Constant transmission properties of variant Creutzfeldt-Jakob disease in 5 countries

Abstract

Variant Creutzfeldt-Jakob disease (vCJD) has been reported in 12 countries. We hypothesized that a common strain of agent is responsible for all vCJD cases, regardless of geographic origin. To test this hypothesis, we inoculated strain-typing panels of wild-type mice with brain material from human vCJD case-patients from France, the Netherlands, Italy, and the United States. Mice were assessed for clinical disease, neuropathologic changes, and glycoform profile; results were compared with those for 2 reference vCJD cases from the United Kingdom. Transmission to mice occurred from each sample tested, and data were similar between non-UK and UK cases, with the exception of the ranking of mean clinical incubation times of mouse lines. These findings support the hypothesis that a single strain of infectious agent is responsible for all vCJD infections. However, differences in incubation times require further subpassage in mice to establish any true differences in strain properties between cases.

Figure 1

Comparison of variant Creutzfeldt-Jakob disease incubation periods from 5 sources in wild-type mice. Data show mean incubation period ± SEM. i.c., intracerebral; i.p., intraperitoneal; UK, United Kingdom.

Figure 2

Lesion profile comparison of variant Creutzfeldt-Jakob disease cases show similarities in vacuolar pathology levels and regional distribution in mouse brains. Wild-type mouse lines RIII (A), C57 (B), and VM (C) are shown. Data show mean lesion profile ± SEM (n>6). G1–G9, gray matter scoring regions: G1, dorsal medulla; G2, cerebellar cortex; G3, superior colliculus; G4, hypothalamus; G5, thalamus; G6, hippocampus; G7, septum; G8, retrosplenial and adjacent motor cortex; G9, cingulate and adjacent motor cortex. W1–W3, white matter scoring regions: W1, cerebellar white matter; W2, mesencephalic tegmentum; W3, pyramidal tract.

Figure 3

Immunohistochemical detection of abnormal prion protein (PrP^Sc) in the hippocampus and thalamus of RIII, C57, and VM wild-type mice after inoculation with variant Creutzfeldt-Jakob disease brain tissue. Scale bars = 500 µm. The anti–prion protein detection antibody used was 6H4.

Figure 4

Western blot analysis of brain extracts from RIII (A) and VM (B) wild-type mice inoculated with variant Creutzfeldt-Jakob disease (vCJD) brain tissue. Lane M, positive control; lane 1, human vCJD brain homogenate (UK origin) showing the typical abnormal prion protein (PrP^Sc) type 2B; lane 2, United Kingdom; lane 3, The Netherlands; lane 4: Italy (cortex); lane 5, Italy (cerebellum); lane 6, France; lane 7, United States; lane 8, human sporadic Creutzfeldt-Jakob disease brain homogenate showing the typical PrP^Sc type 1. Type 2B and 1 differ in mobility of the unglycosylated band (≈19 kDa and ≈20 kDa, respectively). All samples were treated with proteinase K. The anti–prion protein detection antibody used was 6H4.