Human prion protein sequence elements impede cross-species chronic wasting disease transmission

Kurt, Timothy D.; Jiang, Lin; Fernández‐Borges, Natalia; Bett, Cyrus; Li, Jun; Yang, Tom; Spraker, Terry R.; Castilla, Joaquı́n; Eisenberg, David; Kong, Qingzhong; Sigurdson, Christina J.

doi:10.1172/jci82647

Cited by 23 publications

(28 citation statements)

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“…In one study, the impact of creating a human‐elk chimeric PrP was evaluated (Kurt et al., ). The chimeric PrP was more susceptible to elk and deer CWD prions, but was concurrently less susceptible to human CJD prions (Kurt et al., ). This is consistent with known determinants of inter‐species prion conversion, including PrP C and PrP Sc sequence similarity and the conformation of the infectious prion.…”

Section: Resultssupporting

confidence: 65%

“…The low risk of bias and the consistency of the research conclusions across these studies, despite the use of different lines of transgenic mice, gives this group of studies a *** GRADE indicating that we have some confidence the overall conclusions of this research will not change with future research. In one study, the impact of creating a human‐elk chimeric PrP was evaluated (Kurt et al., ). The chimeric PrP was more susceptible to elk and deer CWD prions, but was concurrently less susceptible to human CJD prions (Kurt et al., ).…”

Section: Resultsmentioning

confidence: 99%

“…Authors examined conversion, differences in amino acids and the conformation of the human PrP and CWD prion to explain/predict the efficiency with which a CWD prion could convert human PrP. For example, one study evaluated the effects of four single amino acid differences in the β2‐α2 loop sequence segment of human PrP and found that two specific amino acids had a significant impact on the efficiency of the conversion (Kurt et al., ). This may be due to changes in the conformation of the prion protein, which may be a better indicator of conversion potential than the amino acid sequence alone (Luers et al., ).…”

Section: Resultsmentioning

confidence: 99%

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Current evidence on the transmissibility of chronic wasting disease prions to humans-A systematic review

Waddell

Greig

Mascarenhas

et al. 2017

Transbound Emerg Dis

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SummaryA number of prion diseases affect humans, including Creutzfeldt-Jakob disease; most of these are due to genetic mutations in the affected individual and occur sporadically, but some result from transmission of prion proteins from external sources.Of the known animal prion diseases, only bovine spongiform encephalopathy prions have been shown to be transmissible from animals to humans under non-experimental conditions. Chronic wasting disease (CWD) is a prion disease that affects cervids (e.g., deer and elk) in North America and isolated populations in Korea and Europe. Systematic review methodology was used to identify, select, critically appraise and analyse data from relevant research. Studies were evaluated for adherence to good conduct based on their study design following the Cochrane collaboration's approach to grading the quality of evidence and the strength of recommendations (GRADE). Twenty-three studies were included after screening 800 citations from the literature search and evaluating 78 full papers. Studies examined the transmissibility of CWD prions to humans using epidemiological study design, in vitro and in vivo experiments. Five epidemiological studies, two studies on macaques and seven studies on humanized transgenic mice provided no evidence to support the possibility of transmission of CWD prions to humans. Ongoing surveillance in the United States and Canada has not documented CWD transmission to humans. However, two studies on squirrel monkeys provided evidence that transmission of CWD prions resulting in prion disease is possible in these monkeys under experimental conditions and seven in vitro experiments provided evidence that CWD prions can convert human prion protein to a misfolded state. Therefore, future discovery of CWD transmission to humans cannot be entirely ruled out on the basis of current studies, particularly in the light of possible decades-long incubation periods for CWD prions in humans. It would be prudent to continue CWD research and epidemiologic surveillance, exercise caution when handling potentially contaminated material and explore CWD management opportunities.cervid, chronic wasting disease, prion, systematic review, zoonoticThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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Section: Resultssupporting

confidence: 65%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Current evidence on the transmissibility of chronic wasting disease prions to humans-A systematic review

Waddell

Greig

Mascarenhas

et al. 2017

Transbound Emerg Dis

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“…Recent studies focused on the role of specific structural elements during adaptive transspecies transmissions, particularly the loop connecting PrP β2 and α2 regions (22,23), which is disordered in most species but conformationally defined in others such as elk and bank vole PrP C . Although β2-α2 loop rigidity was thought to potentiate PrP C to PrP Sc conversion (24), subsequent studies revealed that PrP C of species considered resistant to prions, including horses, also contained rigid β2-α2 loops (25)(26)(27).…”

Section: Significancementioning

confidence: 99%

Prion replication without host adaptation during interspecies transmissions

Bian

Khaychuk

Angers

et al. 2017

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

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Adaptation of prions to new species is thought to reflect the capacity of the host-encoded cellular form of the prion protein (PrPC) to selectively propagate optimized prion conformations from larger ensembles generated in the species of origin. Here we describe an alternate replicative process, termed nonadaptive prion amplification (NAPA), in which dominant conformers bypass this requirement during particular interspecies transmissions. To model susceptibility of horses to prions, we produced transgenic (Tg) mice expressing cognate PrPC. Although disease transmission to only a subset of infected TgEq indicated a significant barrier to EqPrPCconversion, the resulting horse prions unexpectedly failed to cause disease upon further passage to TgEq. TgD expressing deer PrPCwas similarly refractory to deer prions from diseased TgD infected with mink prions. In both cases, the resulting prions transmitted to mice expressing PrPCfrom the species of prion origin, demonstrating that transmission barrier eradication of the originating prions was ephemeral and adaptation superficial in TgEq and TgD. Horse prions produced in vitro by protein misfolding cyclic amplification of mouse prions using horse PrPCalso failed to infect TgEq but retained tropism for wild-type mice. Concordant patterns of neuropathology and prion deposition in susceptible mice infected with NAPA prions and the corresponding prion of origin confirmed preservation of strain properties. The comparable responses of both prion types to guanidine hydrochloride denaturation indicated this occurs because NAPA precludes selection of novel prion conformations. Our findings provide insights into mechanisms regulating interspecies prion transmission and a framework to reconcile puzzling epidemiological features of certain prion disorders.

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“…For the transmission of GSS in bank voles, the peculiar features of the vole PrP amino acid sequence might have been one of these factors. It has been found that the presence of asparagines in or near the β2-α2 loop might create a permissive PrP sequence able to overcome some species barriers, 42 and that recombinant vole PrP with methionine at residue 109 is an apparently universal substrate for RT-QuIC-based in vitro replication of disease-linked PrP Sc isoforms 38 . However, ongoing studies in bank voles carrying methionine instead of isoleucine at residue 109 of PrP (Bv109M) show that, at variance with Bv109I, Bv109M are rather resistant to GSS with 8 kDa PrP res (unpublished data).…”

Section: The Elusive Nature Of the Experimental Transmissibility Of Gssmentioning

confidence: 99%

Transmissibility of Gerstmann–Sträussler–Scheinker syndrome in rodent models: New insights into the molecular underpinnings of prion infectivity

Nonno

Bari

Agrimi

et al. 2016

Prion

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Prion diseases, or transmissible spongiform encephalopathies, have revealed the bewildering phenomenon of transmissibility in neurodegenerative diseases. Hence, the experimental transmissibility of prion-like neurodegenerative diseases via template directed misfolding has become the focus of intense research. Gerstmann-Sträussler-Scheinker disease (GSS) is an inherited prion disease associated with mutations in the prion protein gene. However, with the exception of a few GSS cases with P102L mutation characterized by co-accumulation of protease-resistant PrP core (PrPres) of ∼21 kDa, attempts to transmit to rodents GSS associated to atypical misfolded prion protein with ∼8 kDa PrPres have been unsuccessful. As a result, these GSS subtypes have often been considered as non-transmissible proteinopathies rather than true prion diseases. In a recent study we inoculated bank voles with GSS cases associated with P102L, A117V and F198S mutations and found that they transmitted efficiently and produced distinct pathological phenotypes, irrespective of the presence of 21 kDa PrPres in the inoculum. This study demonstrates that GSS is a genuine prion disease characterized by both transmissibility and strain variation. We discuss the implications of these findings for the understanding of the heterogeneous clinic-pathological phenotypes of GSS and of the molecular underpinnings of prion infectivity.

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Human prion protein sequence elements impede cross-species chronic wasting disease transmission

Abstract: A r t i c l e A m e n d m e n t s2 5The label for Figure 1E misidentified the prion inoculum administered to the mice depicted. The correct label is below. CJD-inoculatedThe JCI regrets the error.

Cited by 23 publications

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Current evidence on the transmissibility of chronic wasting disease prions to humans-A systematic review

Current evidence on the transmissibility of chronic wasting disease prions to humans-A systematic review

Prion replication without host adaptation during interspecies transmissions

Transmissibility of Gerstmann–Sträussler–Scheinker syndrome in rodent models: New insights into the molecular underpinnings of prion infectivity

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