Abstract
BackgroundTwo distinct forms of atypical spongiform encephalopathies (H-BSE and L-BSE) have recently been identified in cattle. Transmission studies in several wild-type or transgenic mouse models showed that these forms were associated with two distinct major strains of infectious agents, which also differed from the unique strain that had been isolated from cases of classical BSE during the food-borne epizootic disease.Methodology/Principal FindingsH-BSE was monitored during three serial passages in C57BL/6 mice. On second passage, most of the inoculated mice showed molecular features of the abnormal prion protein (PrPd) and brain lesions similar to those observed at first passage, but clearly distinct from those of classical BSE in this mouse model. These features were similarly maintained during a third passage. However, on second passage, some of the mice exhibited distinctly different molecular and lesion characteristics, reminiscent of classical BSE in C57Bl/6 mice. These similarities were confirmed on third passage from such mice, for which the same survival time was also observed as with classical BSE adapted to C57Bl/6 mice. Lymphotropism was rarely detected in mice with H-BSE features. In contrast, PrPd was detectable, on third passage, in the spleens of most mice exhibiting classical BSE features, the pattern being indistinguishable from that found in C57Bl/6 mice infected with classical BSE.Conclusion/SignificanceOur data demonstrate the emergence of a prion strain with features similar to classical BSE during serial passages of H-BSE in wild-type mice. Such findings might help to explain the origin of the classical BSE epizootic disease, which could have originated from a putatively sporadic form of BSE.
Highlights
The unique features of the transmissible agent involved in the food-borne epizootic disease of bovine spongiform encephalopathy (BSE), namely the incubation periods of the disease, the distribution and features of the neuropathological lesions, as well as the molecular features of the disease-associated prion protein (PrPd), have been characterized following transmission studies in inbred wild-type mice [1,2,3,4]
BSE epizootic disease in Europe since the 1980’s, (ii) H-type BSE (H-BSE), which is an uncommon type originally described in France [13] and (iii) L-type BSE (L-BSE), known as bovine amyloidotic spongiform encephalopathy (BASE), a rare form of BSE first identified in Italy [12]
Primary transmission of two H-BSE isolates (01-2604 and 032095) was previously reported in C57Bl/6 mice, which showed the same molecular features of the protease-resistant prion protein (PrPres) in Western blot as initially described in cattle. These features were a,1.5 kDa higher apparent molecular mass of the three PrPres glycoforms compared to that found in mice infected with a classical BSE isolate, associated with strong labeling by the 12B2 antibody in H-BSE but not in classical BSE (Figure 1A and B, lanes 1 and 5)[27]
Summary
The unique features of the transmissible agent involved in the food-borne epizootic disease of bovine spongiform encephalopathy (BSE), namely the incubation periods of the disease, the distribution and features of the neuropathological lesions, as well as the molecular features of the disease-associated prion protein (PrPd), have been characterized following transmission studies in inbred wild-type mice [1,2,3,4]. H- and L-BSE differ notably from classical BSE by the respectively higher or lower apparent molecular mass of unglycosylated PrPres observed in Western blot [15] These two diseases have been recognized in other European countries [15], Japan [16] and North America [17,18], and are suspected to represent sporadic forms of prion diseases, as are most cases of Creutzfeldt-Jakob disease in humans [11,19]. Transmission studies in several wild-type or transgenic mouse models showed that these forms were associated with two distinct major strains of infectious agents, which differed from the unique strain that had been isolated from cases of classical BSE during the food-borne epizootic disease
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