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Functional genomics analysis of WNV-infected fibroblasts from wild-type mice and RIG-I null mice revealed that the normal antiviral response to this virus occurs in two distinct waves. The initial response to WNV resulted in the expression of interferon (IFN) regulatory factor 3 target genes and IFN-stimulated genes, including several subtypes of alpha IFN. Subsequently, a second phase of IFN-dependent antiviral gene expression occurred very late in infection. In cells lacking RIG-I, both the initial and the secondary responses to WNV were delayed, indicating that RIG-I plays a critical role in initiating innate immunity against WNV. However, another PRR(s) was able to trigger a response to WNV in the absence of RIG-I. Disruption of both MDA5 and RIG-I pathways abrogated activation of the antiviral response to WNV, suggesting that MDA5 is involved in the host's defense against WNV infection. In addition, ablation of the function of IPS-1, an essential RIG-I and MDA5 adaptor molecule, completely disabled the innate antiviral response to WNV. Our data indicate that RIG-I and MDA5 are responsible for triggering downstream gene expression in response to WNV infection by signaling through IPS-1. We propose a model in which RIG-I and MDA5 operate cooperatively to establish an antiviral state and mediate an IFN amplification loop that supports immune effector gene expression during WNV infection.<\/jats:p>","DOI":"10.1128\/jvi.01305-07","type":"journal-article","created":{"date-parts":[[2007,11,1]],"date-time":"2007-11-01T00:54:42Z","timestamp":1193878482000},"page":"609-616","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":289,"title":["Establishment and Maintenance of the Innate Antiviral Response to West Nile Virus Involves both RIG-I and MDA5 Signaling through IPS-1"],"prefix":"10.1128","volume":"82","author":[{"given":"Brenda L.","family":"Fredericksen","sequence":"first","affiliation":[{"name":"Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian C.","family":"Keller","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie","family":"Fornek","sequence":"additional","affiliation":[{"name":"Department of Microbiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael G.","family":"Katze","sequence":"additional","affiliation":[{"name":"Department of Microbiology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Michael","family":"Gale","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas"},{"name":"Department of Immunology, University of Washington School of Medicine, Seattle, Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0407639101"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1089\/107999002753452665"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M400726200"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1201-365"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2006.09.023"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cimid.2004.03.009"},{"key":"e_1_3_2_8_2","first-page":"913","volume":"80","year":"2006","unstructured":"Fredericksen, B. 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