Infectivity in bone marrow from sporadic CJD patients

Abstract

Prion infectivity was recently identified in the blood of both sporadic and variant Creutzfeldt-Jakob disease (CJD) patients. In variant CJD (vCJD), the widespread distribution of prions in peripheral tissues of both asymptomatic and symptomatic patients is likely to explain the occurrence of the observed prionaemia. However, in sporadic CJD (sCJD), prion infectivity is described to be located principally in the central nervous system. In this study, we investigated the presence of prion infectivity in bone marrow collected after death in patients affected with different sCJD agents. Bioassays in transgenic mice expressing the human prion protein revealed the presence of unexpectedly high levels of infectivity in the bone marrow from seven out of eight sCJD cases. These findings may explain the presence of blood-borne infectivity in sCJD patients. They also suggest that the distribution of prion infectivity in peripheral tissues in sCJD patients could be wider than currently believed, with potential implications for the iatrogenic transmission risk of this disease. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Complementation between pathological prion protein subassemblies to cross existing species barriers

“…The existence of a complex such as suPrP A :suPrP B within the inoculum is further supported by the striking observation that endpoint dilutions aberrantly impaired LA21K fast prions transfer to tgHa mice (1000-fold decreased efficacy); the dilution steps would make certain PrP Sc subpopulations disappearing given their ratio/amount and/or induce the dissociation of an existing complex [51,15]. While cross-species transmission of prions has rarely been done at high dilution, it may be noted that comparing the limiting dilution values of MM1 sporadic CJD prions (homozygous for Met at codon 129) in transgenic mice expressing human PrP with either Met or Val at codon 129 resulted in 103-fold decrease [52], a negative impact quantitatively comparable to our observations.…”

Is sporadic Creutzfeldt‐Jakob disease transfusion‐transmissible?

“…Blood and plasma from sCJD and iCJD patients have been demonstrated to harbor infectivity and cause disease following intracerebral inoculation into animals . Although previously contested, these findings have been supported by a recent study demonstrating infectivity following intracranial injection of plasma from two sCJD patients into humanized transgenic mice and by the detection of infectivity in the bone marrow from sCJD patients . Attempts have been made to detect PrP TSE in soluble and cellular blood fractions from clinical sCJD patients by biochemical methods following amplification or concentration protocols, but these have yielded either unsuccessful or inconsistent results .…”

“…Albeit less frequently, PrP TSE and/or infectivity can also be found in non‐neuronal tissues from sCJD patients, including the spleen, muscle and bone marrow . Blood and plasma from sCJD and iCJD patients have been demonstrated to harbor infectivity and cause disease following intracerebral inoculation into animals .…”

“…Albeit less frequently, PrP TSE and/or infectivity can also be found in non-neuronal tissues from sCJD patients, including the spleen, muscle 18 and bone marrow. 19 Blood and plasma from sCJD and iCJD patients have been demonstrated to harbor infectivity and cause disease following intracerebral inoculation into animals. 20,21 Although previously contested, 22 these findings have been supported by a recent study demonstrating infectivity following intracranial injection of plasma from two sCJD patients into humanized transgenic mice and by the detection of infectivity in the bone marrow from sCJD patients.…”

“…20,21 Although previously contested, 22 these findings have been supported by a recent study demonstrating infectivity following intracranial injection of plasma from two sCJD patients into humanized transgenic mice and by the detection of infectivity in the bone marrow from sCJD patients. 19,23 Attempts have been made to detect PrP TSE in soluble and cellular blood fractions from clinical sCJD patients by biochemical methods following amplification or concentration protocols, but these have yielded either unsuccessful 5 or inconsistent results. 24,25 This is notable, considering that one of these techniques, protein misfolding cyclic amplification (PMCA), has reliably detected PrP TSE in blood from different experimental models of prion disease as well as vCJD patients.…”