Comparative analysis of prions in nervous and lymphoid tissues of chronic wasting disease-infected cervids

Davenport, Kristen A.; Christiansen, Jeffrey R.; Bian, Jifeng; Young, Michael C.; Gallegos, Joseph; Kim, Sehun; Balachandran, Aru; Mathiason, Candace K.; Hoover, Edward A.; Telling, Glenn C.

doi:10.1099/jgv.0.001053

Cited by 18 publications

(27 citation statements)

References 44 publications

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“…This implies that saliva plays a greater role in horizontal transmission of CWD and environmental contamination than other excreta and body fluids. Nevertheless, our previous investigations found inconsistent detection of saliva prions throughout the course of disease (13,51). Despite our improved PMCA method, we were still unable to detect prions in two samples.…”

Section: Discussionmentioning

confidence: 60%

Modified Protein Misfolding Cyclic Amplification Overcomes Real-Time Quaking-Induced Conversion Assay Inhibitors in Deer Saliva To Detect Chronic Wasting Disease Prions

et al. 2018

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Chronic wasting disease (CWD), a fatal neurodegenerative prion disease of cervids, has spread across North America and has been detected in The Republic of Korea, Finland, and Norway. CWD appears to spread by horizontal transmission, and prions shed in saliva, feces, and urine are thought to contribute. However, studies investigating the rapid spread of CWD have been hampered by assay inhibitors and a lack of consistent and sensitive means to detect the relatively low levels of prions in these samples. Here we show that saliva frequently contains an inhibitor of the real-time quaking-induced conversion assay (RT-QuIC) and that the inhibitor is a member of the mucin family. To circumvent the inhibitor, we developed a modified protein misfolding cyclic amplification (PMCA) method to amplify CWD prions in saliva that were undetectable or ambiguous by RT-QuIC. Our results reinforce the impact of saliva in horizontal CWD transmission and highlight the importance of detection optimization.

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Section: Discussionmentioning

confidence: 60%

Modified Protein Misfolding Cyclic Amplification Overcomes Real-Time Quaking-Induced Conversion Assay Inhibitors in Deer Saliva To Detect Chronic Wasting Disease Prions

et al. 2018

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“…Going forward, additional longitudinal studies on living animals using both assays are likely the most practical way to help address assay agreement issues. Likewise, bioassays or cervid cell panel in vitro infection assays [35] on such RT-QuIC+/IHC-samples will also be valuable. Continued improvements in RT-QuIC methodology, enrichment protocols [36,37], and multi-laboratory confirmation assays on blinded sample panels will advance the use of amplification assays in CWD detection.…”

Section: Discussionmentioning

confidence: 99%

Progression of chronic wasting disease in white-tailed deer analyzed by serial biopsy RT-QuIC and immunohistochemistry

et al. 2020

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Chronic wasting disease (CWD) continues to spread or be recognized in the United States, Canada, and Europe. CWD is diagnosed by demonstration of the causative misfolded prion protein (PrP CWD) in either brain or lymphoid tissue using immunodetection methods, with immunohistochemistry (IHC) recognized as the gold standard. In recent years, in vitro amplification assays have been developed that can detect CWD prion seeding activity in tissues, excreta, and body fluids of affected cervids. These methods potentially offer earlier and more facile detection of CWD, both pre-and post-mortem. Here we provide a longitudinal profile of CWD infection progression, as assessed by both real-time quaking-induced conversion (RT-QuIC) and IHC on serial biopsies of mucosal lymphoid tissues of white-tailed deer orally exposed to low doses of CWD prions. We report that detection of CWD infection by RT-QuIC preceded that by IHC in both tonsil and recto-anal lymphoid tissue (RAMALT) in 14 of 19 deer (74%). Of the 322 biopsy samples collected in post-exposure longitudinal monitoring, positive RT-QuIC results were obtained for 146 samples, 91 of which (62%) were concurrently also IHC-positive. The lower frequency of IHC positivity was manifest most in the earlier post-exposure periods and in biopsies in which lymphoid follicles were not detected. For all deer in which RT-QuIC seeding activity was detected in a tonsil or RAMALT biopsy, PrP CWD was subsequently or concurrently detected by IHC. Overall, this study (a) provides a longitudinal profile of CWD infection in deer after low yet infectious oral prion exposure; (b) illustrates the value of RT-QuIC for sensitive detection of CWD; and (c) demonstrates an ultimate high degree of correlation between RT-QuIC and IHC positivity as CWD infection progresses.

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“…Chronic wasting disease (CWD), a burgeoning epidemic of deer, elk, and other cervids is of particular concern (2). The unparalleled efficiency of its contagious transmission in wild as well as captive animals (3, 4) is related not only to extensive peripheralization and shedding of CWD prions during infection (5), but also to their seemingly unlimited environmental persistence (6). Both the geographic range of CWD and the number of naturally susceptible host species continue to increase.…”

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confidence: 99%

Primary structural differences at residue 226 of deer and elk PrP dictate selection of distinct CWD prion strains in gene-targeted mice

Bian

Christiansen

Moreno

et al. 2019

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

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Although the unifying hallmark of prion diseases is CNS neurodegeneration caused by conformational corruption of host prion protein (PrP) to its infective counterpart, contagious transmission of chronic wasting disease (CWD) results from shedding of prions produced at high titers in the periphery of diseased cervids. While deer and elk PrP primary structures are equivalent except at residue 226, which is glutamate in elk and glutamine in deer, the effect of this difference on CWD pathogenesis is largely unknown. Using a gene-targeting approach where the mouse PrP coding sequence was replaced with elk or deer PrP, we show that the resulting GtE226 and GtQ226 mice had distinct kinetics of disease onset, prion conformations, and distributions of prions in the brains of diseased mice following intracerebral CWD challenge. These findings indicate that amino acid differences at PrP residue 226 dictate the selection and propagation of divergent strains in deer and elk with CWD. Because prion strain properties largely dictate host-range potential, our findings suggest that prion strains from elk and deer pose distinct risks to sympatric species or humans exposed to CWD. GtE226 and GtQ226 mice were also highly susceptible to CWD prions following intraperitoneal and oral exposures, a characteristic that stood in stark contrast to previously produced transgenic models. Remarkably, disease transmission was effective when infected mice were cohoused with naïve cagemates. Our findings indicate that gene-targeted mice provide unprecedented opportunities to accurately investigate CWD peripheral pathogenesis, CWD strains, and mechanisms of horizontal CWD transmission.

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Comparative analysis of prions in nervous and lymphoid tissues of chronic wasting disease-infected cervids

Cited by 18 publications

References 44 publications

Modified Protein Misfolding Cyclic Amplification Overcomes Real-Time Quaking-Induced Conversion Assay Inhibitors in Deer Saliva To Detect Chronic Wasting Disease Prions

Modified Protein Misfolding Cyclic Amplification Overcomes Real-Time Quaking-Induced Conversion Assay Inhibitors in Deer Saliva To Detect Chronic Wasting Disease Prions

Progression of chronic wasting disease in white-tailed deer analyzed by serial biopsy RT-QuIC and immunohistochemistry

Primary structural differences at residue 226 of deer and elk PrP dictate selection of distinct CWD prion strains in gene-targeted mice

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