Evaluation of the Human Transmission Risk of an Atypical Bovine Spongiform Encephalopathy Prion Strain

Abstract

Bovine spongiform encephalopathy (BSE), the prion disease in cattle, was widely believed to be caused by only one strain, BSE-C. BSE-C causes the fatal prion disease named new variant Creutzfeldt-Jacob disease in humans. Two atypical BSE strains, bovine amyloidotic spongiform encephalopathy (BASE, also named BSE-L) and BSE-H, have been discovered in several countries since 2004; their transmissibility and phenotypes in humans are unknown. We investigated the infectivity and human phenotype of BASE strains by inoculating transgenic (Tg) mice expressing the human prion protein with brain homogenates from two BASE straininfected cattle. Sixty percent of the inoculated Tg mice became infected after 20 to 22 months of incubation, a transmission rate higher than those reported for BSE-C. A quarter of BASE strain-infected Tg mice, but none of the Tg mice infected with prions causing a sporadic human prion disease, showed the presence of pathogenic prion protein isoforms in the spleen, indicating that the BASE prion is intrinsically lymphotropic. The pathological prion protein isoforms in BASE strain-infected humanized Tg mouse brains are different from those from the original cattle BASE or sporadic human prion disease. Minimal brain spongiosis and long incubation times are observed for the BASE strain-infected Tg mice. These results suggest that in humans, the BASE strain is a more virulent BSE strain and likely lymphotropic.

Scientific Opinion on BSE risk in bovine intestines and mesentery

“…In addition, studies carried out in transgenic mice that express the human PrP (Beringue et al, 2008;Kong et al, 2008;Padilla et al, 2011) and in cynomolgus monkeys (Macaca fascicularis) (Comoy et al, 2008) all concurred to indicate that L-BSE may be more virulent to humans than C-BSE.…”

Prion agent diversity and species barrier

“…Properties of the BSE agent may be altered on passage in humanized mice, leading to the emergence of a sporadic CJDlike (sCJD) strain [5]. L-type is also transmissible to humanized mice [21,114]. Whereas the H-type is faithfully propagated in PrP VRQ transgenic mice [20], a new strain, converging to BSE appears on transmission of L-type BSE to these mice [21].…”

“…Finally, it is to note that, although more thorough strain phenotype examination will be necessary, L-type BSE exhibits a distinct molecular phenotype as compared to BSE on transmission to transgenic mice expressing human PrP [21,114]. Worryingly, it seems to replicate faster than BSE in these mice [21].…”

Atypical Transmissible Spongiform Encephalopathies in Ruminants: A Challenge for Disease Surveillance and Control

“…The BASE readily transmitted to conventional C57/BL6 mice and to human-PrP, bovine-PrP, and ovine-PrP transgenic mice, as well as to a primate. 20,40,51,112 Interestingly, upon transmission and serial passage in ovine PrP VRQ transgenic mice and C57/BL6 mice, its phenotype shifted toward that observed in classical BSE. This supports the hypothesis that BASE was possibly the origin of the C-BSE epidemic and eventually changed its phenotypic representation upon subpassage in cattle or other hosts.…”

“…Still, the molecular signature in BASE was reported to be reminiscent of some sporadic CJD cases, and upon transmission to human PrP transgenic mice and primates, the BASE agent seemed to replicate more efficiently compared with classical BSE. 20,51,112 It is currently unknown whether tissues other than those defined for C-BSE carry infectivity in BASE or H-BSE. More data are needed from transmission studies or from in-depth analysis of tissues harvested from field cases, where whole carcasses have been available.…”