Wide distribution of prion infectivity in the peripheral tissues of vCJD and sCJD patients

Douet, Jean‐Yves; Huor, Alvina; Cassard, Hervé; Lugan, Séverine; Aron, Naïma; Arnold, Mark; Vilette, Didier; Torres, Juan María; Ironside, James W.; Andréoletti, Olivier

doi:10.1007/s00401-021-02270-x

Cited by 16 publications

(9 citation statements)

References 54 publications

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“…The detection of PrP Sc in blood was also demonstrated in blood samples taken at the presymptomatic stage of vCJD [112]. No such detection of PrP Sc in blood has been described with other human prion diseases, although PMCA has recently detected PrP Sc in widespread peripheral tissues of sCJD patients [148].…”

Section: Peripheral Pathologymentioning

confidence: 97%

“…More recently, the use of the in vitro conversion assay PMCA in the detection of minute quantities of PrP Sc has suggested that the distribution of PrP Sc in both clinical and asymptomatic vCJD cases, and sCJD cases may be more widespread than initially thought [147,148]. While PMCA is not currently included as a diagnostic tool for prion diseases, recent studies have demonstrated that PMCA protocols offer sufficient sensitivity and specificity for the amplification of minute amounts of PrP Sc in biological fluids from vCJD patients including, urine [149], blood [112,113,115] and CSF [150,151].…”

Section: Peripheral Pathologymentioning

confidence: 99%

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Variant CJD: Reflections a Quarter of a Century on

2021

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Twenty-five years has now passed since variant Creutzfeldt-Jakob disease (vCJD) was first described in the United Kingdom (UK). Early epidemiological, neuropathological and biochemical investigations suggested that vCJD represented a new zoonotic form of human prion disease resulting from dietary exposure to the bovine spongiform encephalopathy (BSE) agent. This hypothesis has since been confirmed though a large body of experimental evidence, predominantly using animal models of the disease. Today, the clinical, pathological and biochemical phenotype of vCJD is well characterized and demonstrates a unique and remarkably consistent pattern between individual cases when compared to other human prion diseases. While the numbers of vCJD cases remain reassuringly low, with 178 primary vCJD cases reported in the UK and a further 54 reported worldwide, concerns remain over the possible appearance of new vCJD cases in other genetic cohorts and the numbers of asymptomatic individuals in the population harboring vCJD infectivity. This review will provide a historical perspective on vCJD, examining the origins of this acquired prion disease and its association with BSE. We will investigate the epidemiology of the disease along with the unique clinicopathological and biochemical phenotype associated with vCJD cases. Additionally, this review will examine the impact vCJD has had on public health in the UK and the ongoing concerns raised by this rare group of disorders.

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Section: Peripheral Pathologymentioning

confidence: 97%

Section: Peripheral Pathologymentioning

confidence: 99%

Variant CJD: Reflections a Quarter of a Century on

2021

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“…Since the current PrP Sc disinfection/decontamination procedures had been developed using scrapie and CJD isolates before sCJD classification was established, the efficacy of these procedures against the V2 sCJD strain needs to be reconfirmed. In addition, as the presence of infectivity has been reported in a wide variety of peripheral tissues of sCJD MM1 patients including the lung, heart, kidney, pancreas, salivary gland, thyroid, adrenal gland, skeletal muscle, and lymphoid tissues [29], the distribution of infectivity in peripheral tissues should be investigated also in sCJD VV2 and MV2 patients. Furthermore, elucidation of the reason for the reduced infectivity of the M1 sCJD strain through the peripheral route will pave the way for the development of preventive measures against iatrogenic CJD transmission through peripheral routes.…”

Section: Discussionmentioning

confidence: 99%

Potential for transmission of sporadic Creutzfeldt–Jakob disease through peripheral routes

Kobayashi

Munesue

Shimazaki

et al. 2021

Laboratory Investigation

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Five sporadic Creutzfeldt-Jakob disease (CJD) strains have been identified to date, based on differences in clinicopathological features of the patients, the biochemical properties of abnormal prion proteins, and transmission properties. Recent advances in our knowledge about iatrogenic transmission of sporadic CJD have raised the possibility that the infectivity of sporadic CJD strains through peripheral routes is different from that of intracranial infection.To test this possibility, here we assessed systematically the infectivity of sporadic CJD strains through the peripheral route for the first time using a mouse model expressing human prion protein. Although the infectivity of the V2 and M1 sporadic CJD strains is almost the same in intracerebral transmission studies, the V2 strain infected more efficiently than the M1 strain through the peripheral route. The other sporadic CJD strains examined lacked infectivity. Of note, both the V2 and M1 strains showed preference for mice with the valine homozygosity at the PRNP polymorphic codon. These results indicate that the V2 strain is the most infectious sporadic CJD strain for infection through peripheral routes. In addition, these findings raise the possibility that individuals with the valine homozygosity at the PRNP polymorphic codon might have higher risks of infection through peripheral routes compared with the methionine homozygotes. Thus, preventive measures against the transmission of the V2 sporadic CJD strain will be important for the eradication of iatrogenic CJD transmission through peripheral routes.

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“…Although the precise relationship between prion strain diversity and the clinicopathological subtypes of sCJD remains imperfectly characterized, two strains named M1 CJD and V2 CJD seem to account for the most frequent forms of sCJD; M1 CJD is predominantly found in the brain of MM/MV1 sCJD patients, while the V2 CJD strain is generally found in VV/MV2 sCJD patients [ 8 , 9 , 11 , 14 ]. However, in up to 35% of sCJD patients the co-existence of both M1 CJD and V2 CJD strains was demonstrated by bioassay [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…These observations raised the hypothesis that different prion strains (most likely originating from undetected cases of sCJD in the donor population) contaminated the hGH preparations administered to recipients in the UK and in France, resulting in different incubation periods for each of the PRNP codon 129 subgroups between these countries [ 16 , 23 ]. This study aims to test this hypothesis by performing experimental transmissions of 22 hGH-iCJD brain homogenates from patients with all three codon 129 genotypes from France (11 cases) and the UK (11 cases) into a panel of well characterized human-PrP-expressing transgenic mice (tgHu), following an established methodology that has been used extensively to identify sCJD prion strains in a range of tissue samples from France, the UK and Spain [ 11 , 14 ]. Sporadic CJD cases originating from France and the UK were also used as controls in this study.…”

Section: Introductionmentioning

confidence: 99%

Prion strains associated with iatrogenic CJD in French and UK human growth hormone recipients

Douet

Huor

Cassard

et al. 2021

acta neuropathol commun

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Treatment with human pituitary-derived growth hormone (hGH) was responsible for a significant proportion of iatrogenic Creutzfeldt–Jakob disease (iCJD) cases. France and the UK experienced the largest case numbers of hGH-iCJD, with 122 and 81 cases respectively. Differences in the frequency of the three PRNP codon 129 polymorphisms (MM, MV and VV) and the estimated incubation periods associated with each of these genotypes in the French and the UK hGH-iCJD cohorts led to the suggestion that the prion strains responsible for these two hGH-iCJD cohorts were different. In this study, we characterized the prion strains responsible for hGH-iCJD cases originating from UK (n = 11) and France (n = 11) using human PrP expressing mouse models. The cases included PRNP MM, MV and VV genotypes from both countries. UK and French sporadic CJD (sCJD) cases were included as controls. The prion strains identified following inoculation with hGH-iCJD homogenates corresponded to the two most frequently observed sCJD prion strains (M1CJD and V2CJD). However, in clear contradiction to the initial hypothesis, the prion strains that were identified in the UK and the French hGH-iCJD cases were not radically different. In the vast majority of the cases originating from both countries, the V2CJD strain or a mixture of M1CJD + V2CJD strains were identified. These data strongly support the contention that the differences in the epidemiological and genetic profiles observed in the UK and France hGH-iCJD cohorts cannot be attributed only to the transmission of different prion strains.

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Wide distribution of prion infectivity in the peripheral tissues of vCJD and sCJD patients

Cited by 16 publications

References 54 publications

Variant CJD: Reflections a Quarter of a Century on

Variant CJD: Reflections a Quarter of a Century on

Potential for transmission of sporadic Creutzfeldt–Jakob disease through peripheral routes

Prion strains associated with iatrogenic CJD in French and UK human growth hormone recipients

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