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Gamma interferon (IFN-\u03b3) may confer anti-EV71 activity; however, the claim that disease severity is highly correlated to an increase in IFN-\u03b3 is controversial and would indicate an immune escape initiated by EV71. This study, investigating the role of IFN-\u03b3 in EV71 infection using a murine model, showed that IFN-\u03b3 was elevated. Moreover, IFN-\u03b3 receptor-deficient mice showed higher mortality rates and more severe disease progression with slower viral clearance than wild-type mice.<jats:italic>In vitro<\/jats:italic>results showed that IFN-\u03b3 pretreatment reduced EV71 yield, whereas EV71 infection caused IFN-\u03b3 resistance with attenuated IFN-\u03b3 signaling in IFN regulatory factor 1 (IRF1) gene transactivation. To study the immunoediting ability of EV71 proteins in IFN-\u03b3 signaling, 11 viral proteins were stably expressed in cells without cytotoxicity; however, viral proteins 2A and 3D blocked IFN-\u03b3-induced<jats:italic>IRF1<\/jats:italic>transactivation following a loss of signal transducer and activator of transcription 1 (STAT1) nuclear translocation. Viral 3D attenuated IFN-\u03b3 signaling accompanied by a STAT1 decrease without interfering with IFN-\u03b3 receptor expression. Restoration of STAT1 or blocking 3D activity was able to rescue IFN-\u03b3 signaling. Interestingly, viral 2A attenuated IFN-\u03b3 signaling using another mechanism by reducing the serine phosphorylation of STAT1 following the inactivation of extracellular signal-regulated kinase without affecting STAT1 expression. These results demonstrate the anti-EV71 ability of IFN-\u03b3 and the immunoediting ability by EV71 2A and 3D, which attenuate IFN-\u03b3 signaling through different mechanisms.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>Immunosurveillance by gamma interferon (IFN-\u03b3) may confer anti-enterovirus 71 (anti-EV71) activity; however, the claim that disease severity is highly correlated to an increase in IFN-\u03b3 is controversial and would indicate an immune escape initiated by EV71. IFN-\u03b3 receptor-deficient mice showed higher mortality and more severe disease progression, indicating the anti-EV71 property of IFN-\u03b3. However, EV71 infection caused cellular insusceptibility in response to IFN-\u03b3 stimulation. We used an<jats:italic>in vitro<\/jats:italic>system with viral protein expression to explore the novel IFN-\u03b3 inhibitory properties of the EV71 2A and 3D proteins through the different mechanisms. According to this study, targeting either 2A or 3D pharmacologically and\/or genetically may sustain a cellular susceptibility in response to IFN-\u03b3, particularly for IFN-\u03b3-mediated anti-EV71 activity.<\/jats:p>","DOI":"10.1128\/jvi.00205-15","type":"journal-article","created":{"date-parts":[[2015,4,30]],"date-time":"2015-04-30T02:12:03Z","timestamp":1430359923000},"page":"7028-7037","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":54,"title":["Enterovirus 71 Proteins 2A and 3D Antagonize the Antiviral Activity of Gamma Interferon via Signaling Attenuation"],"prefix":"10.1128","volume":"89","author":[{"given":"Li-Chiu","family":"Wang","sequence":"first","affiliation":[{"name":"Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su-O","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Ping","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Ping","family":"Lee","sequence":"additional","affiliation":[{"name":"Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Keung","family":"Yu","sequence":"additional","affiliation":[{"name":"Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan"},{"name":"Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Ling","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Translational Medicine, Taipei Medical University, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Po-Chun","family":"Tseng","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Yuan","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4585-9279","authenticated-orcid":false,"given":"Shun-Hua","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan"},{"name":"Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan"},{"name":"Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiou-Feng","family":"Lin","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, Department of Microbiology and Immunology, College of Medicine, Taipei Medical University, Taipei, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/0168-1702(95)00087-9"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.3109\/1040841X.2011.580723"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02070-12"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.71.12.9743-9752.1997"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000593"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1006\/viro.2001.1310"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v16.i2.201"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkp502"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2011.08.016"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6976.2002.tb00601.x"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1586\/eri.09.45"},{"key":"e_1_3_2_13_2","first-page":"29","article-title":"Enterovirus 71 infection induces apoptosis in Vero cells","volume":"25","author":"Chan YF","year":"2003","unstructured":"Chan YF, Abubakar S. 2003. 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