1887

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Volume 103, Issue 7

Abnormal prion protein, infectivity and neurofilament light-chain in blood of macaques with experimental variant Creutzfeldt-Jakob disease Open Access

Abstract

Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative infections. Variant Creutzfeldt-Jakob disease (vCJD) and sporadic CJD (sCJD) are human TSEs that, in rare cases, have been transmitted by human-derived therapeutic products. There is a need for a blood test to detect infected donors, identify infected individuals in families with TSEs and monitor progression of disease in patients, especially during clinical trials. We prepared panels of blood from cynomolgus and rhesus macaques experimentally infected with vCJD, as a surrogate for human blood, to support assay development. We detected abnormal prion protein (PrP) in those blood samples using the protein misfolding cyclic amplification (PMCA) assay. PrP first appeared in the blood of pre-symptomatic cynomolgus macaques as early as 2 months post-inoculation (mpi). In contrast, PMCA detected PrP much later in the blood of two pre-symptomatic rhesus macaques, starting at 19 and 20 mpi, and in one rhesus macaque only when symptomatic, at 38 mpi. Once blood of either species of macaque became PMCA-positive, PrP persisted through terminal illness at relatively constant concentrations. Infectivity in buffy coat samples from terminally ill cynomolgus macaques as well as a sample collected 9 months before clinical onset of disease in one of the macaques was assayed in vCJD-susceptible transgenic mice. The infectivity titres varied from 2.7 to 4.3 infectious doses ml. We also screened macaque blood using a four-member panel of biomarkers for neurodegenerative diseases to identify potential non-PrP pre-symptomatic diagnostic markers. Neurofilament light-chain protein (NfL) increased in blood before the onset of clinical vCJD. Cumulatively, these data confirmed that, while PrP is the first marker to appear in blood of vCJD-infected cynomolgus and rhesus macaques, NfL might offer a useful, though less specific, marker for forthcoming neurodegeneration. These studies support the use of macaque blood panels to investigate PrP and other biomarkers to predict onset of CJD in humans.

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  • Accepted:
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Keyword(s): assay , biomarkers , blood , infectivity , macaque and prion
Funding
This study was supported by the:
  • U.S. Food and Drug Administration
    • Principle Award Recipient: NotApplicable
© Microbiology Society
  • This is an open-access article distributed under the terms of the Creative Commons Attribution NonCommercial License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
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2022-07-11
2024-04-19
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Abnormal prion protein, infectivity and neurofilament light-chain in blood of macaques with experimental variant Creutzfeldt-Jakob disease
J. Gen. Virol. 103, 001764 (2022); https://doi.org/10.1099/jgv.0.001764
/content/journal/jgv/10.1099/jgv.0.001764
/content/journal/jgv/10.1099/jgv.0.001764
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