{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:16:11Z","timestamp":1760148971401,"version":"build-2065373602"},"reference-count":32,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,6,28]],"date-time":"2023-06-28T00:00:00Z","timestamp":1687910400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"United States Food and Drug Administration"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Transmissible spongiform encephalopathies (TSEs) or prion diseases are characterized by the accumulation in affected tissues of the abnormal prion protein PrPTSE. We previously demonstrated PrPTSE in the blood of macaques experimentally infected with variant Creutzfeldt\u2013Jakob disease (vCJD), a human TSE, months to years prior to clinical onset. That work supported the prospect of using PrPTSE as a blood biomarker to detect vCJD and possibly other human TSEs before the onset of overt illness. However, our results also raised questions about the origin of PrPTSE detected in blood early after inoculation and the effects of dose and route on the timing of the appearance of PrPTSE. To investigate these questions, we inoculated vCJD-susceptible transgenic mice and non-infectable prion protein-knockout mice under inoculation conditions resembling those used in macaques, with additional controls. We assayed PrPTSE in mouse blood using the protein misfolding cyclic amplification (PMCA) method. PrPTSE from the inoculum cleared from the blood of all mice before 2 months post-inoculation (mpi). Mouse PrPTSE generated de novo appeared in blood after 2 mpi. These results were consistent regardless of dose or inoculation route. We also demonstrated that a commercial ELISA-like PrPTSE test detected and quantified PMCA products and provided a useful alternative to Western blots.<\/jats:p>","DOI":"10.3390\/v15071466","type":"journal-article","created":{"date-parts":[[2023,6,29]],"date-time":"2023-06-29T00:49:47Z","timestamp":1687999787000},"page":"1466","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Kinetics of Abnormal Prion Protein in Blood of Transgenic Mice Experimentally Infected by Multiple Routes with the Agent of Variant Creutzfeldt\u2013Jakob Disease"],"prefix":"10.3390","volume":"15","author":[{"given":"Oksana","family":"Yakovleva","sequence":"first","affiliation":[{"name":"U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, Silver Spring, MD 20993, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa","family":"Pilant","sequence":"additional","affiliation":[{"name":"U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, Silver Spring, MD 20993, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David M.","family":"Asher","sequence":"additional","affiliation":[{"name":"U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, Silver Spring, MD 20993, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luisa","family":"Gregori","sequence":"additional","affiliation":[{"name":"U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, Silver Spring, MD 20993, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Bonda, D.J., Manjila, S., Mehndiratta, P., Khan, F., Miller, B.R., Onwuzulike, K., Puoti, G., Cohen, M.L., Schonberger, L.B., and Cali, I. (2016). Human prion diseases: Surgical lessons learned from iatrogenic prion transmission. Neurosurg. Focus, 41.","DOI":"10.3171\/2016.5.FOCUS15126"},{"key":"ref_2","first-page":"50","article-title":"Variant Creutzfeldt-Jakob disease: An update","volume":"50","author":"Ironside","year":"2012","journal-title":"Folia Neuropathol."},{"key":"ref_3","first-page":"77","article-title":"Variant Creutzfeldt-Jakob disease","volume":"42","author":"Will","year":"2004","journal-title":"Folia Neuropathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/S0272-2712(02)00024-0","article-title":"Variant Creutzfeldt-Jakob disease and bovine spongiform encephalopathy","volume":"22","author":"Belay","year":"2002","journal-title":"Clin. Lab. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1038\/s41582-021-00488-7","article-title":"The importance of ongoing international surveillance for Creutzfeldt-Jakob disease","volume":"17","author":"Watson","year":"2021","journal-title":"Nat. Rev. Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Ritchie, D.L., Peden, A.H., and Barria, M.A. (2021). Variant CJD: Reflections a Quarter of a Century on. Pathogens, 10.","DOI":"10.3390\/pathogens10111413"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/S1474-4422(20)30477-4","article-title":"Biomarkers and diagnostic guidelines for sporadic Creutzfeldt-Jakob disease","volume":"20","author":"Hermann","year":"2021","journal-title":"Lancet Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4138","DOI":"10.1007\/s12035-016-9918-y","article-title":"Hereditary human prion diseases: An update","volume":"54","author":"Schmitz","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1038\/35081095","article-title":"Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding","volume":"411","author":"Saborio","year":"2001","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/nmeth0308-211","article-title":"Simplified ultrasensitive prion detection by recombinant PrP conversion with shaking","volume":"5","author":"Atarashi","year":"2008","journal-title":"Nat. Methods"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/B978-0-444-63945-5.00019-2","article-title":"Prion protein amplification techniques","volume":"153","author":"Green","year":"2018","journal-title":"Handb. Clin. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Lacroux, C., Comoy, E., Moudjou, M., Perret-Liaudet, A., Lugan, S., Litaise, C., Simmons, H., Jas-Duval, C., Lantier, I., and Beringue, V. (2014). Preclinical detection of variant CJD and BSE prions in blood. PLoS Pathog., 10.","DOI":"10.1371\/journal.ppat.1004202"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Concha-Marambio, L., Pritzkow, S., Moda, F., Tagliavini, F., Ironside, J.W., Schulz, P.E., and Soto, C. (2016). Detection of prions in blood from patients with variant Creutzfeldt-Jakob disease. Sci. Transl. Med., 8.","DOI":"10.1126\/scitranslmed.aaf6188"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Bougard, D., Brandel, J.P., B\u00e9londrade, M., B\u00e9ringue, V., Segarra, C., Fleury, H., Laplanche, J.L., Mayran, C., Nicot, S., and Green, A. (2016). Detection of prions in the plasma of presymptomatic and symptomatic patients with variant Creutzfeldt-Jakob disease. Sci. Transl. Med., 8.","DOI":"10.1126\/scitranslmed.aag1257"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1182\/blood-2013-11-539239","article-title":"A highly specific blood test for vCJD","volume":"123","author":"Jackson","year":"2014","journal-title":"Blood"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"114","DOI":"10.3201\/eid2001.130353","article-title":"Detection of infectivity in blood of persons with variant and sporadic Creutzfeldt-Jakob disease","volume":"20","author":"Douet","year":"2014","journal-title":"Emerg. Infect. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1111\/trf.12841","article-title":"Blood reference materials from macaques infected with variant Creutzfeldt-Jakob disease agent","volume":"55","author":"McDowell","year":"2015","journal-title":"Transfusion"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Yakovleva, O., Bett, C., Pilant, T., Asher, D.M., and Gregori, L. (2022). Abnormal prion protein, infectivity and neurofilament light-chain in blood of macaques with experimental variant Creutzfeldt-Jakob disease. J. Gen. Virol., 103.","DOI":"10.1099\/jgv.0.001764"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1007\/s00705-002-0958-4","article-title":"Early detection of PrPres in BSE-infected bovine PrP transgenic mice","volume":"148","author":"Castilla","year":"2003","journal-title":"Arch. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1099\/jgv.0.001017","article-title":"Both murine host and inoculum modulate expression of experimental variant Creutzfeldt-Jakob disease","volume":"99","author":"Bett","year":"2018","journal-title":"J. Gen. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1111\/tbed.12884","article-title":"Presumptive BSE cases with an aberrant prion protein phenotype in Switzerland, 2011: Lack of prion disease in experimentally inoculated cattle and bovine prion protein transgenic mice","volume":"65","author":"Serra","year":"2018","journal-title":"Transbound Emerg. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1016\/0092-8674(93)90360-3","article-title":"Mice devoid of PrP are resistant to scrapie","volume":"73","author":"Aguzzi","year":"1993","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Sawyer, E.B., Edgeworth, J.A., Thomas, C., Collinge, J., and Jackson, G.S. (2015). Preclinical detection of infectivity and disease-specific PrP in blood throughout the incubation period of prion disease. Sci. Rep., 5.","DOI":"10.1038\/srep17742"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1126\/science.1129051","article-title":"Presymptomatic detection of prions in blood","volume":"313","author":"Castilla","year":"2006","journal-title":"Science"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2590","DOI":"10.1111\/trf.13190","article-title":"Expression of the cellular prion protein affects posttransfusion recovery and survival of red blood cells in mice","volume":"55","author":"Glier","year":"2015","journal-title":"Transfusion"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1002\/jat.727","article-title":"A good practice guide to the administration of substances and removal of blood, including routes and volumes","volume":"21","author":"Diehl","year":"2001","journal-title":"J. Appl. Toxicol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Nemecek, J., Nag, N., Carlson, C.M., Schneider, J.R., Heisey, D.M., Johnson, C.J., Asher, D.M., and Gregori, L. (2013). Red-backed vole brain promotes highly efficient in vitro amplification of abnormal prion protein from macaque and human brains infected with variant Creutzfeldt-Jakob disease agent. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0078710"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e120","DOI":"10.1097\/TP.0000000000001636","article-title":"Rapid Testing for Creutzfeldt-Jakob disease in donors of cornea","volume":"101","author":"Gregori","year":"2017","journal-title":"Transplantation"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Salamat, M.K.F., Stewart, P., Brown, H., Tan, K.B.C., Smith, A., de Wolf, C., Alejo Blanco, A.R., Turner, M., Manson, J.C., and McCutcheon, S. (2022). Subclinical infection occurs frequently following low dose exposure to prions by blood transfusion. Sci. Rep., 12.","DOI":"10.1038\/s41598-022-15105-w"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"7421","DOI":"10.1128\/JVI.00760-15","article-title":"Immediate and ongoing detection of prions in the blood of hamsters and deer following oral, nasal, or blood inoculations","volume":"89","author":"Elder","year":"2015","journal-title":"J. Virol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"34","DOI":"10.3201\/eid2601.181423","article-title":"Preclinical detection of prions in blood of nonhuman primates infected with variant Creutzfeldt-Jakob disease","volume":"26","author":"Chacon","year":"2020","journal-title":"Emerg. Infect. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2792","DOI":"10.1096\/fj.11-180729","article-title":"Initial fate of prions upon peripheral infection: Half-life, distribution, clearance, and tissue uptake","volume":"25","author":"Urayama","year":"2011","journal-title":"FASEB J."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/7\/1466\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:02:35Z","timestamp":1760126555000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/15\/7\/1466"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,28]]},"references-count":32,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["v15071466"],"URL":"https:\/\/doi.org\/10.3390\/v15071466","relation":{},"ISSN":["1999-4915"],"issn-type":[{"type":"electronic","value":"1999-4915"}],"subject":[],"published":{"date-parts":[[2023,6,28]]}}}