Absence of Evidence for a Causal Link between Bovine Spongiform Encephalopathy Strain Variant L-BSE and Known Forms of Sporadic Creutzfeldt-Jakob Disease in Human PrP Transgenic Mice

Abstract

Prions are proteinaceous pathogens responsible for subacute spongiform encephalopathies in animals and humans. The prions responsible for bovine spongiform encephalopathy (BSE) are zoonotic agents, causing variant Creutzfeldt-Jakob disease (CJD) in humans. The transfer of prions between species is limited by a species barrier, which is thought to reflect structural incompatibilities between the host cellular prion protein (PrP C ) and the infecting pathological PrP assemblies (PrP Sc ) constituting the prion. A BSE strain variant, designated L-BSE and responsible for atypical, supposedly spontaneous forms of prion diseases in aged cattle, demonstrates zoonotic potential, as evidenced by its capacity to propagate more easily than classical BSE in transgenic mice expressing human PrP C and in nonhuman primates. In humanized mice, L-BSE propagates without any apparent species barrier and shares similar biochemical PrP Sc signatures with the CJD subtype designated MM2-cortical, thus opening the possibility that certain CJD cases classified as sporadic may actually originate from L-type BSE cross-transmission. To address this issue, we compared the biological properties of L-BSE and those of a panel of CJD subtypes representative of the human prion strain diversity using standard strain-typing criteria in human PrP transgenic mice. We found no evidence that L-BSE causes a known form of sporadic CJD. IMPORTANCESince the quasi-extinction of classical BSE, atypical BSE forms are the sole BSE variants circulating in cattle worldwide. They are observed in rare cases of old cattle, making them difficult to detect. Extrapolation of our results suggests that L-BSE may propagate in humans as an unrecognized form of CJD, and we urge both the continued utilization of precautionary measures to eliminate these agents from the human food chain and active surveillance for CJD phenotypes in the general population. P rions are pathogens formed from abnormally folded assemblies (PrP Sc ) of the host-encoded prion protein PrP C . Upon infection, they self-replicate by converting host PrP C into PrP Sc assemblies (1). Within defined host species, PrP C can transconform into multiple strains differing in their PrP Sc conformations and in their biological properties in tissues from reporter animals or in cell lines (2-6).In humans, prions can form sporadically and induce Creutzfeldt-Jakob disease (CJD), mainly in elderly people. The worldwide incidence of sporadic CJD (sCJD) ranges from one to two cases per million people per year (7). Evaluation of both the PrP Sc electrophoretic pattern after proteinase K treatment and the methionine/valine polymorphism at codon 129 of the gene encoding PrP allows the definition of multiple sCJD molecular subtypes, which exhibit specific clinical and neuropathological features (8-10). The most common form of sCJD is associated with the presence of type 1 (T1) protease-resistant PrP Sc (PrP res ) and methionine homozygosity (MM) at codon 129. Rare forms of MM sporadic CJD with a type 2 (T2) PrP r...

Recent advances in the histo‐molecular pathology of human prion disease

“…The results of the studies conducted to date with sCJD prions indicate that five of the sCJD subtypes defined by the current classification behave as different prion strains (Figure ). As the only exception, prions associated with VV2 and MV2K shared transmission properties despite the different phenotypic features in the natural host, suggesting a host genotype effect related to PRNP codon 129.…”

“…Specifically, sCJD MM1 and MV1 isolates showed identical transmission properties (M1 strain), which significantly differed from those of sCJD VV2 or MV2K (V2 strain) . Furthermore, sCJD MM2C, MM2T and VV1 isolates generated distinctive transmission properties, suggesting they are caused by specific strains too .…”

“…Some concern in this regard came from the observation that a BSE strain variant, designated L‐BSE, responsible for an atypical phenotype of prion disease in aged cattle, propagated more easily than classical BSE in transgenic mice expressing human PrP C (tgHu) and shared biochemical PrP Sc properties with sCJD M2C prions . However, a recent comparison of the transmission properties in tgHu mice between L‐BSE isolates and a series sCJD cases representative of the human prion strain diversity disclosed no etiological link between L‐BSE and sCJD M2C prions . Specifically, although the two isolates showed similar immunoblot profiles and conformational stabilities of PrP Sc , a shared limited trophism for lymphoid tissue, and a comparable regional profile of PrP Sc deposition, they significantly differed in the disease incubation time over serial passages and in the resistance to PK digestion of PrP Sc aggregates.…”

Animal prion diseases: the risks to human health

“…Transmission of C‐BSE to transgenic mice over‐expressing human 129 MM, 129 VV or 129 MV PrP resulted in low attack rates and long incubation times in 129 MM and apparent absence of transmission of the agent in 129 MV and VV PrP expressing mice (Table ) . Iterative passages of C‐BSE into 129 MM mice led to an increase in the attack rate and a slight reduction of the incubation period, but did not result in disease transmission to 129 MV‐ and 129 VV‐expressing mice . In contrast, vCJD isolates transmitted to all three humanized lines, producing a gradation in transmission efficiency from MM (most efficient) to VV (less efficient) .…”

Les prions, agents d’encéphalopathies transmissibles chez les mammifères

“…Il se propage en effet plus rapidement que l'ESB classique chez le macaque Cynomolgus et sans barrière d'espèce apparente chez la souris transgénique humanisée , Comoy et al, 2008. Dans ce modèle, la typologie de souche observée est différente des cas de MCJ sporadique transmis (Jaumain et al, 2016). La surveillance de ces cas, par nature difficiles à repérer devra donc être poursuivie.…”