Detection of Infectivity in Blood of Persons with Variant and Sporadic Creutzfeldt-Jakob Disease

Douet, Jean‐Yves; Zafar, Saima; Perret‐Liaudet, Armand; Lacroux, Caroline; Lugan, Séverine; Aron, Naïma; Cassard, Hervé; Ponto, Claudia; Corbière, Fabien; Torres, Juan María; Zerr, Inga; Andréoletti, Olivier

doi:10.3201/eid2001.130353

Cited by 71 publications

(78 citation statements)

References 14 publications

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“…Recently, infectivity measurements in blood fractions collected from a vCJD-infected patient and those from a scrapie-infected sheep indicated that in both situations prion levels and the partition of infectivity in blood compartments are similar (10,11). This further reinforced the pertinence of data collected in TSE-infected sheep for assessing the vCJD blood-borne transmission risk.…”

Section: Importancementioning

confidence: 60%

Mononucleated Blood Cell Populations Display Different Abilities To Transmit Prion Disease by the Transfusion Route

Douet

Lacroux

Litaise

et al. 2016

J Virol

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Previous experiments carried out in a sheep scrapie model demonstrated that the transfusion of 200 l of prion-infected whole blood has an apparent 100% efficacy for disease transmission. These experiments also indicated that, despite the apparent low infectious titer, the intravenous administration of white blood cells (WBC) resulted in efficient disease transmission. In the study presented here, using the same transmissible spongiform encephalopathy (TSE) animal model, our aim was to determine the minimal number of white blood cells and the specific abilities of mononucleated cell populations to transmit scrapie by the transfusion route. Our results confirmed that the transfusion of 100 l, but not 10 l, of fresh whole blood collected in asymptomatic scrapie-infected donor sheep can transmit the disease. The data also show that the intravenous administration of 10 5WBCs is sufficient to cause scrapie in recipient sheep. Cell-sorted CD45R ؉ (predominantly B lymphocytes), CD4 ؉ /CD8 ؉ (T lymphocytes), and CD14؉ (monocytes/macrophages) blood cell subpopulations all were shown to contain prion infectivity by bioassays in ovine PrP transgenic mice. However, while the intravenous administration of 10 6 CD45 ؉ or CD4 ؉ /8 ؉ living cells was able to transmit the disease, similar numbers of CD14؉ cells failed to infect the recipients. These data support the contention that mononucleated blood cell populations display different abilities to transmit TSE by the transfusion route. They also represent an important input for the risk assessment of blood-borne prion disease transmission and for refining the target performance of leukoreduction processes that currently are applied to mitigate the transmission risk in transfusion medicine. IMPORTANCEInterindividual variant Creutzfeldt-Jakob disease (vCJD) transmission through blood and blood-derived products is considered a major public health issue in transfusion medicine. Over the last decade, TSE in sheep has emerged as a relevant model for assessing the blood-borne vCJD transmission risk. In this study, using a sheep TSE model, we characterized the ability of different peripheral blood mononucleated cell populations to infect TSE-free recipients by the transfusion route. Our results indicate that as little as 10 5 WBC and 100 l of blood collected from asymptomatic scrapie infected animals can transmit the disease. They also demonstrate unambiguously that peripheral blood mononuclear cell subpopulations display dramatically different abilities to transmit the disease. These data represent an important input for the risk assessment of blood-borne prion disease transmission and for refining the target performance of leukoreduction processes that currently are applied to mitigate the transmission risk in transfusion medicine.

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Section: Importancementioning

confidence: 60%

Mononucleated Blood Cell Populations Display Different Abilities To Transmit Prion Disease by the Transfusion Route

Douet

Lacroux

Litaise

et al. 2016

J Virol

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“…Moreover, a number of healthy people have been found to harbor this agent in lymphoreticular tissues (3,9,10); however, it is not known whether PrP TSE circulates in the blood of these individuals and whether they will develop the disease later in life. Recently, infectivity was reported in the plasma of two out of four patients affected by sporadic CJD (sCJD) (11). Although similar levels of PrP TSE have been detected in spleens, tonsils, and lymph nodes of vCJD and sCJD patients by Western blotting (12), the identification of this protein in the blood of individuals afflicted with the latter by various methods, including PrP TSE capture coupled to direct immunodetection of surface-bound material (6), capillary electrophoresis (13), and protein misfolding cyclic amplification (PMCA) coupled to surrounding optical fiber immunoassay (12), has been highly elusive for decades, with only two cases recently reported (8).…”

mentioning

confidence: 99%

First Demonstration of Transmissible Spongiform Encephalopathy-associated Prion Protein (PrPTSE) in Extracellular Vesicles from Plasma of Mice Infected with Mouse-adapted Variant Creutzfeldt-Jakob Disease by in Vitro Amplification

Saá

Yakovleva

Castro

et al. 2014

Journal of Biological Chemistry

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Background: Prions can be transmitted by blood transfusion, but their origin and distribution in blood are unknown. Results: Prions were detected in plasma extracellular vesicles from preclinical and clinically sick mice. Conclusion: Prions associate with blood-circulating extracellular vesicles. Significance: These findings provide information about prion distribution in blood and set the groundwork for novel prion removal and disease diagnosis technologies.

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“…Our studies here support the view that the level of prion infectivity in blood from prion-diseased individuals may be underestimated when assessed by intracerebral inoculation of rodents in comparison with bioassay of similar material in other experimental systems. This is particularly pertinent to our assessment here of prion-infected plasma that could be diluted by several orders of magnitude and still trigger a phenotypic response in the PrP transgenic Drosophila, but appears to contain a low level of infectivity when assayed in other systems [10,[15][16][17][18][19][20][21]. One possibility for the efficient detection of scrapie-infected sheep plasma by PrP transgenic Drosophila is that this invertebrate host does not normally express PrP and may therefore not have evolved suitable defence mechanisms that efficiently remove or sequester misfolded neurotoxic forms of this protein.…”

Section: Discussionmentioning

confidence: 99%

“…Collectively, these studies revealed that prion infectivity titres of blood samples harvested during the asymptomatic phase of prion disease were up to 10-fold less than those collected during the clinical phase [10,19,20,22]. Infectious prions were found to be associated with white and red blood cells, platelets and plasma, although interspecies variations existed with regard to the distribution of prion infectivity in these different blood fractions [10,[15][16][17][18][19][20][21]. Studies in ruminants have analysed bioassays of autologous whole or fractionated blood by the intravenous route [19,20].…”

Section: Introductionmentioning

confidence: 96%

“…The bioassay of blood-borne prion infectivity has been performed for a variety of different species, such as rodents, sheep, cervids and primates including humans, undergoing, collectively, either experimental or natural prion disease [10,[15][16][17][18][19][20][21]. These bioassays have typically involved intracerebral inoculation of blood, or blood fractions, into a recipient indicator species, usually rodents including mice with a PrP transgene autologous for the donor species.…”

Section: Introductionmentioning

confidence: 99%

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Bioassay of prion-infected blood plasma in PrP transgenic Drosophila

Thackray

Andréoletti

Bujdoso

2016

Biochemical Journal

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In pursuit of a tractable bioassay to assess blood prion infectivity, we have generated prion protein (PrP) transgenic Drosophila, which show a neurotoxic phenotype in adulthood after exposure to exogenous prions at the larval stage. Here, we determined the sensitivity of ovine PrP transgenic Drosophila to ovine prion infectivity by exposure of these flies to a dilution series of scrapie-infected sheep brain homogenate. Ovine PrP transgenic Drosophila showed a significant neurotoxic response to dilutions of 10−2 to 10−10 of the original scrapie-infected sheep brain homogenate. Significantly, we determined that this prion-induced neurotoxic response in ovine PrP transgenic Drosophila was transmissible to ovine PrP transgenic mice, which is indicative of authentic mammalian prion detection by these flies. As a consequence, we considered that PrP transgenic Drosophila were sufficiently sensitive to exogenous mammalian prions to be capable of detecting prion infectivity in the blood of scrapie-infected sheep. To test this hypothesis, we exposed ovine PrP transgenic Drosophila to scrapie-infected plasma, a blood fraction notoriously difficult to assess by conventional prion bioassays. Notably, pre-clinical plasma from scrapie-infected sheep induced neurotoxicity in PrP transgenic Drosophila and this effect was more pronounced after exposure to samples collected at the clinical phase of disease. The neurotoxic phenotype in ovine PrP transgenic Drosophila induced by plasma from scrapie-infected sheep was transmissible since head homogenate from these flies caused neurotoxicity in recipient flies during fly-to-fly transmission. Our data show that PrP transgenic Drosophila can be used successfully to bioassay prion infectivity in blood from a prion-diseased mammalian host.

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Detection of Infectivity in Blood of Persons with Variant and Sporadic Creutzfeldt-Jakob Disease

Cited by 71 publications

References 14 publications

Mononucleated Blood Cell Populations Display Different Abilities To Transmit Prion Disease by the Transfusion Route

Mononucleated Blood Cell Populations Display Different Abilities To Transmit Prion Disease by the Transfusion Route

First Demonstration of Transmissible Spongiform Encephalopathy-associated Prion Protein (PrPTSE) in Extracellular Vesicles from Plasma of Mice Infected with Mouse-adapted Variant Creutzfeldt-Jakob Disease by in Vitro Amplification

Bioassay of prion-infected blood plasma in PrP transgenic Drosophila

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