{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:20:07Z","timestamp":1760149207677,"version":"build-2065373602"},"reference-count":48,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2023,7,18]],"date-time":"2023-07-18T00:00:00Z","timestamp":1689638400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NSERC Discovery"},{"name":"Alberta Prion Research Institute"},{"name":"Genome Canada"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Prion diseases are progressive neurodegenerative disorders affecting humans and various mammals. The prominent neuropathological change in prion-affected brains is neuroinflammation, histopathologically characterized by reactive gliosis surrounding prion deposition. The cause and effect of these cellular responses are still unclear. Here we investigate the impact of innate immune responses on prion replication using in vitro cell culture models. Hamster-adapted transmissible mink encephalopathy prions, hyper (HY) and drowsy (DY) strains, were assayed for accumulation of pathogenic prion protein (PrPSc) in primary glial cultures derived from 8-day-old hamster pups. The kinetics of PrPSc accumulation largely depended on prion strain and brain regions from where glial cells originated. Glial cells derived from the cerebellum were susceptible to HY, but resistant to DY strain as determined by western blot analysis, immunocytochemistry, and animal bioassay. Glial cells from the cerebral cortex were, however, refractory to both strains. PrPSc accumulation was affected by innate immune modulators. Priming glial cells with lipopolysaccharide decreased prion replication, whereas pre-treatment with dexamethasone, inhibiting innate immunity, increased susceptibility to DY infection. Our results suggest that neuroinflammation resulting from prion infection is a response to resolve and\/or prevent prion propagation in the brain. It implies a therapeutic potential of innate immune modulation in the early stages of prion disease.<\/jats:p>","DOI":"10.3390\/cells12141878","type":"journal-article","created":{"date-parts":[[2023,7,18]],"date-time":"2023-07-18T01:35:16Z","timestamp":1689644116000},"page":"1878","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Innate Immune Status of Glia Modulates Prion Propagation in Early Stage of Infection"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6875-113X","authenticated-orcid":false,"given":"Sang-Gyun","family":"Kang","sequence":"first","affiliation":[{"name":"Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB T6G 2M8, Canada"},{"name":"Department of Medicine, University of Alberta, Edmonton, AB T6G 2R7, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiye","family":"Kim","sequence":"additional","affiliation":[{"name":"Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB T6G 2M8, Canada"},{"name":"Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judd","family":"Aiken","sequence":"additional","affiliation":[{"name":"Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB T6G 2M8, Canada"},{"name":"Department of Agricultural, Food and Nutritional Sciences, University of Alberta, Edmonton, AB T6G 1C9, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Debbie","family":"McKenzie","sequence":"additional","affiliation":[{"name":"Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB T6G 2M8, Canada"},{"name":"Department of Biological Sciences, University of Alberta, Edmonton, AB T6G 2E9, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1126\/science.6801762","article-title":"Novel proteinaceous infectious particles cause scrapie","volume":"216","author":"Prusiner","year":"1982","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"a006833","DOI":"10.1101\/cshperspect.a006833","article-title":"Prions","volume":"3","author":"Colby","year":"2011","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1146\/annurev.pathmechdis.3.121806.154326","article-title":"Molecular mechanisms of prion pathogenesis","volume":"3","author":"Aguzzi","year":"2008","journal-title":"Annu. Rev. Pathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1152\/physrev.00006.2009","article-title":"Prions: Protein aggregation and infectious diseases","volume":"89","author":"Aguzzi","year":"2009","journal-title":"Physiol. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1038\/nri3553","article-title":"The immunobiology of prion diseases","volume":"13","author":"Aguzzi","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/nri2565","article-title":"Regulation of innate immune responses in the brain","volume":"9","author":"Rivest","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/s41586-019-1769-z","article-title":"NLRP3 inflammasome activation drives tau pathology","volume":"575","author":"Ising","year":"2019","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"109720","DOI":"10.1016\/j.celrep.2021.109720","article-title":"Proteopathic tau primes and activates interleukin-1beta via myeloid-cell-specific MyD88- and NLRP3-ASC-inflammasome pathway","volume":"36","author":"Jiang","year":"2021","journal-title":"Cell Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1007\/s00401-018-01957-y","article-title":"Aggregated Tau activates NLRP3-ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo","volume":"137","author":"Stancu","year":"2019","journal-title":"Acta Neuropathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1038\/s41467-022-29552-6","article-title":"Microglial NF-kappaB drives tau spreading and toxicity in a mouse model of tauopathy","volume":"13","author":"Wang","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/nrneurol.2013.275","article-title":"Extracellular alpha--synuclein-a novel and crucial factor in Lewy body diseases","volume":"10","author":"Lee","year":"2014","journal-title":"Nat. Rev. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e984","DOI":"10.1212\/NXI.0000000000000984","article-title":"Microglia Activation in Basal Ganglia Is a Late Event in Huntington Disease Pathophysiology","volume":"8","author":"Rocha","year":"2021","journal-title":"Neurol.-Neuroimmunol. Neuroinflam."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e13056","DOI":"10.1111\/bpa.13056","article-title":"Glial activation in prion diseases is selectively triggered by neuronal PrP(Sc)","volume":"32","author":"Lakkaraju","year":"2022","journal-title":"Brain Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/s40478-021-01123-8","article-title":"Non-cell autonomous astrocyte-mediated neuronal toxicity in prion diseases","volume":"9","author":"Kushwaha","year":"2021","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1038\/s41577-019-0165-0","article-title":"The NLRP3 inflammasome: Molecular activation and regulation to therapeutics","volume":"19","author":"Swanson","year":"2019","journal-title":"Nat. Rev. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1084\/jem.20151000","article-title":"A neuroprotective role for microglia in prion diseases","volume":"213","author":"Zhu","year":"2016","journal-title":"J. Exp. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1128\/JVI.00549-18","article-title":"Microglia Are Critical in Host Defense against Prion Disease","volume":"92","author":"Carroll","year":"2018","journal-title":"J. Virol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/s40478-019-0735-1","article-title":"Complement 3(+)-astrocytes are highly abundant in prion diseases, but their abolishment led to an accelerated disease course and early dysregulation of microglia","volume":"7","author":"Hartmann","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1186\/s40478-021-01192-9","article-title":"The degree of astrocyte activation is predictive of the incubation time to prion disease","volume":"9","author":"Makarava","year":"2021","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e62911","DOI":"10.7554\/eLife.62911","article-title":"Ribosomal profiling during prion disease uncovers progressive translational derangement in glia but not in neurons","volume":"9","author":"Scheckel","year":"2020","journal-title":"Elife"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1016\/S1474-4422(15)70016-5","article-title":"Neuroinflammation in Alzheimer\u2019s disease","volume":"14","author":"Heneka","year":"2015","journal-title":"Lancet Neurol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e01457-17","DOI":"10.1128\/JVI.01457-17","article-title":"Flow Cytometric Detection of PrP(Sc) in Neurons and Glial Cells from Prion-Infected Mouse Brains","volume":"92","author":"Yamasaki","year":"2018","journal-title":"J. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Carroll, J.A., Striebel, J.F., Rangel, A., Woods, T., Phillips, K., Peterson, K.E., Race, B., and Chesebro, B. (2016). Prion Strain Differences in Accumulation of PrPSc on Neurons and Glia Are Associated with Similar Expression Profiles of Neuroinflammatory Genes: Comparison of Three Prion Strains. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005551"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.4103\/1673-5374.332202","article-title":"Astrocyte in prion disease: A double-edged sword","volume":"17","author":"Tahir","year":"2022","journal-title":"Neural Regen. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1073\/pnas.88.2.375","article-title":"Scrapie-associated prion protein accumulates in astrocytes during scrapie infection","volume":"88","author":"Diedrich","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1002\/glia.22973","article-title":"Toll-like receptor-mediated immune response inhibits prion propagation","volume":"64","author":"Kang","year":"2016","journal-title":"Glia"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1089\/hyb.2006.25.271","article-title":"Generation of monoclonal antibody recognized by the GXXXG motif (glycine zipper) of prion protein","volume":"25","author":"Choi","year":"2006","journal-title":"Hybridoma"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1128\/JVI.01745-08","article-title":"Prion strain targeting independent of strain-specific neuronal tropism","volume":"83","author":"Ayers","year":"2009","journal-title":"J. Virol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"12880","DOI":"10.1074\/jbc.M115.681791","article-title":"Role of Prion Replication in the Strain-dependent Brain Regional Distribution of Prions","volume":"291","author":"Hu","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2565","DOI":"10.1099\/0022-1317-81-10-2565","article-title":"Strain-specific propagation of PrP(Sc) properties into baculovirus-expressed hamster PrP(C)","volume":"81","author":"Iniguez","year":"2000","journal-title":"J. Gen. Virol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"104783","DOI":"10.1016\/j.nbd.2020.104783","article-title":"Region-specific glial homeostatic signature in prion diseases is replaced by a uniform neuroinflammation signature, common for brain regions and prion strains with different cell tropism","volume":"137","author":"Makarava","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Shikiya, R.A., Langenfeld, K.A., Eckland, T.E., Trinh, J., Holec, S.A.M., Mathiason, C.K., Kincaid, A.E., and Bartz, J.C. (2017). PrPSc formation and clearance as determinants of prion tropism. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006298"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1038\/ncb1841","article-title":"Prions hijack tunnelling nanotubes for intercellular spread","volume":"11","author":"Gousset","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1242\/jcs.058099","article-title":"Neuronal low-density lipoprotein receptor-related protein 1 binds and endocytoses prion fibrils via receptor cluster 4","volume":"123","author":"Jen","year":"2010","journal-title":"J. Cell Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/s41586-020-2156-5","article-title":"LRP1 is a master regulator of tau uptake and spread","volume":"580","author":"Rauch","year":"2020","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s13024-022-00560-w","article-title":"LRP1 is a neuronal receptor for alpha-synuclein uptake and spread","volume":"17","author":"Chen","year":"2022","journal-title":"Mol. Neurodegener."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"443","DOI":"10.4161\/pri.22579","article-title":"Protective role of MyD88-independent innate immune responses against prion infection","volume":"6","author":"Ishibashi","year":"2012","journal-title":"Prion"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1186\/1742-2094-9-73","article-title":"The NALP3 inflammasome is involved in neurotoxic prion peptide-induced microglial activation","volume":"9","author":"Shi","year":"2012","journal-title":"J. Neuroinflam."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"13433","DOI":"10.1128\/JVI.02072-13","article-title":"Absence of CD14 delays progression of prion diseases accompanied by increased microglial activation","volume":"87","author":"Sakai","year":"2013","journal-title":"J. Virol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s13041-020-00610-8","article-title":"RNA-seq and network analysis reveal unique glial gene expression signatures during prion infection","volume":"13","author":"Carroll","year":"2020","journal-title":"Mol. Brain"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3230","DOI":"10.1172\/JCI90605","article-title":"Microglia in prion diseases","volume":"127","author":"Aguzzi","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"608073","DOI":"10.3389\/fncel.2020.608073","article-title":"Astrocyte-Oligodendrocyte-Microglia Crosstalk in Astrocytopathies","volume":"14","author":"Bugiani","year":"2020","journal-title":"Front. Cell. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"11858","DOI":"10.1128\/JVI.79.18.11858-11863.2005","article-title":"Extraneural prion neuroinvasion without lymphoreticular system infection","volume":"79","author":"Bartz","year":"2005","journal-title":"J. Virol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6435","DOI":"10.1128\/JVI.00018-09","article-title":"Role of the lymphoreticular system in prion neuroinvasion from the oral and nasal mucosa","volume":"83","author":"Bessen","year":"2009","journal-title":"J. Virol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1016\/j.jcpa.2012.03.008","article-title":"Disease-associated prion protein in neural and lymphoid tissues of mink (Mustela vison) inoculated with transmissible mink encephalopathy","volume":"147","author":"Schneider","year":"2012","journal-title":"J. Comp. Pathol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5706","DOI":"10.1128\/JVI.00243-10","article-title":"Coinfecting prion strains compete for a limiting cellular resource","volume":"84","author":"Shikiya","year":"2010","journal-title":"J. Virol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1146\/annurev-med-050715-104343","article-title":"Innate Immunity and Neurodegeneration","volume":"69","author":"Labzin","year":"2018","journal-title":"Annu. Rev. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1128\/JVI.01751-06","article-title":"Prion interference is due to a reduction in strain-specific PrPSc levels","volume":"81","author":"Bartz","year":"2007","journal-title":"J. Virol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/14\/1878\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:13:44Z","timestamp":1760127224000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/14\/1878"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,18]]},"references-count":48,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["cells12141878"],"URL":"https:\/\/doi.org\/10.3390\/cells12141878","relation":{},"ISSN":["2073-4409"],"issn-type":[{"type":"electronic","value":"2073-4409"}],"subject":[],"published":{"date-parts":[[2023,7,18]]}}}