High Titers of Transmissible Spongiform Encephalopathy Infectivity Associated with Extremely Low Levels of PrPSc in Vivo

Barron, Rona; Campbell, Susan L.; King, Declan; Bellon, Alfredo; Chapman, Karen; Williamson, R. Anthony; Manson, Jean

doi:10.1074/jbc.m704329200

Cited by 150 publications

(120 citation statements)

References 42 publications

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“…Other recent in vitro experiments support the concept that different PrP conversion pathways can result in differences in both infectivity and in vitro amyloid formation (39). Further evidence for extensive variation in the quantitative correlation between PrPres and infectivity in brain has also been noted previously by others (40,41). Together all these findings support the conclusion that measurement of PrPres from PMCA or in vivo tissue sources is not a reliable quantitative marker for prion infectivity.…”

Section: Discussionsupporting

confidence: 77%

Lower specific infectivity of protease-resistant prion protein generated in cell-free reactions

Klingeborn

Race

Meade-White

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Prions are unconventional infectious agents that cause transmissible spongiform encephalopathy (TSE) diseases, or prion diseases. The biochemical nature of the prion infectious agent remains unclear. Previously, using a protein misfolding cyclic amplification (PMCA) reaction, infectivity and disease-associated protease-resistant prion protein (PrPres) were both generated under cell-free conditions, which supported a nonviral hypothesis for the agent. However, these studies lacked comparative quantitation of both infectivity titers and PrPres, which is important both for biological comparison with in vivo-derived infectivity and for excluding contamination to explain the results. Here during four to eight rounds of PMCA, end-point dilution titrations detected a >320-fold increase in infectivity versus that in controls. These results provide strong support for the hypothesis that the agent of prion infectivity is not a virus. PMCA-generated samples caused the same clinical disease and neuropathology with the same rapid incubation period as the input brain-derived scrapie samples, providing no evidence for generation of a new strain in PMCA. However, the ratio of the infectivity titer to the amount of PrPres (specific infectivity) was much lower in PMCA versus brain-derived samples, suggesting the possibility that a substantial portion of PrPres generated in PMCA might be noninfectious.Creutzfeldt-Jakob disease | amyloid | neurodegeneration | protein polymerization | protein aggregation

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Section: Discussionsupporting

confidence: 77%

Lower specific infectivity of protease-resistant prion protein generated in cell-free reactions

Klingeborn

Race

Meade-White

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…It is nevertheless possible that limited muscle sampling and methodological insensitivity could fail to detect the irregular distribution of low levels of PrP TSE in muscle. Moreover, the absence of PrP TSE does not necessarily imply absence of infectivity (Barron et al, 2007;Berardi et al, 2006;Lasmézas et al, 1997). A more thorough examination of entire muscle groups using the ultrasensitive proteinmisfolding cyclic-amplification technique (Soto et al, 2005) might yield a positive result, but would need to be verified by infectivity bioassay before inferring a risk of disease transmission.…”

mentioning

confidence: 99%

PrPTSE in muscle-associated lymphatic tissue during the preclinical stage of mice infected orally with bovine spongiform encephalopathy

Cardone

Thomzig

Schulz‐Schaeffer

et al. 2009

Journal of General Virology

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The involvement of muscles in the pathogenesis of transmissible spongiform encephalopathies (TSEs) is irregular and unpredictable. We show that the TSE-specific protein (PrP TSE ) is present in muscles of mice fed with a mouse-adapted strain of bovine spongiform encephalopathy as early as 100 days post-infection, corresponding to about one-third of the incubation period. The proportion of mice with PrP TSE -positive muscles and the number of muscles involved increased as infection progressed, but never attained more than a limited distribution, even at the clinical stage of disease. The appearance of PrP TSE in muscles during the preclinical stage of disease was probably due to the haematogenous/lymphatic spread of infectivity from the gastrointestinal tract to lymphatic tissues associated with muscles, whereas in symptomatic animals, the presence of PrP TSE in the nervous system, in neuromuscular junctions and in muscle fibres suggests a centrifugal spread from the central nervous system, as already observed in other TSE models.

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“…18,19 In particular, Barron and coworkers demonstrated that tissues with very low levels of PK-resistant PrP Sc could be highly infective. 20 In this regard, the expression of scFvD18 could have hampered the formation of PK-resistant PrP Sc without interfering with an alternative PK-sensitive PrP Sc isoform.…”

Section: Distribution Of Aav9 In the Cnsmentioning

confidence: 99%

Brain delivery of AAV9 expressing an anti-PrP monovalent antibody delays prion disease in mice

Moda

Vimercati

Campagnani

et al. 2012

Prion

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High Titers of Transmissible Spongiform Encephalopathy Infectivity Associated with Extremely Low Levels of PrPSc in Vivo

Abstract: Diagnosis of transmissible spongiform encephalopathy (TSE) disease in humans and

Cited by 150 publications

References 42 publications

Lower specific infectivity of protease-resistant prion protein generated in cell-free reactions

Lower specific infectivity of protease-resistant prion protein generated in cell-free reactions

PrPTSE in muscle-associated lymphatic tissue during the preclinical stage of mice infected orally with bovine spongiform encephalopathy

Brain delivery of AAV9 expressing an anti-PrP monovalent antibody delays prion disease in mice

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