{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T03:20:02Z","timestamp":1778642402926,"version":"3.51.4"},"reference-count":88,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2021,6,29]],"date-time":"2021-06-29T00:00:00Z","timestamp":1624924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["BE 4200\/1 3 & LE 2498\/6-1"],"award-info":[{"award-number":["BE 4200\/1 3 & LE 2498\/6-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Neurotropic viruses target the brain and contribute to neurologic diseases. Caspase recruitment domain containing family member 9 (CARD9) controls protective immunity in a variety of infectious disorders. To investigate the effect of CARD9 in neurotropic virus infection, CARD9\u2212\/\u2212 and corresponding C57BL\/6 wild-type control mice were infected with Theiler\u2019s murine encephalomyelitis virus (TMEV). Brain tissue was analyzed by histology, immunohistochemistry and molecular analyses, and spleens by flow cytometry. To determine the impact of CARD9 deficiency on T cell responses in vitro, antigen presentation assays were utilized. Genetic ablation of CARD9 enhanced early pro-inflammatory cytokine responses and accelerated infiltration of T and B cells in the brain, together with a transient increase in TMEV-infected cells in the hippocampus. CARD9\u2212\/\u2212 mice showed an increased loss of neuronal nuclear protein+ mature neurons and doublecortin+ neuronal precursor cells and an increase in \u03b2-amyloid precursor protein+ damaged axons in the hippocampus. No effect of CARD9 deficiency was found on the initiation of CD8+ T cell responses by flow cytometry and co-culture experiments using virus-exposed dendritic cells or microglia-enriched glial cell mixtures, respectively. The present study indicates that CARD9 is dispensable for the initiation of early antiviral responses and TMEV elimination but may contribute to the modulation of neuroinflammation, thereby reducing hippocampal injury following neurotropic virus infection.<\/jats:p>","DOI":"10.3390\/ijms22136982","type":"journal-article","created":{"date-parts":[[2021,6,29]],"date-time":"2021-06-29T04:31:07Z","timestamp":1624941067000},"page":"6982","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["CARD9 Deficiency Increases Hippocampal Injury Following Acute Neurotropic Picornavirus Infection but Does Not Affect Pathogen Elimination"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4395-5766","authenticated-orcid":false,"given":"Suvarin","family":"Pavasutthipaisit","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany"},{"name":"Center for Systems Neuroscience, 30559 Hannover, Germany"},{"name":"Department of Pathology, Faculty of Veterinary Medicine, Mahanakorn University of Technology, Bangkok 10530, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8034-000X","authenticated-orcid":false,"given":"Melanie","family":"Stoff","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tim","family":"Ebbecke","sequence":"additional","affiliation":[{"name":"Center for Systems Neuroscience, 30559 Hannover, Germany"},{"name":"Institute for Immunology and Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, 30559 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6277-7366","authenticated-orcid":false,"given":"Malgorzata","family":"Ciurkiewicz","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabine","family":"Mayer-Lambertz","sequence":"additional","affiliation":[{"name":"Institute for Immunology and Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, 30559 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Theresa","family":"St\u00f6rk","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7555-1315","authenticated-orcid":false,"given":"Kevin D.","family":"Pavelko","sequence":"additional","affiliation":[{"name":"Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bernd","family":"Lepenies","sequence":"additional","affiliation":[{"name":"Center for Systems Neuroscience, 30559 Hannover, Germany"},{"name":"Institute for Immunology and Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine Hannover, 30559 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Beineke","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Veterinary Medicine Hannover, 30559 Hannover, Germany"},{"name":"Center for Systems Neuroscience, 30559 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s00401-015-1511-3","article-title":"Neurotropic virus infections as the cause of immediate and delayed neuropathology","volume":"131","author":"Ludlow","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.nbd.2016.12.020","article-title":"Viral mouse models of multiple sclerosis and epilepsy: Marked differences in neuropathogenesis following infection with two naturally occurring variants of Theiler\u2019s virus BeAn strain","volume":"99","author":"Hage","year":"2017","journal-title":"Neurobiol. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1086\/506939","article-title":"Long-term clinical and neuropsychological outcomes of West Nile virus infection","volume":"43","author":"Carson","year":"2006","journal-title":"Clin. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e828","DOI":"10.1542\/peds.2009-3188","article-title":"Long-term outcomes of acute encephalitis in childhood","volume":"126","author":"Fowler","year":"2010","journal-title":"Pediatrics"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/s00401-015-1481-5","article-title":"Infections, inflammation and epilepsy","volume":"131","author":"Vezzani","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1073\/pnas.1711977115","article-title":"Hippocampal expression of a virus-derived protein impairs memory in mice","volume":"115","author":"Betourne","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"De Chiara, G., Piacentini, R., Fabiani, M., Mastrodonato, A., Marcocci, M.E., Limongi, D., Napoletani, G., Protto, V., Coluccio, P., and Celestino, I. (2019). Recurrent herpes simplex virus-1 infection induces hallmarks of neurodegeneration and cognitive deficits in mice. PLoS Pathog., 15.","DOI":"10.1371\/journal.ppat.1007617"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1186\/s12974-020-01951-w","article-title":"Langat virus infection affects hippocampal neuron morphology and function in mice without disease signs","volume":"17","author":"Cornelius","year":"2020","journal-title":"J. Neuroinflamm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1126\/science.80.2066.122.b","article-title":"Spontaneous encephalomyelitis of mice\u2014A new virus disease","volume":"80","author":"Theiler","year":"1934","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1111\/j.1528-1167.2008.01535.x","article-title":"Seizures following picornavirus infection","volume":"49","author":"Libbey","year":"2008","journal-title":"Epilepsia"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1097\/NEN.0b013e3181ffc420","article-title":"Development of Post-infection Epilepsy Following Theiler Virus Infection of C57BL\/6 Mice","volume":"69","author":"Stewart","year":"2010","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.nbd.2006.07.003","article-title":"Disrupted spatial memory is a consequence of picornavirus infection","volume":"24","author":"Buenz","year":"2006","journal-title":"Neurobiol. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.2217\/fvl.11.107","article-title":"Neurotropic viral infections leading to epilepsy: Focus on Theiler\u2019s murine encephalomyelitis virus","volume":"6","author":"Libbey","year":"2011","journal-title":"Future Virol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.nbd.2013.12.015","article-title":"Impaired cognitive ability and anxiety-like behavior following acute seizures in the Theiler\u2019s virus model of temporal lobe epilepsy","volume":"64","author":"Umpierre","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Gerhauser, I., Hansmann, F., Ciurkiewicz, M., L\u00f6scher, W., and Beineke, A. (2019). Facets of Theiler\u2019s Murine Encephalomyelitis Virus-Induced Diseases: An Update. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20020448"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1089\/vim.2013.0004","article-title":"IFNgamma influences type I interferon response and susceptibility to Theiler\u2019s virus-induced demyelinating disease","volume":"26","author":"Bowen","year":"2013","journal-title":"Viral Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1186\/s12974-015-0462-x","article-title":"Interferon-stimulated genes-essential antiviral effectors implicated in resistance to Theiler\u2019s virus-induced demyelinating disease","volume":"12","author":"Li","year":"2015","journal-title":"J. Neuroinflamm."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Drappier, M., Jha, B.K., Stone, S., Elliott, R., Zhang, R., Vertommen, D., Weiss, S.R., Silverman, R.H., and Michiels, T. (2018). A novel mechanism of RNase L inhibition: Theiler\u2019s virus L* protein prevents 2\u20135A from binding to RNase, L. PLoS Pathog., 14.","DOI":"10.1371\/journal.ppat.1006989"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1111\/j.1528-1167.2009.02390.x","article-title":"Innate but not adaptive immune responses contribute to behavioral seizures following viral infection","volume":"51","author":"Kirkman","year":"2010","journal-title":"Epilepsia"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1742-2094-9-50","article-title":"Inflammatory monocytes damage the hippocampus during acute picornavirus infection of the brain","volume":"9","author":"Howe","year":"2012","journal-title":"J. Neuroinflamm."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1038\/srep00545","article-title":"Hippocampal protection in mice with an attenuated inflammatory monocyte response to acute CNS picornavirus infection","volume":"2","author":"Howe","year":"2012","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1128\/JVI.02747-12","article-title":"Infiltrating macrophages are key to the development of seizures following virus infection","volume":"87","author":"Cusick","year":"2013","journal-title":"J. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.bbi.2018.09.006","article-title":"Microglia have a protective role in viral encephalitis-induced seizure development and hippocampal damage","volume":"74","author":"Waltl","year":"2018","journal-title":"Brain Behav. Immun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/nature04926","article-title":"Card9 controls a non-TLR signalling pathway for innate anti-fungal immunity","volume":"442","author":"Gross","year":"2006","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1038\/ni1417","article-title":"Myeloid C-type lectins in innate immunity","volume":"7","author":"Robinson","year":"2006","journal-title":"Nat. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/s00418-016-1523-7","article-title":"C-type lectins: Their network and roles in pathogen recognition and immunity","volume":"147","author":"Mayer","year":"2017","journal-title":"Histochem. Cell Biol."},{"key":"ref_27","first-page":"177","article-title":"Physiological and Pathological Functions of CARD9 Signaling in the Innate Immune System","volume":"429","author":"Vornholz","year":"2020","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1038\/ni1460","article-title":"Syk-and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17","volume":"8","author":"Robinson","year":"2007","journal-title":"Nat. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2417","DOI":"10.4049\/jimmunol.1500102","article-title":"Contribution of MINCLE\u2013SYK signaling to activation of primary human APCs by mycobacterial cord factor and the novel adjuvant TDB","volume":"195","author":"Ostrop","year":"2015","journal-title":"J. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"E10662","DOI":"10.1073\/pnas.1809100115","article-title":"Lipoteichoic acid anchor triggers Mincle to drive protective immunity against invasive group A Streptococcus infection","volume":"115","author":"Imai","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1016\/j.celrep.2018.01.001","article-title":"CD209a synergizes with Dectin-2 and mincle to drive severe Th17 cell-mediated schistosome egg-induced immunopathology","volume":"22","author":"Kalantari","year":"2018","journal-title":"Cell Rep."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Monteiro, J.T., Sch\u00f6n, K., Ebbecke, T., Goethe, R., Ruland, J., Baumg\u00e4rtner, W., Becker, S.C., and Lepenies, B. (2019). The CARD9-Associated C-Type Lectin, Mincle, Recognizes La Crosse Virus (LACV) but Plays a Limited Role in Early Antiviral Responses against LACV. Viruses, 11.","DOI":"10.3390\/v11030303"},{"key":"ref_33","first-page":"647","article-title":"Activation of C-Type Lectin Receptor and (RIG)-I-Like Receptors Contributes to Proinflammatory Response in Middle East Respiratory Syndrome Coronavirus-Infected Macrophages","volume":"221","author":"Zhao","year":"2020","journal-title":"J. Infect. Dis."},{"key":"ref_34","first-page":"511","article-title":"S-Layer From Lactobacillus brevis Modulates Antigen-Presenting Cell Functions via the Mincle-Syk-Card9 Axis","volume":"12","author":"Scheffel","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1038\/ni1426","article-title":"The adaptor protein CARD9 is required for innate immune responses to intracellular pathogens","volume":"8","author":"Hsu","year":"2007","journal-title":"Nat. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1038\/ni.1824","article-title":"Recognition of RNA virus by RIG-I results in activation of CARD9 and inflammasome signaling for interleukin 1 beta production","volume":"11","author":"Poeck","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1038\/ni.2888","article-title":"Rad50-CARD9 interactions link cytosolic DNA sensing to IL-1beta production","volume":"15","author":"Roth","year":"2014","journal-title":"Nat. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"17577","DOI":"10.1038\/srep17577","article-title":"Loss of CARD9-mediated innate activation attenuates severe influenza pneumonia without compromising host viral immunity","volume":"5","author":"Uematsu","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"107261","DOI":"10.1016\/j.carpath.2020.107261","article-title":"CARD9 mediates T cell inflammatory response in Coxsackievirus B3-induced acute myocarditis","volume":"49","author":"Sun","year":"2020","journal-title":"Cardiovasc. Pathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1006\/viro.2000.0646","article-title":"Differential expression of TGF-beta, IL-2, and other cytokines in the CNS of Theiler\u2019s murine encephalomyelitis virus-infected susceptible and resistant strains of mice","volume":"278","author":"Chang","year":"2000","journal-title":"Virology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1128\/CMR.17.1.174-207.2004","article-title":"Theiler\u2019s virus infection: A model for multiple sclerosis","volume":"17","author":"Oleszak","year":"2004","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Monteiro, J.T., and Lepenies, B. (2017). Myeloid C-type lectin receptors in viral recognition and antiviral immunity. Viruses, 9.","DOI":"10.3390\/v9030059"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/B978-0-12-819475-1.00063-8","article-title":"C-Type Lectins and Their Roles in Disease and Immune Homeostasis","volume":"5","author":"Ebbecke","year":"2021","journal-title":"Compr. Glycosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1111\/bpa.12518","article-title":"Cytotoxic CD8(+) T cell ablation enhances the capacity of regulatory T cells to delay viral elimination in Theiler\u2019s murine encephalomyelitis","volume":"28","author":"Ciurkiewicz","year":"2018","journal-title":"Brain Pathol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6584","DOI":"10.1128\/JVI.00008-07","article-title":"Differential outcome of tolerance induction in naive versus activated Theiler\u2019s virus epitope-specific CD8+ cytotoxic T cells","volume":"81","author":"Getts","year":"2007","journal-title":"J. Virol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.virol.2010.02.031","article-title":"A critical role for virus-specific CD8(+) CTLs in protection from Theiler\u2019s virus-induced demyelination in disease-susceptible SJL mice","volume":"402","author":"Getts","year":"2010","journal-title":"Virology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1038\/ni1466","article-title":"The adaptor protein CARD9 is essential for the activation of myeloid cells through ITAM-associated and Toll-like receptors","volume":"8","author":"Hara","year":"2007","journal-title":"Nat. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1056\/NEJMoa0810719","article-title":"A homozygous CARD9 mutation in a family with susceptibility to fungal infections","volume":"361","author":"Glocker","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1093\/cid\/ciu215","article-title":"CARD9 deficiency and spontaneous central nervous system candidiasis: Complete clinical remission with GM-CSF therapy","volume":"59","author":"Gavino","year":"2014","journal-title":"Clin. Infect. Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1038\/s41419-017-0084-6","article-title":"Molecular and physiological roles of the adaptor protein CARD9 in immunity","volume":"9","author":"Zhong","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/s41590-019-0377-2","article-title":"CARD9(+) microglia promote antifungal immunity via IL-1beta- and CXCL1-mediated neutrophil recruitment","volume":"20","author":"Drummond","year":"2019","journal-title":"Nat. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1016\/S0002-9440(10)63922-3","article-title":"Axonal injury heralds virus-induced demyelination","volume":"162","author":"Tsunoda","year":"2003","journal-title":"Am. J. Pathol."},{"key":"ref_53","first-page":"579","article-title":"Axonal degeneration as a self-destructive defense mechanism against neurotropic virus infection","volume":"3","author":"Tsunoda","year":"2008","journal-title":"Future Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"214","DOI":"10.2353\/ajpath.2007.060683","article-title":"Contrasting roles for axonal degeneration in an autoimmune versus viral model of multiple sclerosis: When can axonal injury be beneficial?","volume":"170","author":"Tsunoda","year":"2007","journal-title":"Am. J. Pathol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1111\/j.1365-2990.2012.01256.x","article-title":"Impact of Theiler\u2019s virus infection on hippocampal neuronal progenitor cells: Differential effects in two mouse strains","volume":"38","author":"Jafari","year":"2012","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1038\/cr.2013.155","article-title":"Identification of IFN-\u03b3-producing innate B cells","volume":"24","author":"Bao","year":"2014","journal-title":"Cell Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1111\/imr.12621","article-title":"Overview of the IL-1 family in innate inflammation and acquired immunity","volume":"281","author":"Dinarello","year":"2018","journal-title":"Immunol. Rev."},{"key":"ref_58","first-page":"1","article-title":"Viral pathogen-induced mechanisms to antagonize mammalian interferon (IFN) signaling pathway","volume":"78","author":"Rojas","year":"2020","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"6441","DOI":"10.1128\/JVI.79.10.6441-6448.2005","article-title":"Interleukin-1 is responsible for acute lung immunopathology but increases survival of respiratory influenza virus infection","volume":"79","author":"Schmitz","year":"2005","journal-title":"J. Virol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1128\/JVI.80.1.119-129.2006","article-title":"CD8+ T cells require perforin to clear West Nile virus from infected neurons","volume":"80","author":"Shrestha","year":"2006","journal-title":"J. Virol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"4497","DOI":"10.4049\/jimmunol.155.9.4497","article-title":"Treatment with bacterial LPS renders genetically resistant C57BL\/6 mice susceptible to Theiler\u2019s virus-induced demyelinating disease","volume":"155","author":"Pullen","year":"1995","journal-title":"J. Immunol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1742-2094-9-217","article-title":"IL-1 signal affects both protection and pathogenesis of virus-induced chronic CNS demyelinating disease","volume":"9","author":"Kim","year":"2012","journal-title":"J. Neuroinflamm."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.jneuroim.2005.07.009","article-title":"Differential effects of interleukin-1beta on neurotoxicity, cytokine induction and glial reaction in specific brain regions","volume":"168","author":"Depino","year":"2005","journal-title":"J. Neuroimmunol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1073\/pnas.0708092105","article-title":"IL-1\u03b2 is an essential mediator of the antineurogenic and anhedonic effects of stress","volume":"105","author":"Koo","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1880","DOI":"10.1093\/brain\/awn101","article-title":"Central and systemic IL-1 exacerbates neurodegeneration and motor symptoms in a model of Parkinson\u2019s disease","volume":"131","author":"Tarelli","year":"2008","journal-title":"Brain"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1111\/j.1471-4159.2008.05230.x","article-title":"The inflammatory cytokine, interleukin-1 beta, mediates loss of astroglial glutamate transport and drives excitotoxic motor neuron injury in the spinal cord during acute viral encephalomyelitis","volume":"105","author":"Prow","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"12874","DOI":"10.1038\/ncomms12874","article-title":"CARD9 negatively regulates NLRP3-induced IL-1beta production on Salmonella infection of macrophages","volume":"7","author":"Pereira","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41419-019-1777-9","article-title":"Microglial TREM-1 receptor mediates neuroinflammatory injury via interaction with SYK in experimental ischemic stroke","volume":"10","author":"Xu","year":"2019","journal-title":"Cell Death Dis."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"e03005-19","DOI":"10.1128\/mBio.03005-19","article-title":"CARD9 Is Required for Classical Macrophage Activation and the Induction of Protective Immunity against Pulmonary Cryptococcosis","volume":"11","author":"Campuzano","year":"2020","journal-title":"mBio"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"603","DOI":"10.3389\/fimmu.2014.00603","article-title":"TH1\/TH2 paradigm extended: Macrophage polarization as an unappreciated pathogen-driven escape mechanism?","volume":"5","author":"Muraille","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.jaut.2010.12.005","article-title":"Virus expanded regulatory T cells control disease severity in the Theiler\u2019s virus mouse model of MS","volume":"36","author":"Richards","year":"2011","journal-title":"J. Autoimmun."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1111\/bpa.12119","article-title":"Protective and detrimental roles for regulatory T cells in a viral model for multiple sclerosis","volume":"24","author":"Martinez","year":"2014","journal-title":"Brain Pathol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1084\/jem.96.6.517","article-title":"Observations on encephalomyelitis of mice (DA strain)","volume":"96","author":"Daniels","year":"1952","journal-title":"J. Exp. Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1007\/BF02149971","article-title":"\u00dcber die Z\u00fcchtung des Theiler-TO-Virus in der Gewebekultur","volume":"143","author":"Falke","year":"1957","journal-title":"Zeitschrift f\u00fcr Hygiene und Infektionskrankheiten"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"357","DOI":"10.4049\/jimmunol.117.2.357","article-title":"Cellular immunity in chronic Theiler\u2019s virus central nervous system infection","volume":"117","author":"Rabinowitz","year":"1976","journal-title":"J. Immunol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1128\/iai.20.3.869-872.1978","article-title":"Characterization of the TO strains of Theiler\u2019s mouse encephalomyelitis viruses","volume":"20","author":"Lipton","year":"1978","journal-title":"Infect. Immun."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1080\/13550280802008305","article-title":"Differential transcription of matrix-metalloproteinase genes in primary mouse astrocytes and microglia infected with Theiler\u2019s murine encephalomyelitis virus","volume":"14","author":"Kumnok","year":"2008","journal-title":"J. Neurovirol."},{"key":"ref_78","first-page":"E8929","article-title":"Chemokine receptors CCR2 and CX3CR1 regulate viral encephalitis-induced hippocampal damage but not seizures","volume":"115","author":"Chhatbar","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.nbd.2017.12.001","article-title":"Macrophage depletion by liposome-encapsulated clodronate suppresses seizures but not hippocampal damage after acute viral encephalitis","volume":"110","author":"Waltl","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref_80","unstructured":"Paxinos, G., and Franklin, K. (2007). The Mouse Brain in Stereotaxic Coordinates, Academic Press. [3rd ed.]."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.eplepsyres.2012.09.015","article-title":"The intrahippocampal kainate model of temporal lobe epilepsy revisited: Epileptogenesis, behavioral and cognitive alterations, pharmacological response, and hippoccampal damage in epileptic rats","volume":"103","author":"Rattka","year":"2013","journal-title":"Epilepsy Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1097\/01.jnen.0000229990.32795.0d","article-title":"MMP-12, MMP-3, and TIMP-1 are markedly upregulated in chronic demyelinating theiler murine encephalomyelitis","volume":"65","author":"Ulrich","year":"2006","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.jneuroim.2012.01.010","article-title":"Cuprizone inhibits demyelinating leukomyelitis by reducing immune responses without virus exacerbation in an infectious model of multiple sclerosis","volume":"244","author":"Herder","year":"2012","journal-title":"J. Neuroimmunol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/gb-2002-3-7-research0034","article-title":"Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes","volume":"3","author":"Vandesompele","year":"2002","journal-title":"Genome Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/j.ijdevneu.2005.06.004","article-title":"Spatio-temporal expression of immediate early genes in the central nervous system of SJL\/J mice","volume":"23","author":"Gerhauser","year":"2005","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Pavelko, K.D., Girtman, M.A., Mitsunaga, Y., Mendez-Fernandez, Y.V., Bell, M.P., Hansen, M.J., Allen, K.S., Rodriguez, M., and Pease, L.R. (2011). Theiler\u2019s murine encephalomyelitis virus as a vaccine candidate for immunotherapy. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0020217"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1038\/mt.2013.52","article-title":"The epitope integration site for vaccine antigens determines virus control while maintaining efficacy in an engineered cancer vaccine","volume":"21","author":"Pavelko","year":"2013","journal-title":"Mol. Ther."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12974-014-0180-9","article-title":"Limited role of regulatory T cells during acute Theiler virus-induced encephalitis in resistant C57BL\/6 mice","volume":"11","author":"Prajeeth","year":"2014","journal-title":"J. Neuroinflamm."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/13\/6982\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:26:27Z","timestamp":1760163987000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/13\/6982"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,29]]},"references-count":88,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["ijms22136982"],"URL":"https:\/\/doi.org\/10.3390\/ijms22136982","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,29]]}}}