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Flaviviruses modulate DC function, but the mechanisms underpinning this are not defined. We examined the maturation phenotype and function of murine bone marrow\u2013derived DCs infected with Langat virus (LGTV), a naturally attenuated member of the TBEV serogroup. LGTV infection failed to induce DC maturation or a cytokine response. Treatment with LPS or LPS\/IFN-\u03b3, strong inducers of inflammatory cytokines, resulted in enhanced TNF-\u03b1 and IL-6 production, but suppressed IL-12 production in infected DCs compared with uninfected \u201cbystander\u201d cells or mock-infected controls. LGTV-mediated antagonism of type I IFN (IFN-I) signaling contributed to inhibition of IL-12p40 mRNA expression at late time points after stimulation. However, early suppression was still observed in DCs lacking the IFN-I receptor (Ifnar\u2212\/\u2212), suggesting that additional mechanisms of antagonism exist. The early IFN-independent inhibition of IL-12p40 was nearly abolished in DCs deficient in IFN regulatory factor-1 (IRF-1), a key transcription factor required for IL-12 production. LGTV infection did not affect Irf-1 mRNA expression, but rather diminished IRF-1 protein levels and nuclear localization. The effect on IRF-1 was also observed in DCs infected with the highly virulent Sofjin strain of TBEV. Thus, antagonism of IRF-1 is a novel mechanism that synergizes with the noted ability of flaviviruses to suppress IFN-\u03b1\/\u03b2 receptor\u2013dependent signaling, resulting in the orchestrated evasion of host innate immunity.<\/jats:p>","DOI":"10.4049\/jimmunol.1302110","type":"journal-article","created":{"date-parts":[[2014,2,15]],"date-time":"2014-02-15T02:01:49Z","timestamp":1392429709000},"page":"2744-2755","source":"Crossref","is-referenced-by-count":54,"title":["Tick-Borne Flaviviruses Antagonize Both IRF-1 and Type I IFN Signaling To Inhibit Dendritic Cell Function"],"prefix":"10.1093","volume":"192","author":[{"given":"Shelly J","family":"Robertson","sequence":"first","affiliation":[{"name":"Innate Immunity and Pathogenesis Unit, Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Hamilton, MT 59840"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirk J","family":"Lubick","sequence":"additional","affiliation":[{"name":"Innate Immunity and Pathogenesis Unit, Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Hamilton, MT 59840"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett A","family":"Freedman","sequence":"additional","affiliation":[{"name":"Innate Immunity and Pathogenesis Unit, Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Hamilton, MT 59840"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron B","family":"Carmody","sequence":"additional","affiliation":[{"name":"Research Technologies Branch, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Hamilton, MT 59840"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja M","family":"Best","sequence":"additional","affiliation":[{"name":"Innate Immunity and Pathogenesis Unit, Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Hamilton, MT 59840"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,3,15]]},"reference":[{"key":"2025032404185695800_r1","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/S0166-3542(02)00206-1","article-title":"Tick-borne encephalitis","volume":"57","author":"Gritsun","year":"2003","journal-title":"Antiviral Res."},{"key":"2025032404185695800_r2","doi-asserted-by":"crossref","first-page":"1861","DOI":"10.1016\/S0140-6736(08)60800-4","article-title":"Tick-borne encephalitis","volume":"371","author":"Lindquist","year":"2008","journal-title":"Lancet"},{"key":"2025032404185695800_r3","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.1099\/vir.0.011437-0","article-title":"Tick-borne encephalitis virus - a review of an emerging zoonosis","volume":"90","author":"Mansfield","year":"2009","journal-title":"J. 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