The PrP gene of the host exerts a major in¯uence over the outcome of transmissible spongiform encephalo-pathy (TSE) disease, but the mechanism by which this is achieved is not understood. We have introduced a speci®c mutation into the endogenous murine PrP gene using gene targeting to produce transgenic mice with a single amino acid alteration (proline to leucine) at amino acid position 101 in their PrP protein (P101L). The effect of this alteration on incubation time, targeting and PrP Sc formation has been studied in TSE-infected animals. Transgenic mice carrying the P101L mutation in PrP have remarkable differences in incubation time and targeting of central nervous system pathology compared with wild-type littermates, following inoculation with infectivity from human, hamster, sheep and murine sources. This single mutation can alter incubation time across three species barriers in a strain-dependent manner. These ®ndings suggest a critical role for the structurally`¯exible structurally`¯exible' region of PrP in agent replication and targeting of TSE pathology. Keywords: P101L PrP/prion diseases/species barrier/ transmissible spongiform encephalopathies/vCJD ã European Molecular Biology Organization 101L PrP and the TSE species barrier
The PrP protein is central to the transmissible spongiform encephalopathies (TSEs), and the amino acid sequence of this protein in the host can influence both incubation time of disease and targeting of disease pathology. The N terminus of murine PrP has been proposed to be important in the replication of TSE agents, as mutations or deletions in that region can alter the efficiency of agent replication. To address this hypothesis and to investigate the mechanisms by which host PrP sequence controls the outcome of disease, we have assessed the influence of a single amino acid alteration in the N-terminal region of murine PrP (P101L) on the transmission of TSE agents between mice. Mice homozygous for the mutation (101LL) were inoculated with TSE strains 139A and 79A derived from mice carrying a Prnp a allele, and 79V and 301V derived from mice carrying a Prnp b allele. Incubation times in 101LL mice were extended with all four strains of agent when compared with those in the corresponding mouse genotype from which the infectivity was derived. However, the degree to which the incubation period was increased showed considerable variation between each strain of agent. Moreover, the presence of this single amino acid alteration resulted in a 70 day reduction in incubation time of the 301V strain in Prnp a mice. The effect of the 101L mutation on murine scrapie incubation time appears therefore to be strain specific.
BackgroundThe identification of transmission of variant Creutzfeldt-Jakob disease (vCJD) by blood transfusion has prompted investigation to establish whether there has been any alteration in the vCJD agent following this route of secondary transmission. Any increase in virulence or host adaptation would require a reassessment of the risk analyses relating to the possibility of a significant secondary outbreak of vCJD. Since there are likely to be carriers of the vCJD agent in the general population, there is a potential for further infection by routes such as blood transfusion or contaminated surgical instruments.MethodologyWe inoculated both wild-type and transgenic mice with material from the first case of transfusion associated vCJD infection.Principal FindingsThe strain transmission properties of blood transfusion associated vCJD infection show remarkable similarities to the strain of vCJD associated with transmission from bovine spongiform encephalopathy (BSE).ConclusionsAlthough it has been hypothesized that adaptation of the BSE agent through secondary passage in humans may result in a greater risk of onward transmission due to an increased virulence of the agent for humans, our data presented here in two murine models suggest no significant alterations to transmission efficiency of the agent following human-to-human transmission of vCJD.
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