{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T04:22:13Z","timestamp":1783052533439,"version":"3.54.6"},"reference-count":45,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2019,12,4]],"date-time":"2019-12-04T00:00:00Z","timestamp":1575417600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST-107-3017-F-182-001"],"award-info":[{"award-number":["MOST-107-3017-F-182-001"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST106-2362-B-182-001"],"award-info":[{"award-number":["MOST106-2362-B-182-001"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST-107-2320-B-182-001"],"award-info":[{"award-number":["MOST-107-2320-B-182-001"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST108-2320-B-182-033"],"award-info":[{"award-number":["MOST108-2320-B-182-033"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012283","name":"Chiayi Chang Gung Memorial Hospital","doi-asserted-by":"publisher","award":["CMRPD1G0431"],"award-info":[{"award-number":["CMRPD1G0431"]}],"id":[{"id":"10.13039\/501100012283","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012283","name":"Chiayi Chang Gung Memorial Hospital","doi-asserted-by":"publisher","award":["CORPD1H0021"],"award-info":[{"award-number":["CORPD1H0021"]}],"id":[{"id":"10.13039\/501100012283","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Enterovirus 71 (EV71) can invade the central nervous system (CNS) and cause neurological disease. Accumulating evidence indicates that EV71 can directly infect neurons in the CNS. Innate immune responses in the CNS have been known to play an essential role in limiting pathogen infections. Thus, investigating the effects of EV71 infection of neural cells is important for understanding disease pathogenesis. In this study, human neural cells were infected with EV71, and interferon\u03b2 (IFN\u03b2) expression was examined. Our results show that IFN\u03b2 expression was upregulated in EV71-infected neural cells via pattern recognition receptors (PRRs) sensing of virus RNA. The PRRs Toll-like receptor 3 (TLR3), Toll-like receptor 8 (TLR8), and melanoma differentiation-associated gene-5 (MDA-5), but not retinoic acid-inducible gene-I (RIG-I) and Toll-like receptor 7 (TLR7), were found to be EV71-mediated IFN\u03b2 induction. Although viral proteins exhibited the ability to cleave mitochondrial antiviral signaling protein (MAVS) and Toll\/IL-1 receptor (TIR) domain-containing adaptor-inducing IFN-\u03b2 (TRIF) in neural cells, levels of viral protein expression were low in these cells. Furthermore, neural cells efficiently produced IFN\u03b2 transcripts upon EV71 vRNA stimulation. Treating infected cells with anti-IFN\u03b2 antibodies resulted in increased virus replication, indicating that IFN\u03b2 release may play a role in limiting viral growth. These results indicate that EV71 infection can induce IFN\u03b2 expression in neural cells through PRR pathways.<\/jats:p>","DOI":"10.3390\/v11121121","type":"journal-article","created":{"date-parts":[[2019,12,5]],"date-time":"2019-12-05T03:16:36Z","timestamp":1575515796000},"page":"1121","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["EV71 Infection Induces IFN\u03b2 Expression in Neural Cells"],"prefix":"10.3390","volume":"11","author":[{"given":"Hsing-I","family":"Huang","sequence":"first","affiliation":[{"name":"Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan 33303, Taiwan"},{"name":"Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan 33303, Taiwan"},{"name":"Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan 33303, Taiwan"},{"name":"Department of Pediatrics, Chang Gung Memorial Hospital, Linkou 33303, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jhao-Yin","family":"Lin","sequence":"additional","affiliation":[{"name":"Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan 33303, Taiwan"},{"name":"Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan 33303, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng-Hung","family":"Chen","sequence":"additional","affiliation":[{"name":"Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan 33303, Taiwan"},{"name":"Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan 33303, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2981","DOI":"10.1099\/vir.0.79883-0","article-title":"Differential localization of neurons susceptible to enterovirus 71 and poliovirus type 1 in the central nervous system of cynomolgus monkeys after intravenous inoculation","volume":"85","author":"Nagata","year":"2004","journal-title":"J. Gen. Virol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1097\/nen.0b013e318163a990","article-title":"The distribution of inflammation and virus in human enterovirus 71 encephalomyelitis suggests possible viral spread by neural pathways","volume":"67","author":"Wong","year":"2008","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.coviro.2011.10.008","article-title":"Interferon-stimulated genes and their antiviral effector functions","volume":"6","author":"Schoggins","year":"2011","journal-title":"Curr. Opin. Virol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e23820","DOI":"10.4161\/jkst.23820","article-title":"The regulation of inflammation by interferons and their STATs","volume":"2","author":"Rauch","year":"2013","journal-title":"JAK STAT"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Koestner, W., Spanier, J., Klause, T., Tegtmeyer, P.K., Becker, J., Herder, V., Borst, K., Todt, D., Lienenklaus, S., and Gerhauser, I. (2018). Interferon-beta expression and type I interferon receptor signaling of hepatocytes prevent hepatic necrosis and virus dissemination in Coxsackievirus B3-infected mice. PLoS Pathog., 14.","DOI":"10.1371\/journal.ppat.1007235"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/S0022-2828(85)80019-5","article-title":"Coxsackie B3 virus can replicate in cultured human foetal heart cells and is inhibited by interferon","volume":"17","author":"Kandolf","year":"1985","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e2016","DOI":"10.1002\/rmv.2016","article-title":"An update on enterovirus 71 infection and interferon type I response","volume":"29","author":"Rasti","year":"2019","journal-title":"Rev. Med. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3767","DOI":"10.1128\/JVI.06687-11","article-title":"Enterovirus 71 Disrupts Interferon Signaling by Reducing the Level of Interferon Receptor 1","volume":"86","author":"Lu","year":"2012","journal-title":"J. Virol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/intimm\/dxh186","article-title":"Toll-like receptors in innate immunity","volume":"17","author":"Takeda","year":"2005","journal-title":"Int. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1038\/sj.cr.7310018","article-title":"IRF family proteins and type I interferon induction in dendritic cells","volume":"16","author":"Tailor","year":"2006","journal-title":"Cell Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.chom.2017.07.012","article-title":"Ten Strategies of Interferon Evasion by Viruses","volume":"22","year":"2017","journal-title":"Cell Host Microbe"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"8359","DOI":"10.1128\/JVI.01122-12","article-title":"Influenza virus protein PB1-F2 inhibits the induction of type I interferon by binding to MAVS and decreasing mitochondrial membrane potential","volume":"86","author":"Varga","year":"2012","journal-title":"J. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1128\/JVI.02175-15","article-title":"Identification of a Novel Viral Protein Expressed from the PB2 Segment of Influenza A Virus","volume":"90","author":"Yamayoshi","year":"2015","journal-title":"J. Virol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"17717","DOI":"10.1073\/pnas.0508531102","article-title":"Hepatitis C virus protease NS3\/4A cleaves mitochondrial antiviral signaling protein off the mitochondria to evade innate immunity","volume":"102","author":"Li","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Aguirre, S., Maestre, A.M., Pagni, S., Patel, J.R., Savage, T., Gutman, D., Maringer, K., Bernal-Rubio, D., Shabman, R.S., and Simon, V. (2012). DENV inhibits type I IFN production in infected cells by cleaving human STING. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002934"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e00222","DOI":"10.1128\/JVI.00222-19","article-title":"Essential Role of Enterovirus 2A Protease in Counteracting Stress Granule Formation and the Induction of Type I Interferon","volume":"93","author":"Visser","year":"2019","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Al-Shujairi, W.H., Clarke, J.N., Davies, L.T., Alsharifi, M.S.M., Pitson, S.M., and Carr, J.M. (2017). Intracranial Injection of Dengue Virus Induces Interferon Stimulated Genes and CD8+ T Cell Infiltration by Sphingosine Kinase 1 Independent Pathways. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0169814"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4845","DOI":"10.1128\/JVI.02514-09","article-title":"Dengue Virus Inhibits the Production of Type I Interferon in Primary Human Dendritic Cells","volume":"84","author":"Kaminski","year":"2010","journal-title":"J. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.jneuroim.2006.07.019","article-title":"Expression and distribution of Toll like receptors in the brain during murine neurocysticercosis","volume":"181","author":"Mishra","year":"2006","journal-title":"J. Neuroimmunol."},{"key":"ref_20","doi-asserted-by":"crossref","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. USA"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"12893","DOI":"10.1128\/JVI.79.20.12893-12904.2005","article-title":"Virus infection switches TLR-3-positive human neurons to become strong producers of beta interferon","volume":"79","author":"Lafage","year":"2005","journal-title":"J. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1089\/jir.2009.0050","article-title":"Interferon-alpha\/beta genes are up-regulated in murine brain astrocytes after infection with Theiler\u2019s murine encephalomyelitis virus","volume":"30","author":"Rubio","year":"2010","journal-title":"J. Interf. Cytokine Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"113","DOI":"10.4236\/jbpc.2010.12014","article-title":"Biological effects of EV71 infection in neural cells","volume":"2543","author":"Cao","year":"2010","journal-title":"J. Biophys. Chem."},{"key":"ref_24","first-page":"1","article-title":"Enterovirus 71 infection of motor neuron-like NSC-34 cells undergoes a non-lytic exit pathway","volume":"36983","author":"Too","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"8051","DOI":"10.1128\/JVI.02491-09","article-title":"The 3C protein of enterovirus 71 inhibits retinoid acid-inducible gene I-mediated interferon regulatory factor 3 activation and type I interferon responses","volume":"84","author":"Lei","year":"2010","journal-title":"J. Virol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"8811","DOI":"10.1128\/JVI.00447-11","article-title":"Cleavage of the adaptor protein TRIF by enterovirus 71 3C inhibits antiviral responses mediated by Toll-like receptor 3","volume":"85","author":"Lei","year":"2011","journal-title":"J. Virol."},{"key":"ref_27","first-page":"1","article-title":"New animal model containing human SCARB2 and lacking stat-1 is highly susceptible to EV71","volume":"31151","author":"Liou","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"10208","DOI":"10.1128\/JVI.73.12.10208-10213.1999","article-title":"Interferon regulatory factor 3 is required for viral induction of beta interferon in primary cardiac myocyte cultures","volume":"73","author":"Noah","year":"1999","journal-title":"J. Virol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"9839","DOI":"10.1523\/JNEUROSCI.2496-09.2009","article-title":"Systemic lipopolysaccharide protects the brain from ischemic injury by reprogramming the response of the brain to stroke: A critical role for IRF3","volume":"29","author":"Marsh","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3369","DOI":"10.1128\/JVI.02712-13","article-title":"Enterovirus 2Apro targets MDA5 and MAVS in infected cells","volume":"88","author":"Feng","year":"2014","journal-title":"J. Virol."},{"key":"ref_31","first-page":"209","article-title":"Differential induction of Toll-like receptors & type 1 interferons by Sabin attenuated & wild type 1 polioviruses in human neuronal cells","volume":"138","author":"Mohanty","year":"2013","journal-title":"Indian J. Med. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3677","DOI":"10.1128\/JVI.01360-06","article-title":"MDA-5 is cleaved in poliovirus-infected cells","volume":"81","author":"Barral","year":"2007","journal-title":"J. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.virol.2009.06.045","article-title":"RIG-I is cleaved during picornavirus infection","volume":"391","author":"Barral","year":"2009","journal-title":"Virology"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Wang, B., Xi, X., Lei, X., Zhang, X., Cui, S., Wang, J., Jin, Q., and Zhao, Z. (2013). Enterovirus 71 protease 2Apro targets MAVS to inhibit anti-viral type I interferon responses. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003231"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"12273","DOI":"10.1128\/JVI.79.19.12273-12279.2005","article-title":"Toll-like receptor 3 is induced by and mediates antiviral activity against rhinovirus infection of human bronchial epithelial cells","volume":"79","author":"Hewson","year":"2005","journal-title":"J. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"23208","DOI":"10.1074\/jbc.M109.047464","article-title":"A role for Toll-like receptor 3 variants in host susceptibility to enteroviral myocarditis and dilated cardiomyopathy","volume":"285","author":"Gorbea","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Chen, K.R., Yu, C.K., Kung, S.H., Chen, S.H., Chang, C.F., Ho, T.C., Lee, Y.P., Chang, H.C., Huang, L.Y., and Lo, S.Y. (2018). Toll-Like Receptor 3 Is Involved in Detection of Enterovirus A71 Infection and Targeted by Viral 2A Protease. Viruses, 10.","DOI":"10.3390\/v10120689"},{"key":"ref_38","first-page":"1051","article-title":"Expression and significance of toll-like receptors 7 and 8 in brain and lung tissues of death cases caused by EV71 infection","volume":"17","author":"Li","year":"2015","journal-title":"Zhongguo Dang Dai Er Ke Za Zhi"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1111\/j.1462-5822.2005.00537.x","article-title":"Human cardiac inflammatory responses triggered by Coxsackie B viruses are mainly Toll-like receptor (TLR) 8-dependent","volume":"7","author":"Triantafilou","year":"2005","journal-title":"Cell. Microbiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"7010","DOI":"10.4049\/jimmunol.0904133","article-title":"Human neuronal cells possess functional cytoplasmic and TLR-mediated innate immune pathways influenced by phosphatidylinositol-3 kinase signaling","volume":"184","author":"Peltier","year":"2010","journal-title":"J. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.nbd.2014.05.036","article-title":"TLR7 is a key regulator of innate immunity against Japanese encephalitis virus infection","volume":"69","author":"Nazmi","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1093\/infdis\/jir469","article-title":"Induction of Innate Immune Responses by SIV In Vivo and In Vitro: Differential Expression and Function of RIG-I and MDA5","volume":"204","author":"Co","year":"2011","journal-title":"J. Infect. Dis."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Kuo, R.L., Kao, L.T., Lin, S.J., Wang, R.Y., and Shih, S.R. (2013). MDA5 plays a crucial role in enterovirus 71 RNA-mediated IRF3 activation. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0063431"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1002\/pros.22912","article-title":"Interferon inducible antiviral MxA is inversely associated with prostate cancer and regulates cell cycle, invasion and Docetaxel induced apoptosis","volume":"75","author":"Brown","year":"2015","journal-title":"Prostate"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"392","DOI":"10.1038\/aps.2016.110","article-title":"Rheum emodin inhibits enterovirus 71 viral replication and affects the host cell cycle environment","volume":"38","author":"Zhong","year":"2017","journal-title":"Acta Pharmacol. Sin."}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/11\/12\/1121\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:40:03Z","timestamp":1760190003000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/11\/12\/1121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,4]]},"references-count":45,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["v11121121"],"URL":"https:\/\/doi.org\/10.3390\/v11121121","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,4]]}}}