Chronic Subclinical Prion Disease Induced by Low-Dose Inoculum

Abstract

We have compared the transmission characteristics of the two mouse-adapted scrapie isolates, ME7 and Rocky Mountain Laboratory (RML), in tga20 mice. These mice express elevated levels of PrP protein compared to wild-type mice and display a relatively short disease incubation period following intracerebral prion inoculation. Terminal prion disease in tga20 mice induced by ME7 or RML was characterized by a distinct pattern of clinical signs and different incubation times. High-dose RML inoculated intracerebrally into tga20 mice induced the most rapid onset of clinical signs, with mice succumbing to terminal disease after only 58 ؎ 3 days. In contrast, high-dose ME7 gave a mean time to terminal disease of 74 ؎ 0 days. Histological examination of brain sections from prion-inoculated tga20 mice at terminal disease showed that ME7 gave rise to a more general and extensive pattern of vacuolation than RML. Low-dose inoculum failed to induce terminal disease but did cause preclinical symptoms, including the appearance of reversible clinical signs. Some mice oscillated between showing no clinical signs and early clinical signs for many months but never progressed to terminal disease. Brain tissue from these mice with chronic subclinical prion disease, sacrificed at >200 days postinoculation, contained high levels of infectivity and showed the presence of PrP Sc . Parallel analysis of brain tissue from mice with terminal disease showed similar levels of infectivity and detectable PrP Sc . These results show that high levels of infectivity and the presence of the abnormal isomer of PrP can be detected in mice with subclinical disease following low-dose prion inoculation.

Formation of native prions from minimal components in vitro

“…Although less likely, it is also possible that normal hamsters have low levels of endogenous PrP Sc molecules in their brains. Previous experiments have shown that PrP Sc molecules can persist chronically in animals without causing disease (51)(52)(53). In this scenario, the rate of endogenous PrP Sc production in normal animals might be balanced by a putative clearance mechanism, preventing accumulation.…”

Conservation of a Glycine-rich Region in the Prion Protein Is Required for Uptake of Prion Infectivity

“…G125A-inoculated mice displayed spongiform change and minor plaque deposition, despite remaining outwardly healthy. It is likely that the prion titer associated with the partially prion-resistant G125A cell line is adequate to lead to infection but insufficient to cause illness within the time frame of the experiment, a condition that may be similar to previously described cases of subclinical prion infection (33,36). Proteinase K digestion of infected brain homogenates reveals the presence of protease-resistant PrP Sc in MoPrP-inoculated mice but none in the brains of mice inoculated with wild-type, G125A, G130L, G130P, or A119P lysate (Fig.…”

Effect of fixation on brain and lymphoreticular vCJD prions and bioassay of key positive specimens from a retrospective vCJD prevalence study

“…While the risk of new dietary exposure to BSE prions in the UK is now remote [9], the majority of the UK population may have been exposed during the late 1980s and early 1990s. While the number of recorded clinical cases (∼200) has been relatively low, and epidemiological modelling argued against a large number of additional cases [10], it is increasingly clear that sub-clinical carrier states of prion infection may occur, particularly on crossing a species barrier and with low-dose exposure [11][12][13][14][15]. Modelling cannot estimate the number of sub-clinically infected carriers, and the discrepancy between numbers of clinical cases and prevalence estimates from 512 JDF Wadsworth et al population screening remains unexplained [16][17][18][19].…”