in the PrP(Sc) subpopulation underlie the traceback phenomenon. Here we report the first direct evidence of the traceback in prion infection.

The clinicopathological phenotypes of sporadic Creutzfeldt-Jakob disease (sCJD) correlate with the allelotypes (M or V) of the polymorphic codon 129 of the human prion protein (PrP) gene and the electrophoretic mobility patterns of abnormal prion protein (PrP(Sc)). Transmission of sCJD prions to mice expressing human PrP with a heterologous genotype (referred to as cross-sequence transmission) results in prolonged incubation periods. We previously reported that cross-sequence transmission can generate a new prion strain with unique transmissibility designated as a traceback phenomenon. To verify experimentally the traceback of sCJD-VV2 prions, we inoculated sCJD-VV2 prions into mice expressing human PrP with the 129M/M genotype. These 129M/M mice showed altered neuropathology and a novel PrP(Sc) type after a long incubation period. We then passaged the brain homogenate from the 129M/M mouse inoculated with sCJD-VV2 prions into further 129M/M or 129V/V mice. Despite cross-sequence transmission, 129V/V mice were highly susceptible to these prions compared to the 129M/M mice. The neuropathology and PrP(Sc) type of the 129V/V mice inoculated with the 129M/M mouse-passaged sCJD-VV2 prions were identical to those of the 129V/V mice inoculated with sCJD-VV2 prions. Moreover, we generated for the first time type 2 PrP(Sc)-specific antibody in addition to type 1 PrP(Sc)-specific antibody and discovered that drastic changes in the PrP(Sc) subpopulation underlie the traceback phenomenon. Here we report the first direct evidence of the traceback in prion infection.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2010
Deposited On:21 Mar 2010 08:44
Last Modified:05 Apr 2016 13:50
Publisher:American Society for Microbiology
ISSN:0022-538X
Publisher DOI:10.1128/JVI.02387-09
PubMed ID:20089646
Permanent URL: http://doi.org/10.5167/uzh-28837

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