Effectiveness of leucoreduction for removal of infectivity of transmissible spongiform encephalopathies from blood

Gregori, Luisa; McCombie, N.; Palmer, Douglas S.; Birch, Paul; Sowemimo-Coker, Samuel; Giulivi, Antonio; Rohwer, Robert G.

doi:10.1016/s0140-6736(04)16812-8

Cited by 175 publications

(179 citation statements)

References 6 publications

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“…Such findings are consistent with earlier reports of low levels of prions in blood (21)(22)(23) and the replication of prions in the lymphoreticular system (24)(25)(26)(27)(28)(29). The distribution of prions in blood has been difficult to resolve, because the levels of infectivity are so low (21,(30)(31)(32). Whether some prions are nonspecifically bound to circulating lymphocytes, perhaps by PrP C , or whether they reproduce at low levels in a distinct set of lymphoid cells is unclear (33)(34)(35)(36).…”

Section: Prions In Bloodsupporting

confidence: 89%

Human prions and plasma lipoproteins

Safar

Wille

Geschwind

et al. 2006

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

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Prions are composed solely of an alternatively folded isoform of the prion protein (PrP), designated PrP Sc . The polyoxometalate phosphotungstic acid has been used to separate PrP Sc from its precursor PrP C by selective precipitation; notably, native PrP Sc has not been solubilized by using nondenaturing detergents. Because of the similarities between PrP Sc and lipoproteins with respect to hydrophobicity and formation of phosphotungstic acid complexes, we asked whether these molecules are bound to each other in blood. Here we report that prions from the brains of patients with sporadic Creutzfeldt-Jakob disease (CJD) bind to very low-density (VLDL) and low-density (LDL) lipoproteins but not to high-density lipoproteins (HDL) or other plasma components, as demonstrated both by affinity assay and electron microscopy. Immunoassays demonstrated that apolipoprotein B (apoB), which is the major protein component of VLDL and LDL, bound PrP Sc through a highly cooperative process. Approximately 50% of the PrP Sc bound to LDL particles was released after exposure to 4 M guanidine hydrochloride at 80°C for 20 min. The apparent binding constants of native human (Hu) PrP Sc or denatured recombinant HuPrP(90 -231) for apoB and LDL ranged from 28 to 212 pM. Whether detection of PrP Sc in VLDL and LDL particles can be adapted into an antemortem diagnostic test for prions in the blood of humans, livestock, and free-ranging cervids remains to be determined. prion protein ͉ apolipoprotein B ͉ blood ͉ Creutzfeldt-Jakob disease P rions are composed solely of an alternatively folded isoform of the prion protein, designated PrP Sc . Despite numerous efforts to solubilize native PrP Sc , no procedure has been developed except for incorporation of the protein into liposomes (1, 2). The hydrophobic properties of PrP Sc not only have impeded biological investigations but also have prevented structural studies at atomic resolution.During the development of an immunoassay for PrP Sc that does not depend upon limited proteolysis to hydrolyze the precursor protein designated PrP C , we found that the Na salt of phosphotungstic acid (PTA) selectively complexes with PrP Sc (3). PTA is a water-soluble salt featuring the nearly spherical trianion [PW 12 O 14 ] 3Ϫ that belongs to a broad class of polynuclear transition metal-oxo complexes known as polyoxometalates (POMs; see ref. 4). Recently, two of us (J.G.S. and S.B.P.) investigated the mechanism of selective complex formation between Keggin-type POMs and PrP Sc using a series of POM analogues (5). The ability of POMs to complex with PrP Sc as well as lipoproteins (6) raised the possibility that these two hydrophobic proteins might copurify.We began by examining the distribution of human (Hu) PrP Sc in human plasma fractions spiked with sporadic CreutzfeldtJakob disease (sCJD) prions from human brain. CJD prions were found with very low-density lipoproteins (VLDL) and low-density lipoproteins (LDL) but not with high-density lipoproteins (HDL) or any other plasma component. In addition to b...

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Section: Prions In Bloodsupporting

confidence: 89%

Human prions and plasma lipoproteins

Safar

Wille

Geschwind

et al. 2006

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

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“…According to Amorfix, this kit allowed detection of as little as 4 fg per well of recombinant human prion protein and a 1 : 1 000 000 dilution of vCJD brain homogenate. Based on comparative bioassays and the blood titres in animal models (Cervenakova et al, 2003;Gregori et al, 2004;Minor, 2004;Herzog et al, 2004), this detection limit was tenfold more sensitive than the minimum required by Blood Transfusion Services in the UK (European Commission DG Health and Consumer Directorate, 2012). However, this test was not suitable for routine testing of blood donations, as it did not meet traceability requirements.…”

Section: Amorfix Ep-vcjdmentioning

confidence: 99%

Factors intrinsic and extrinsic to blood hamper the development of a routine blood test for human prion diseases

Abdel‐Haq

2015

Journal of General Virology

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“…Two other studies have reported infectivity in urine (11) and infectivity with disease-specifi c prion protein (PrP d ) in kidneys of mice with simultaneous scrapie and nephritis but not in those with scrapie alone (12). To resolve these discrepancies, we used a highly sensitive and precise method of measuring low concentrations of TSE infectivity, which we have successfully used for quantitation of TSE infectivity in blood (1,2), to measure the concentration of TSE infectivity in urine of scrapie-infected hamsters.…”

mentioning

confidence: 99%

Excretion of Transmissible Spongiform Encephalopathy Infectivity in Urine

Gregori¹,

Kovács²,

Alexeeva³

et al. 2008

Emerg. Infect. Dis.

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The route of transmission of most naturally acquired transmissible spongiform encephalopathy (TSE) infections remains speculative. To investigate urine as a potential source of TSE exposure, we used a sensitive method for detection and quantitation of TSE infectivity. Pooled urine collected from 22 hamsters showing clinical signs of 263K scrapie contained 3.8 ± 0.9 infectious doses/mL of infectivity. Titration of homogenates of kidneys and urinary bladders from the same animals gave concentrations 20,000-fold greater. Histologic and immunohistochemical examination of these same tissues showed no indications of infl ammatory or other pathologic changes except for occasional deposits of disease-associated prion protein in kidneys. Although the source of TSE infectivity in urine remains unresolved, these results establish that TSE infectivity is excreted in urine and may thereby play a role in the horizontal transmission of natural TSEs. The results also indicate potential risk for TSE transmission from human urine-derived hormones and other medicines.T ransmissible spongiform encephalopathies (TSEs) are fatal neurologic diseases. In humans, a long asymptomatic incubation period is followed by a progressive clinical course that typically lasts a few months to a year. TSE infectivity and pathologic changes are concentrated in the nervous system; however, much of the transmission risk results from parenteral exposure to the much lower concentrations of infectivity found in tissues outside the nervous system. Thus, despite the very low concentration of TSE infectivity in blood (1,2), 4 human cases of transmission of variant Creutzfeldt-Jakob disease through blood transfusions have been documented (3,4). If TSE infectivity were excreted, human urine, which is a source of injectible fertility hormones and other drugs (5,6), could also pose a risk for transmission. Infected urine might also account for the horizontal transmission of sheep scrapie and might contribute to the natural spread of chronic wasting disease in deer and elk.Early attempts to transmit Creutzfeldt-Jakob disease by cross-species inoculation of rodents and primates with urine from diseased patients failed (7,8). More recent attempts in which urine from infected hamsters was injected back into hamsters have produced variable results (9,10). Two other studies have reported infectivity in urine (11) and infectivity with disease-specifi c prion protein (PrP d ) in kidneys of mice with simultaneous scrapie and nephritis but not in those with scrapie alone (12). To resolve these discrepancies, we used a highly sensitive and precise method of measuring low concentrations of TSE infectivity, which we have successfully used for quantitation of TSE infectivity in blood (1,2), to measure the concentration of TSE infectivity in urine of scrapie-infected hamsters. Materials and Methods Urine Collection and ProcessingUrine was collected from a cohort of 22 Syrian hamsters (Harlan Sprague-Dawley, Haslet, MI, USA) that had been infected by intracranial injection with...

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Effectiveness of leucoreduction for removal of infectivity of transmissible spongiform encephalopathies from blood

Cited by 175 publications

References 6 publications

Human prions and plasma lipoproteins

Human prions and plasma lipoproteins

Factors intrinsic and extrinsic to blood hamper the development of a routine blood test for human prion diseases

Excretion of Transmissible Spongiform Encephalopathy Infectivity in Urine

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