Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ASCO Annual Meeting 2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

2024 ASCO Annual Meeting

Keep up to date with all the top stories and latest evidence with our hub page, including official congress videos and expert takeaways.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2023

Open Access 01-12-2023 | Cytokines | Research

IFNAR signaling of neuroectodermal cells is essential for the survival of C57BL/6 mice infected with Theiler’s murine encephalomyelitis virus

Authors: Melanie Bühler, Dandan Li, Lin Li, Sandra Runft, Inken Waltl, Andreas Pavlou, Ulrich Kalinke, Malgorzata Ciurkiewicz, Jochen Huehn, Stefan Floess, Andreas Beineke, Wolfgang Baumgärtner, Ingo Gerhauser

Published in: Journal of Neuroinflammation | Issue 1/2023

Login to get access

Abstract

Background

Theiler’s murine encephalomyelitis virus (TMEV) is a single-stranded RNA virus that causes encephalitis followed by chronic demyelination in SJL mice and spontaneous seizures in C57BL/6 mice. Since earlier studies indicated a critical role of type I interferon (IFN-I) signaling in the control of viral replication in the central nervous system (CNS), mouse strain-specific differences in pathways induced by the IFN-I receptor (IFNAR) might determine the outcome of TMEV infection.

Methods

Data of RNA-seq analysis and immunohistochemistry were used to compare the gene and protein expression of IFN-I signaling pathway members between mock- and TMEV-infected SJL and C57BL/6 mice at 4, 7 and 14 days post-infection (dpi). To address the impact of IFNAR signaling in selected brain-resident cell types, conditional knockout mice with an IFNAR deficiency in cells of the neuroectodermal lineage (NesCre±IFNARfl/fl), neurons (Syn1Cre±IFNARfl/fl), astrocytes (GFAPCre±IFNARfl/fl), and microglia (Sall1CreER±IFNARfl/fl) on a C57BL/6 background were tested. PCR and an immunoassay were used to quantify TMEV RNA and cytokine and chemokine expression in their brain at 4 dpi.

Results

RNA-seq analysis revealed upregulation of most ISGs in SJL and C57BL/6 mice, but Ifi202b mRNA transcripts were only increased in SJL and Trim12a only in C57BL/6 mice. Immunohistochemistry showed minor differences in ISG expression (ISG15, OAS, PKR) between both mouse strains. While all immunocompetent Cre-negative control mice and the majority of mice with IFNAR deficiency in neurons or microglia survived until 14 dpi, lack of IFNAR expression in all cells (IFNAR−/−), neuroectodermal cells, or astrocytes induced lethal disease in most of the analyzed mice, which was associated with unrestricted viral replication. NesCre±IFNARfl/fl mice showed more Ifnb1, Tnfa, Il6, Il10, Il12b and Ifng mRNA transcripts than Cre−/−IFNARfl/fl mice. IFNAR−/− mice also demonstrated increased IFN-α, IFN-β, IL1-β, IL-6, and CXCL-1 protein levels, which highly correlated with viral load.

Conclusions

Ifi202b and Trim12a expression levels likely contribute to mouse strain-specific susceptibility to TMEV-induced CNS lesions. Restriction of viral replication is strongly dependent on IFNAR signaling of neuroectodermal cells, which also controls the expression of key pro- and anti-inflammatory cytokines during viral brain infection.
Appendix
Available only for authorised users
Literature
1.
Gerhauser I, Hansmann F, Ciurkiewicz M, Löscher W, Beineke A. Facets of Theiler’s murine encephalomyelitis virus-induced diseases: an update. Int J Mol Sci. 2019;20:E448.CrossRef
2.
3.
4.
Azoulay-Cayla A, Dethlefs S, Perarnau B, Larsson-Sciard EL, Lemonnier FA, Brahic M, Bureau JF. H-2D(b-/-) mice are susceptible to persistent infection by Theiler’s virus. J Virol. 2000;74:5470–6.PubMedPubMedCentralCrossRef
5.
Brahic M, Bureau JF, Michiels T. The genetics of the persistent infection and demyelinating disease caused by Theiler’s virus. Annu Rev Microbiol. 2005;59:279–98.PubMedCrossRef
6.
Ciurkiewicz M, Floess S, Beckstette M, Kummerfeld M, Baumgärtner W, Huehn J, Beineke A. Transcriptome analysis following neurotropic virus infection reveals faulty innate immunity and delayed antigen presentation in mice susceptible to virus-induced demyelination. Brain Pathol. 2021;31:e13000.PubMedPubMedCentralCrossRef
7.
Bühler M, Runft S, Li D, Götting J, Detje CN, Nippold V, Stoff M, Beineke A, Schulz T, Kalinke U, et al. IFN-beta deficiency results in fatal or demyelinating disease in C57BL/6 mice infected with Theiler’s murine encephalomyelitis viruses. Front Immunol. 2022;13:786940.PubMedPubMedCentralCrossRef
8.
Isaacs A, Lindenmann J. Virus interference. I. The interferon. Proc R Soc Lond B Biol Sci. 1957;147:258–67.PubMedCrossRef
9.
Pestka S. The interferons: 50 years after their discovery, there is much more to learn. J Biol Chem. 2007;282:20047–51.PubMedCrossRef
10.
Billiau A, Matthys P. Interferon-gamma: a historical perspective. Cytokine Growth Factor Rev. 2009;20:97–113.PubMedCrossRef
11.
Lanford RE, Guerra B, Lee H, Chavez D, Brasky KM, Bigger CB. Genomic response to interferon-alpha in chimpanzees: implications of rapid downregulation for hepatitis C kinetics. Hepatology. 2006;43:961–72.PubMedCrossRef
12.
13.
Majoros A, Platanitis E, Kernbauer-Holzl E, Rosebrock F, Muller M, Decker T. Canonical and non-canonical aspects of JAK–STAT signaling: lessons from interferons for cytokine responses. Front Immunol. 2017;8:29.PubMedPubMedCentralCrossRef
14.
Li L, Ulrich R, Baumgärtner W, Gerhauser I. Interferon-stimulated genes-essential antiviral effectors implicated in resistance to Theiler’s virus-induced demyelinating disease. J Neuroinflamm. 2015;12:242.CrossRef
15.
16.
Balachandran S, Roberts PC, Brown LE, Truong H, Pattnaik AK, Archer DR, Barber GN. Essential role for the dsRNA-dependent protein kinase PKR in innate immunity to viral infection. Immunity. 2000;13:129–41.PubMedCrossRef
17.
Clemens MJ, Elia A. The double-stranded RNA-dependent protein kinase PKR: structure and function. J Interferon Cytokine Res. 1997;17:503–24.PubMedCrossRef
18.
19.
20.
Drappier M, Jha BK, Stone S, Elliott R, Zhang R, Vertommen D, Weiss SR, Silverman RH, Michiels T. A novel mechanism of RNase L inhibition: Theiler’s virus L* protein prevents 2–5A from binding to RNase L. PLoS Pathog. 2018;14:e1006989.PubMedPubMedCentralCrossRef
21.
Sorgeloos F, Jha BK, Silverman RH, Michiels T. Evasion of antiviral innate immunity by Theiler’s virus L* protein through direct inhibition of RNase L. PLoS Pathog. 2013;9:e1003474.PubMedPubMedCentralCrossRef
22.
Ricour C, Delhaye S, Hato SV, Olenyik TD, Michel B, van Kuppeveld FJ, Gustin KE, Michiels T. Inhibition of mRNA export and dimerization of interferon regulatory factor 3 by Theiler’s virus leader protein. J Gen Virol. 2009;90:177–86.PubMedCrossRef
23.
van Pesch V, van Eyll O, Michiels T. The leader protein of Theiler’s virus inhibits immediate-early alpha/beta interferon production. J Virol. 2001;75:7811–7.PubMedPubMedCentralCrossRef
24.
Kummerfeld M, Seehusen F, Klein S, Ulrich R, Kreutzer R, Gerhauser I, Herder V, Baumgärtner W, Beineke A. Periventricular demyelination and axonal pathology is associated with subependymal virus spread in a murine model for multiple sclerosis. Intervirology. 2012;55:401–16.PubMedCrossRef
25.
Zheng L, Calenoff MA, Dal Canto MC. Astrocytes, not microglia, are the main cells responsible for viral persistence in Theiler’s murine encephalomyelitis virus infection leading to demyelination. J Neuroimmunol. 2001;118:256–67.PubMedCrossRef
26.
Jin YH, Kim SJ, So EY, Meng L, Colonna M, Kim BS. Melanoma differentiation-associated gene 5 is critical for protection against Theiler’s virus-induced demyelinating disease. J Virol. 2012;86:1531–43.PubMedPubMedCentralCrossRef
27.
Jin YH, Kaneyama T, Kang MH, Kang HS, Koh CS, Kim BS. TLR3 signaling is either protective or pathogenic for the development of Theiler’s virus-induced demyelinating disease depending on the time of viral infection. J Neuroinflamm. 2011;8:178.CrossRef
28.
Kocur M, Schneider R, Pulm AK, Bauer J, Kropp S, Gliem M, Ingwersen J, Goebels N, Alferink J, Prozorovski T, et al. IFNbeta secreted by microglia mediates clearance of myelin debris in CNS autoimmunity. Acta Neuropathol Commun. 2015;3:20.PubMedPubMedCentralCrossRef
29.
Detje CN, Lienenklaus S, Chhatbar C, Spanier J, Prajeeth CK, Soldner C, Tovey MG, Schluter D, Weiss S, Stangel M, Kalinke U. Upon intranasal vesicular stomatitis virus infection, astrocytes in the olfactory bulb are important interferon Beta producers that protect from lethal encephalitis. J Virol. 2015;89:2731–8.PubMedCrossRef
30.
Pfefferkorn C, Kallfass C, Lienenklaus S, Spanier J, Kalinke U, Rieder M, Conzelmann KK, Michiels T, Staeheli P. Abortively infected astrocytes appear to represent the main source of interferon beta in the virus-infected brain. J Virol. 2016;90:2031–8.PubMedPubMedCentralCrossRef
31.
Sorgeloos F, Kreit M, Hermant P, Lardinois C, Michiels T. Antiviral type I and type III interferon responses in the central nervous system. Viruses. 2013;5:834–57.PubMedPubMedCentralCrossRef
32.
Ejlerskov P, Hultberg JG, Wang J, Carlsson R, Ambjorn M, Kuss M, Liu Y, Porcu G, Kolkova K, Friis Rundsten C, et al. Lack of neuronal IFN-beta-IFNAR causes Lewy body- and Parkinson’s disease-like dementia. Cell. 2015;163:324–39.PubMedPubMedCentralCrossRef
33.
Hosseini S, Michaelsen-Preusse K, Grigoryan G, Chhatbar C, Kalinke U, Korte M. Type I interferon receptor signaling in astrocytes regulates hippocampal synaptic plasticity and cognitive function of the healthy CNS. Cell Rep. 2020;31:107666.PubMedCrossRef
34.
Delhaye S, Paul S, Blakqori G, Minet M, Weber F, Staeheli P, Michiels T. Neurons produce type I interferon during viral encephalitis. Proc Natl Acad Sci U S A. 2006;103:7835–40.PubMedPubMedCentralCrossRef
35.
Fiette L, Aubert C, Müller U, Huang S, Aguet M, Brahic M, Bureau JF. Theiler’s virus infection of 129Sv mice that lack the interferon alpha/beta or interferon gamma receptors. J Exp Med. 1995;181:2069–76.PubMedCrossRef
36.
Jin YH, Hou W, Kim SJ, Fuller AC, Kang B, Goings G, Miller SD, Kim BS. Type I interferon signals control Theiler’s virus infection site, cellular infiltration and T cell stimulation in the CNS. J Neuroimmunol. 2010;226:27–37.PubMedPubMedCentralCrossRef
37.
Kolumam GA, Thomas S, Thompson LJ, Sprent J, Murali-Krishna K. Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection. J Exp Med. 2005;202:637–50.PubMedPubMedCentralCrossRef
38.
Crouse J, Kalinke U, Oxenius A. Regulation of antiviral T cell responses by type I interferons. Nat Rev Immunol. 2015;15:231–42.PubMedCrossRef
39.
Daniels BP, Holman DW, Cruz-Orengo L, Jujjavarapu H, Durrant DM, Klein RS. Viral pathogen-associated molecular patterns regulate blood-brain barrier integrity via competing innate cytokine signals. MBio. 2014;5:e01476-e11414.PubMedPubMedCentralCrossRef
40.
Daniels BP, Jujjavarapu H, Durrant DM, Williams JL, Green RR, White JP, Lazear HM, Gale M Jr, Diamond MS, Klein RS. Regional astrocyte IFN signaling restricts pathogenesis during neurotropic viral infection. J Clin Invest. 2017;127:843–56.PubMedPubMedCentralCrossRef
41.
Müller U, Steinhoff U, Reis LF, Hemmi S, Pavlovic J, Zinkernagel RM, Aguet M. Functional role of type I and type II interferons in antiviral defense. Science. 1994;264:1918–21.PubMedCrossRef
42.
Bach P, Kamphuis E, Odermatt B, Sutter G, Buchholz CJ, Kalinke U. Vesicular stomatitis virus glycoprotein displaying retrovirus-like particles induce a type I IFN receptor-dependent switch to neutralizing IgG antibodies. J Immunol. 2007;178:5839–47.PubMedCrossRef
43.
Kamphuis E, Junt T, Waibler Z, Forster R, Kalinke U. Type I interferons directly regulate lymphocyte recirculation and cause transient blood lymphopenia. Blood. 2006;108:3253–61.PubMedCrossRef
44.
Tronche F, Kellendonk C, Kretz O, Gass P, Anlag K, Orban PC, Bock R, Klein R, Schutz G. Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nat Genet. 1999;23:99–103.PubMedCrossRef
45.
Zhu Y, Romero MI, Ghosh P, Ye Z, Charnay P, Rushing EJ, Marth JD, Parada LF. Ablation of NF1 function in neurons induces abnormal development of cerebral cortex and reactive gliosis in the brain. Genes Dev. 2001;15:859–76.PubMedPubMedCentralCrossRef
46.
Bajenaru ML, Zhu Y, Hedrick NM, Donahoe J, Parada LF, Gutmann DH. Astrocyte-specific inactivation of the neurofibromatosis 1 gene (NF1) is insufficient for astrocytoma formation. Mol Cell Biol. 2002;22:5100–13.PubMedPubMedCentralCrossRef
47.
Buttgereit A, Lelios I, Yu X, Vrohlings M, Krakoski NR, Gautier EL, Nishinakamura R, Becher B, Greter M. Sall1 is a transcriptional regulator defining microglia identity and function. Nat Immunol. 2016;17:1397–406.PubMedCrossRef
48.
Ulrich R, Baumgärtner W, Gerhauser I, Seeliger F, Haist V, Deschl U, Alldinger S. MMP-12, MMP-3, and TIMP-1 are markedly upregulated in chronic demyelinating theiler murine encephalomyelitis. J Neuropathol Exp Neurol. 2006;65:783–93.PubMedCrossRef
49.
Kummerfeld M, Meens J, Haas L, Baumgärtner W, Beineke A. Generation and characterization of a polyclonal antibody for the detection of Theiler’s murine encephalomyelitis virus by light and electron microscopy. J Virol Methods. 2009;160:185–8.PubMedCrossRef
50.
Gerhauser I, Li L, Li D, Klein S, Elmarabet SA, Deschl U, Kalkuhl A, Baumgärtner W, Ulrich R, Beineke A. Dynamic changes and molecular analysis of cell death in the spinal cord of SJL mice infected with the BeAn strain of Theiler’s murine encephalomyelitis virus. Apoptosis. 2018;23:170–86.PubMedCrossRef
51.
Bröer S, Käufer C, Haist V, Li L, Gerhauser I, Anjum M, Bankstahl M, Baumgärtner W, Löscher W. Brain inflammation, neurodegeneration and seizure development following picornavirus infection markedly differ among virus and mouse strains and substrains. Exp Neurol. 2016;279:57–74.PubMedCrossRef
52.
Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg SL. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 2013;14:R36.PubMedPubMedCentralCrossRef
53.
Klotz D, Gerhauser I. Interferon-stimulated genes-mediators of the innate immune response during canine distemper virus infection. Int J Mol Sci. 2019;20:1620.PubMedPubMedCentralCrossRef
54.
55.
56.
57.
Gerhauser I, Alldinger S, Ulrich R, Baumgärtner W. Spatio-temporal expression of immediate early genes in the central nervous system of SJL/J mice. Int J Dev Neurosci. 2005;23:637–49.PubMedCrossRef
58.
Gerhauser I, Hansmann F, Puff C, Kumnok J, Schaudien D, Wewetzer K, Baumgärtner W. Theiler’s murine encephalomyelitis virus induced phenotype switch of microglia in vitro. J Neuroimmunol. 2012;252:49–55.PubMedCrossRef
59.
Waltl I, Käufer C, Gerhauser I, Chhatbar C, Ghita L, Kalinke U, Löscher W. Microglia have a protective role in viral encephalitis-induced seizure development and hippocampal damage. Brain Behav Immun. 2018;74:186–204.PubMedPubMedCentralCrossRef
60.
Uhde AK, Herder V, Akram Khan M, Ciurkiewicz M, Schaudien D, Teich R, Floess S, Baumgärtner W, Huehn J, Beineke A. Viral infection of the central nervous system exacerbates interleukin-10 receptor deficiency-mediated colitis in SJL mice. PLoS ONE. 2016;11:e0161883.PubMedPubMedCentralCrossRef
61.
Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002;3:RESEARCH0034.PubMedPubMedCentralCrossRef
62.
Gerhauser I, Alldinger S, Baumgärtner W. Ets-1 represents a pivotal transcription factor for viral clearance, inflammation, and demyelination in a mouse model of multiple sclerosis. J Neuroimmunol. 2007;188:86–94.PubMedCrossRef
63.
Gerhauser I, Ulrich R, Alldinger S, Baumgärtner W. Induction of activator protein-1 and nuclear factor-kappaB as a prerequisite for disease development in susceptible SJL/J mice after Theiler murine encephalomyelitis. J Neuropathol Exp Neurol. 2007;66:809–18.PubMedCrossRef
64.
Carpentier PA, Begolka WS, Olson JK, Elhofy A, Karpus WJ, Miller SD. Differential activation of astrocytes by innate and adaptive immune stimuli. Glia. 2005;49:360–74.PubMedCrossRef
65.
Olson JK, Miller SD. Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol. 2004;173:3916–24.PubMedCrossRef
66.
Kapil P, Butchi NB, Stohlman SA, Bergmann CC. Oligodendroglia are limited in type I interferon induction and responsiveness in vivo. Glia. 2012;60:1555–66.PubMedPubMedCentralCrossRef
67.
Marie I, Durbin JE, Levy DE. Differential viral induction of distinct interferon-alpha genes by positive feedback through interferon regulatory factor-7. EMBO J. 1998;17:6660–9.PubMedPubMedCentralCrossRef
68.
Sato M, Suemori H, Hata N, Asagiri M, Ogasawara K, Nakao K, Nakaya T, Katsuki M, Noguchi S, Tanaka N, Taniguchi T. Distinct and essential roles of transcription factors IRF-3 and IRF-7 in response to viruses for IFN-alpha/beta gene induction. Immunity. 2000;13:539–48.PubMedCrossRef
69.
Wang Y, Ma L, Stipkovits L, Szathmary S, Li X, Liu Y. The strategy of picornavirus evading host antiviral responses: non-structural proteins suppress the production of IFNs. Front Microbiol. 2018;9:2943.PubMedPubMedCentralCrossRef
70.
Ulrich R, Kalkuhl A, Deschl U, Baumgärtner W. Machine learning approach identifies new pathways associated with demyelination in a viral model of multiple sclerosis. J Cell Mol Med. 2010;14:434–48.PubMedCrossRef
71.
72.
Herder V, Gerhauser I, Klein SK, Almeida P, Kummerfeld M, Ulrich R, Seehusen F, Rohn K, Schaudien D, Baumgärtner W, et al. Interleukin-10 expression during the acute phase is a putative prerequisite for delayed viral elimination in a murine model for multiple sclerosis. J Neuroimmunol. 2012;249:27–39.PubMedCrossRef
73.
Choubey D, Duan X, Dickerson E, Ponomareva L, Panchanathan R, Shen H, Srivastava R. Interferon-inducible p200-family proteins as novel sensors of cytoplasmic DNA: role in inflammation and autoimmunity. J Interferon Cytokine Res. 2010;30:371–80.PubMedPubMedCentralCrossRef
74.
75.
Santiago-Raber ML, Baccala R, Haraldsson KM, Choubey D, Stewart TA, Kono DH, Theofilopoulos AN. Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice. J Exp Med. 2003;197:777–88.PubMedPubMedCentralCrossRef
76.
Chang TH, Yoshimi R, Ozato K. Tripartite Motif (TRIM) 12c, a mouse homolog of TRIM5, is a ubiquitin ligase that stimulates type I IFN and NF-kappaB pathways along with TNFR-associated factor 6. J Immunol. 2015;195:5367–79.PubMedPubMedCentralCrossRef
77.
78.
79.
Staeheli P, Grob R, Meier E, Sutcliffe JG, Haller O. Influenza virus-susceptible mice carry Mx genes with a large deletion or a nonsense mutation. Mol Cell Biol. 1988;8:4518–23.PubMedPubMedCentral
80.
81.
Dos Santos PF, Mansur DS. Beyond ISGlylation: functions of free intracellular and extracellular ISG15. J Interferon Cytokine Res. 2017;37:246–53.PubMedCrossRef
82.
Detje CN, Meyer T, Schmidt H, Kreuz D, Rose JK, Bechmann I, Prinz M, Kalinke U. Local type I IFN receptor signaling protects against virus spread within the central nervous system. J Immunol. 2009;182:2297–304.PubMedCrossRef
83.
Prinz M, Schmidt H, Mildner A, Knobeloch KP, Hanisch UK, Raasch J, Merkler D, Detje C, Gutcher I, Mages J, et al. Distinct and nonredundant in vivo functions of IFNAR on myeloid cells limit autoimmunity in the central nervous system. Immunity. 2008;28:675–86.PubMedCrossRef
84.
Chhatbar C, Detje CN, Grabski E, Borst K, Spanier J, Ghita L, Elliott DA, Jordao MJC, Mueller N, Sutton J, et al. Type I interferon receptor signaling of neurons and astrocytes regulates microglia activation during viral encephalitis. Cell Rep. 2018;25:e114.CrossRef
85.
Chappell-Maor L, Kolesnikov M, Kim JS, Shemer A, Haimon Z, Grozovski J, Boura-Halfon S, Masuda T, Prinz M, Jung S. Comparative analysis of CreER transgenic mice for the study of brain macrophages: a case study. Eur J Immunol. 2020;50:353–62.PubMedCrossRef
86.
Giusti SA, Vercelli CA, Vogl AM, Kolarz AW, Pino NS, Deussing JM, Refojo D. Behavioral phenotyping of Nestin-Cre mice: implications for genetic mouse models of psychiatric disorders. J Psychiatr Res. 2014;55:87–95.PubMedCrossRef
87.
Kreit M, Paul S, Knoops L, De Cock A, Sorgeloos F, Michiels T. Inefficient type I interferon-mediated antiviral protection of primary mouse neurons is associated with the lack of apolipoprotein l9 expression. J Virol. 2014;88:3874–84.PubMedPubMedCentralCrossRef
88.
Kreit M, Vertommen D, Gillet L, Michiels T. The interferon-inducible mouse apolipoprotein L9 and prohibitins cooperate to restrict Theiler’s virus replication. PLoS ONE. 2015;10:e0133190.PubMedPubMedCentralCrossRef
89.
Carpentier PA, Williams BR, Miller SD. Distinct roles of protein kinase R and toll-like receptor 3 in the activation of astrocytes by viral stimuli. Glia. 2007;55:239–52.PubMedCrossRef
90.
Rubio N, Sanz-Rodriguez F. Induction of the CXCL1 (KC) chemokine in mouse astrocytes by infection with the murine encephalomyelitis virus of Theiler. Virology. 2007;358:98–108.PubMedCrossRef
91.
Palma JP, Kim BS. The scope and activation mechanisms of chemokine gene expression in primary astrocytes following infection with Theiler’s virus. J Neuroimmunol. 2004;149:121–9.PubMedCrossRef
92.
Kwon D, Fuller AC, Palma JP, Choi IH, Kim BS. Induction of chemokines in human astrocytes by picornavirus infection requires activation of both AP-1 and NF-kappa B. Glia. 2004;45:287–96.PubMedCrossRef
93.
Rubio N, Rojo P, Torres C. Overexpression of basal c-fos and c-jun but not of ras oncogenes after Theiler’s murine encephalomyelitis virus infection of glial cells. J Neurovirol. 1996;2:167–74.PubMedCrossRef
94.
Rubio N, Martin-Clemente B. Theiler’s murine encephalomyelitis virus infection induces early expression of c-fos in astrocytes. Virology. 1999;258:21–9.PubMedCrossRef
95.
So EY, Kang MH, Kim BS. Induction of chemokine and cytokine genes in astrocytes following infection with Theiler’s murine encephalomyelitis virus is mediated by the Toll-like receptor 3. Glia. 2006;53:858–67.PubMedCrossRef
96.
Libbey JE, Kennett NJ, Wilcox KS, White HS, Fujinami RS. Interleukin-6, produced by resident cells of the central nervous system and infiltrating cells, contributes to the development of seizures following viral infection. J Virol. 2011;85:6913–22.PubMedPubMedCentralCrossRef
97.
Cusick MF, Libbey JE, Doty DJ, DePaula-Silva AB, Fujinami RS. The role of peripheral interleukin-6 in the development of acute seizures following virus encephalitis. J Neurovirol. 2017;23:696–703.PubMedPubMedCentralCrossRef
98.
Kang MH, Jin YH, Kim BS. Effects of keratinocyte-derived cytokine (CXCL-1) on the development of Theiler’s virus-induced demyelinating disease. Front Cell Infect Microbiol. 2018;8:9.PubMedPubMedCentralCrossRef
99.
100.
Ghita L, Spanier J, Chhatbar C, Mulenge F, Pavlou A, Larsen PK, Waltl I, Lueder Y, Kohls M, Jung K, et al. MyD88 signaling by neurons induces chemokines that recruit protective leukocytes to the virus-infected CNS. Sci Immunol. 2021;6:eabc9165.PubMedPubMedCentralCrossRef
101.
Waltl I, Kalinke U. Beneficial and detrimental functions of microglia during viral encephalitis. Trends Neurosci. 2022;45:158–70.PubMedCrossRef
102.
Aloisi F, Penna G, Cerase J, Menendez Iglesias B, Adorini L. IL-12 production by central nervous system microglia is inhibited by astrocytes. J Immunol. 1997;159:1604–12.PubMedCrossRef
103.
Wlodarczyk A, Lobner M, Cedile O, Owens T. Comparison of microglia and infiltrating CD11c(+) cells as antigen presenting cells for T cell proliferation and cytokine response. J Neuroinflamm. 2014;11:57.CrossRef
104.
Mack CL, Vanderlugt-Castaneda CL, Neville KL, Miller SD. Microglia are activated to become competent antigen presenting and effector cells in the inflammatory environment of the Theiler’s virus model of multiple sclerosis. J Neuroimmunol. 2003;144:68–79.PubMedCrossRef
105.
Bowen JL, Olson JK. IFNγ influences type I interferon response and susceptibility to Theiler’s virus-induced demyelinating disease. Viral Immunol. 2013;26:223–38.PubMedPubMedCentralCrossRef
106.
Kimura T, Nakayama K, Penninger J, Kitagawa M, Harada H, Matsuyama T, Tanaka N, Kamijo R, Vilcek J, Mak TW, et al. Involvement of the IRF-1 transcription factor in antiviral responses to interferons. Science. 1994;264:1921–4.PubMedCrossRef
107.
Petro TM. Disparate expression of IL-12 by SJL/J and B10.S macrophages during Theiler’s virus infection is associated with activity of TLR7 and mitogen-activated protein kinases. Microbes Infect. 2005;7:224–32.PubMedCrossRef
108.
Cravens PD, Hussain RZ, Miller-Little WA, Ben LH, Segal BM, Herndon E, Stuve O. IL-12/IL-23p40 is highly expressed in secondary lymphoid organs and the CNS during all stages of EAE, but its deletion does not affect disease perpetuation. PLoS ONE. 2016;11:e0165248.PubMedPubMedCentralCrossRef
109.
Gately MK, Carvajal DM, Connaughton SE, Gillessen S, Warrier RR, Kolinsky KD, Wilkinson VL, Dwyer CM, Higgins GF Jr, Podlaski FJ, et al. Interleukin-12 antagonist activity of mouse interleukin-12 p40 homodimer in vitro and in vivo. Ann N Y Acad Sci. 1996;795:1–12.PubMedCrossRef
110.
Hou W, Kang HS, Kim BS. Th17 cells enhance viral persistence and inhibit T cell cytotoxicity in a model of chronic virus infection. J Exp Med. 2009;206:313–28.PubMedPubMedCentralCrossRef
Metadata
Title
IFNAR signaling of neuroectodermal cells is essential for the survival of C57BL/6 mice infected with Theiler’s murine encephalomyelitis virus
Authors
Melanie Bühler
Dandan Li
Lin Li
Sandra Runft
Inken Waltl
Andreas Pavlou
Ulrich Kalinke
Malgorzata Ciurkiewicz
Jochen Huehn
Stefan Floess
Andreas Beineke
Wolfgang Baumgärtner
Ingo Gerhauser
Publication date
01-12-2023
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2023
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-023-02737-6

Other articles of this Issue 1/2023

Journal of Neuroinflammation 1/2023 Go to the issue

Research

M2 macrophage-derived cathepsin S promotes peripheral nerve regeneration via fibroblast–Schwann cell-signaling relay

Research

Unbiased multitissue transcriptomic analysis reveals complex neuroendocrine regulatory networks mediated by spinal cord injury-induced immunodeficiency

Original Paper

Inflammatory panel cytokines are elevated in the neocortex of late-stage Alzheimer’s disease but not Lewy body dementias

Research

H3K18 lactylation of senescent microglia potentiates brain aging and Alzheimer's disease through the NFκB signaling pathway

Research

The cervical lymph node contributes to peripheral inflammation related to Parkinson’s disease

Research

Sexually dimorphic extracellular vesicle responses after chronic spinal cord injury are associated with neuroinflammation and neurodegeneration in the aged brain