{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:14:59Z","timestamp":1753892099204,"version":"3.41.2"},"reference-count":63,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,2,18]],"date-time":"2022-02-18T00:00:00Z","timestamp":1645142400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>Immortalized uninfected septal (SEP) neurons proliferate but after physiological mitotic arrest they express differentiated neuronal characteristics including enhanced cell-to-cell membrane contacts and \u2265\u20098 fold increases in host prion protein (PrP). We compared proliferating uninfected and Creutzfeldt-Jakob Disease (CJD) agent infected cells with their arrested counterparts over 33\u2009days by quantitative mRNA and protein blot analyses. Surprisingly, uninfected arrested cells increased interferon-\u03b2 (IFN-\u03b2) mRNA by 2.5\u20138 fold; IFN-\u03b2 mRNA elevations were not previously associated with neuronal differentiation. SEP cells with high CJD infectivity titers produced a much larger 40\u201368-fold increase in IFN-\u03b2 mRNA, a classic host anti-viral response that is virucidal for RNA but not DNA viruses. High titers of CJD agent also induced dramatic decreases in host PrP, a protein needed for productive agent replication. Uninfected arrested cells produced large sustained 20\u201330-fold increases in PrP mRNA and protein, whereas CJD arrested cells showed only transient small 5-fold increases in PrP. A &amp;gt;\u200910-fold increase in infectivity, but not PrP misfolding, induced host PrP reductions that can limit CJD agent replication. In contrast to neuronal lineage cells, functionally distinct migratory microglia with high titers of CJD agent do not induce an IFN-\u03b2 mRNA response. Because they have 1\/50th of PrP of an average brain cell, microglia would be unable to produce the many new infectious particles needed to induce a large IFN-\u03b2 response by host cells. Instead, microglia and related cells can be persistent reservoirs of infection and spread. Phase separations of agent-associated molecules in neurons, microglia and other cell types can yield new insights into the molecular structure, persistent, and evasive behavior of CJD-type agents.<\/jats:p>","DOI":"10.3389\/fphys.2022.837662","type":"journal-article","created":{"date-parts":[[2022,2,18]],"date-time":"2022-02-18T09:02:41Z","timestamp":1645174961000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Reduced Expression of Prion Protein With Increased Interferon-\u03b2 Fail to Limit Creutzfeldt-Jakob Disease Agent Replication in Differentiating Neuronal Cells"],"prefix":"10.3389","volume":"13","author":[{"given":"Gerard","family":"Aguilar","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathan","family":"Pagano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Manuelidis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,2,18]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1717","DOI":"10.1099\/vir.0.82603-0","article-title":"Local delivery of beta interferon using an adeno-associated virus type 5 effectively inhibits adjuvant arthritis in rats","volume":"88","author":"Adriaansen","year":"2007","journal-title":"J. Gen. Virol."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"e1007505","DOI":"10.1371\/journal.ppat.1007505","article-title":"Human polyomavirus BKV infection of endothelial cells results in interferon pathway induction and persistence","volume":"15","author":"An","year":"2019","journal-title":"PLoS Pathog."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"8768","DOI":"10.1073\/pnas.0400158101","article-title":"Two Creutzfeldt-Jakob disease agents reproduce prion protein-independent identities in cell cultures","volume":"101","author":"Arjona","year":"2004","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1080\/13550280490261761","article-title":"Early induction of interferon-responsive mRNAs in Creutzfeldt-Jakob disease","volume":"10","author":"Baker","year":"2004","journal-title":"J. Neurovirol."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"10905","DOI":"10.1128\/jvi.76.21.10905-10913.2002","article-title":"Microglia from Creutzfeldt-Jakob disease-infected brains are infectious and show specific mRNA activation profiles","volume":"76","author":"Baker","year":"2002","journal-title":"J. Virol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1007\/s00401-016-1594-5","article-title":"PrP aggregation can be seeded by pre-formed recombinant PrP amyloid fibrils without the replication of infectious prions","volume":"132","author":"Barron","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1038\/s12276-020-0407-z","article-title":"The emerging role of RNA modifications in the regulation of mRNA stability","volume":"52","author":"Boo","year":"2020","journal-title":"Exp. Mol. Med."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1947","DOI":"10.1002\/jcb.25495","article-title":"CJD and Scrapie require agent-associated nucleic acids for infection","volume":"117","author":"Botsios","year":"2016","journal-title":"J. Cell. Biochem."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1339","DOI":"10.1016\/0092-8674(93)90360-3","article-title":"Mice devoid of PrP are resistant to scrapie","volume":"73","author":"B\u00fceler","year":"1993","journal-title":"Cell"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"19","DOI":"10.3389\/fmolb.2017.00019","article-title":"Physiological functions of the cellular prion protein","volume":"4","author":"Castle","year":"2017","journal-title":"Front. Mol. Biosci."},{"key":"ref501","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1038\/labinvest.2009.30","article-title":"Prion proteins in subpopulations of white blood cells from patients with sporadic Creutzfeldt-Jakob disease","volume":"89","author":"Choi","year":"2009","journal-title":"Lab. Invest."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"792","DOI":"10.1136\/jnnp.72.6.792","article-title":"Creutzfeldt-Jakob disease 38 years after diagnostic use of human growth hormone","volume":"72","author":"Croes","year":"2002","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"7835","DOI":"10.1073\/pnas.0602460103","article-title":"Neurons produce type I interferon during viral encephalitis","volume":"103","author":"Delhaye","year":"2006","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/bs.pmbts.2021.06.001","article-title":"Intrinsic disorder and phase transitions: pieces in the puzzling role of the prion protein in health and disease","volume":"183","author":"do Amaral","year":"2021","journal-title":"Prog. Mol. Biol. Transl. Sci."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"3439","DOI":"10.1128\/JVI.02783-15","article-title":"Mononucleated blood cell populations display different abilities to transmit prion disease by the transfusion route","volume":"90","author":"Douet","year":"2016","journal-title":"J. Virol."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/infdis\/117.1.15","article-title":"Pathogenesis of scrapie virus infection in the mouse","volume":"117","author":"Eklund","year":"1967","journal-title":"J. Infect. Dis."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1016\/0006-8993(94)91484-2","article-title":"Conditional immortalization of neuronal cells from postmitotic cultures and adult CNS","volume":"656","author":"Eves","year":"1994","journal-title":"Brain Res."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1126\/science.142303","article-title":"Unconventional viruses and the origin and disappearance of kuru","volume":"197","author":"Gajdusek","year":"1977","journal-title":"Science"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"e02290","DOI":"10.1128\/mBio.02290-17","article-title":"Phase transitions drive the formation of vesicular stomatitis virus replication compartments","volume":"9","author":"Heinrich","year":"2018","journal-title":"mBio"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1136\/jcp.2003.012278","article-title":"Specificity of lymphoreticular accumulation of prion protein for variant Creutzfeldt-Jakob disease","volume":"57","author":"Hilton","year":"2004","journal-title":"J. Clin. Pathol."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1016\/j.cell.2011.06.041","article-title":"MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response","volume":"146","author":"Hou","year":"2011","journal-title":"Cell"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1035","DOI":"10.1093\/brain\/awz016","article-title":"Type I interferon protects neurons from prions in in vivo models","volume":"142","author":"Ishibashi","year":"2019","journal-title":"Brain"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"19727","DOI":"10.1073\/pnas.1803521116","article-title":"RNA editing alterations define manifestation of prion diseases","volume":"116","author":"Kanata","year":"2019","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"2012","DOI":"10.1002\/jcb.24873","article-title":"Highly infectious CJD particles lack prion protein but contain many viral-linked peptides by LC-MS\/MS","volume":"115","author":"Kipkorir","year":"2014","journal-title":"J. Cell. Biochem."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1016\/0006-8993(87)90465-3","article-title":"Developmental expression and regional distribution of the scrapie-associated protein mRNA in the rat central nervous system","volume":"417","author":"Lieberburg","year":"1987","journal-title":"Brain Res."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"77","DOI":"10.3389\/fnmol.2017.00077","article-title":"The biological function of the prion protein: A cell surface scaffold of signaling modules","volume":"10","author":"Linden","year":"2017","journal-title":"Front. Mol. Neurosci."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"352","DOI":"10.1080\/13550280802105283","article-title":"A rapid accurate culture assay for infectivity in transmissible Encephalopathies","volume":"14","author":"Liu","year":"2008","journal-title":"J. Neurovirol."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"644","DOI":"10.1002\/jcb.20220","article-title":"New molecular markers of early and progressive CJD brain infection","volume":"93","author":"Lu","year":"2004","journal-title":"J. Cell. Biochem."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1242\/dev.115.1.117","article-title":"The prion protein gene: a role in mouse embryogenesis?","volume":"115","author":"Manson","year":"1992","journal-title":"Development"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1073\/pnas.84.3.871","article-title":"Immortality of cell cultures derived from brains of mice and hamsters infected with Creutzfeldt-Jakob disease agent","volume":"84","author":"Manuelidis","year":"1987","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1069","DOI":"10.1126\/science.349691","article-title":"Viremia in experimental Creutzfeldt-Jakob disease","volume":"200","author":"Manuelidis","year":"1978","journal-title":"Science"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1016\/S0140-6736(85)90165-5","article-title":"Transmission to animals of Creutzfeldt-Jakob disease from human blood","volume":"326","author":"Manuelidis","year":"1985","journal-title":"Lancet"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1002\/jcb.21090","article-title":"A 25 nm virion is the likely cause of transmissible spongiform encephalopathies","volume":"100","author":"Manuelidis","year":"2007","journal-title":"J. Cell. Biochem."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"101","DOI":"10.4161\/viru.1.2.10822","article-title":"Transmissible encephalopathy agents: virulence, geography and clockwork","volume":"1","author":"Manuelidis","year":"2010","journal-title":"Virulence"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1007\/s13365-010-0007-0","article-title":"Nuclease resistant circular DNAs copurify with infectivity in scrapie and CJD","volume":"17","author":"Manuelidis","year":"2011","journal-title":"J. Neurovirol."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"373","DOI":"10.4161\/viru.24838","article-title":"Infectious particles, stress, and induced prion amyloids: a unifying perspective","volume":"4","author":"Manuelidis","year":"2013","journal-title":"Virulence"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"13529","DOI":"10.1073\/pnas.0905825106","article-title":"The kuru infectious agent is a unique geographic isolate distinct from Creutzfeldt-Jakob disease and scrapie agents","volume":"106","author":"Manuelidis","year":"","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"94","DOI":"10.1126\/science.277.5322.94","article-title":"Evolution of a strain of CJD that induces BSE-like plaques","volume":"277","author":"Manuelidis","year":"1997","journal-title":"Science"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1002\/jcb.21988","article-title":"Strain-specific viral properties of variant Creutzfeldt-Jakob disease (vCJD) are encoded by the agent and not by host prion protein","volume":"106","author":"Manuelidis","year":"","journal-title":"J. Cell. Biochem."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"5360","DOI":"10.1073\/pnas.0931192100","article-title":"Virus-like interference in the latency and prevention of Creutzfeldt-Jakob disease","volume":"100","author":"Manuelidis","year":"2003","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref40","first-page":"117","article-title":"Potential involvement of retroviral elements in human dementias","volume":"135","author":"Manuelidis","year":"1988","journal-title":"Ciba Found. Symp."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"1965","DOI":"10.1073\/pnas.0610999104","article-title":"Cells infected with scrapie and Creutzfeldt-Jakob disease agents produce intracellular 25-nm virus-like particles","volume":"104","author":"Manuelidis","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1096\/fj.201901897R","article-title":"Liquid-liquid phase separation and fibrillation of the prion protein modulated by a high-affinity DNA aptamer","volume":"34","author":"Matos","year":"2020","journal-title":"FASEB J."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1002\/jcb.22723","article-title":"Proliferative arrest of neural cells induces prion protein synthesis, nanotube formation, and cell-to-cell contacts","volume":"111","author":"Miyazawa","year":"2010","journal-title":"J. Cell. Biochem."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"188","DOI":"10.4161\/viru.2.3.15880","article-title":"Replication and spread of CJD, kuru and scrapie agents in vivo and in cell culture","volume":"2","author":"Miyazawa","year":"2011","journal-title":"Virulence"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"e35471","DOI":"10.1371\/journal.pone.0035471","article-title":"Continuous production of prions after infectious particles are eliminated: implications for Alzheimer's disease","volume":"7","author":"Miyazawa","year":"2012","journal-title":"PLoS One"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1615\/critrevimmunol.v31.i6.20","article-title":"Induction and function of IFNbeta during viral and bacterial infection","volume":"31","author":"Nagarajan","year":"2011","journal-title":"Crit. Rev. Immunol."},{"key":"ref47","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1016\/j.bbagrm.2012.12.003","article-title":"Interplay between viruses and host mRNA degradation","volume":"1829","author":"Narayanan","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref48","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19092821","article-title":"Monocytes and macrophages as viral targets and reservoirs","volume":"19","author":"Nikitina","year":"2018","journal-title":"Int. J. Mol. Sci."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1126\/science.1118155","article-title":"Reciprocal interference between specific CJD and scrapie agents in neural cell cultures","volume":"310","author":"Nishida","year":"2005","journal-title":"Science"},{"key":"ref50","doi-asserted-by":"crossref","DOI":"10.1101\/2020.12.16.423113","article-title":"Long SARS-CoV-2 nucleocapsid sequences in blood monocytes collected soon after hospital admission","volume-title":"bioRxiv [Preprint].","author":"Pagano","year":"2020"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1016\/j.biochi.2007.02.009","article-title":"Type I interferon response in the central nervous system","volume":"89","author":"Paul","year":"2007","journal-title":"Biochimie"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"562","DOI":"10.1007\/s00239-006-0073-3","article-title":"The mammalian 2'-5' oligoadenylate synthetase gene family: evidence for concerted evolution of paralogous Oas1 genes in Rodentia and Artiodactyla","volume":"63","author":"Perelygin","year":"2006","journal-title":"J. Mol. Evol."},{"key":"ref53","doi-asserted-by":"publisher","first-page":"13363","DOI":"10.1073\/pnas.95.23.13363","article-title":"The Nobel lecture: prions","volume":"95","author":"Prusiner","year":"1998","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref54","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1471-2334-1-20","article-title":"Blood borne transit of CJD from brain to gut at early stages of infection","volume":"1","author":"Radebold","year":"2001","journal-title":"BMC Infect. Dis."},{"key":"ref55","doi-asserted-by":"publisher","DOI":"10.3390\/v13081479","article-title":"How do flaviviruses hijack host cell functions by phase separation?","volume":"13","author":"Saito","year":"2021","journal-title":"Viruses"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1038\/s41579-019-0213-6","article-title":"Microbial genes and pathways in inflammatory bowel disease","volume":"17","author":"Schirmer","year":"2019","journal-title":"Nat. Rev. Microbiol."},{"key":"ref57","doi-asserted-by":"publisher","first-page":"9289","DOI":"10.1073\/pnas.161055198","article-title":"Neuroinvasion by a Creutzfeldt-Jakob disease agent in the absence of B cells and follicular dendritic cells","volume":"98","author":"Shlomchik","year":"2001","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"year":"1991","author":"Sigurdarson","key":"ref58"},{"key":"ref59","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1007\/s12017-019-08581-3","article-title":"A transcriptomic analysis of neuropathic pain in rat dorsal root ganglia following peripheral nerve injury","volume":"22","author":"Sun","year":"2020","journal-title":"NeuroMolecular Med."},{"key":"ref60","doi-asserted-by":"publisher","first-page":"e71081","DOI":"10.1371\/journal.pone.0071081","article-title":"Recombinant prion protein refolded with lipid and RNA has the biochemical hallmarks of a prion but lacks in vivo infectivity","volume":"8","author":"Timmes","year":"2013","journal-title":"PLoS One"},{"key":"ref61","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1046\/j.1471-4159.2003.02201.x","article-title":"Morphological and biochemical changes of neurofilaments in aged rat sciatic nerve axons","volume":"88","author":"Uchida","year":"2004","journal-title":"J. Neurochem."},{"key":"ref62","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1111\/j.1365-2826.2008.01760.x","article-title":"Development of an immortalised, post-pubertal gonadotrophin-releasing hormone neuronal cell line","volume":"20","author":"Wolfe","year":"2008","journal-title":"J. Neuroendocrinol."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2022.837662\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,18]],"date-time":"2022-02-18T09:02:46Z","timestamp":1645174966000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2022.837662\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,18]]},"references-count":63,"alternative-id":["10.3389\/fphys.2022.837662"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2022.837662","relation":{},"ISSN":["1664-042X"],"issn-type":[{"type":"electronic","value":"1664-042X"}],"subject":[],"published":{"date-parts":[[2022,2,18]]},"article-number":"837662"}}