{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T10:24:12Z","timestamp":1790763852988,"version":"4.1.0"},"reference-count":39,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2016,1,1]],"date-time":"2016-01-01T00:00:00Z","timestamp":1451606400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01 AI104972"],"award-info":[{"award-number":["R01 AI104972"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["U19 AI083019"],"award-info":[{"award-number":["U19 AI083019"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2016,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Interferon (IFN)-regulatory factor 5 (IRF-5) is a transcription factor that induces inflammatory responses after engagement and signaling by pattern recognition receptors. To define the role of IRF-5 during bunyavirus infection, we evaluated Oropouche virus (OROV) and La Crosse virus (LACV) pathogenesis and immune responses in primary cells and in mice with gene deletions in\n            <jats:italic>Irf3<\/jats:italic>\n            ,\n            <jats:italic>Irf5<\/jats:italic>\n            , and\n            <jats:italic>Irf7<\/jats:italic>\n            or in\n            <jats:italic>Irf5<\/jats:italic>\n            alone. Deletion of\n            <jats:italic>Irf3<\/jats:italic>\n            ,\n            <jats:italic>Irf5<\/jats:italic>\n            , and\n            <jats:italic>Irf7<\/jats:italic>\n            together resulted in uncontrolled viral replication in the liver and spleen, hypercytokinemia, extensive liver injury, and an early-death phenotype. Remarkably, deletion of\n            <jats:italic>Irf5<\/jats:italic>\n            alone resulted in meningoencephalitis and death on a more protracted timeline, 1 to 2 weeks after initial OROV or LACV infection. The clinical signs in OROV-infected\n            <jats:italic>Irf5<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            mice were associated with abundant viral antigen and terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL)-positive cells in several regions of the brain. Circulating dendritic cell (DC) subsets in\n            <jats:italic>Irf5<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            mice had higher levels of OROV RNA\n            <jats:italic>in vivo<\/jats:italic>\n            yet produced lower levels of type I IFN than wild-type (WT) cells. This result was supported by data obtained\n            <jats:italic>in vitro<\/jats:italic>\n            , since a deficiency of IRF-5 resulted in enhanced OROV infection and diminished type I IFN production in bone marrow-derived DCs. Collectively, these results indicate a key role for IRF-5 in modulating the host antiviral response in peripheral organs that controls bunyavirus neuroinvasion in mice.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            Oropouche virus (OROV) and La Crosse virus (LACV) are orthobunyaviruses that are transmitted by insects and cause meningitis and encephalitis in subsets of individuals in the Americas. Recently, we demonstrated that components of the type I interferon (IFN) induction pathway, particularly the regulatory transcription factors IRF-3 and IRF-7, have key protective roles during OROV infection. However, the lethality in\n            <jats:italic>Irf3<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            <jats:italic>Irf7<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            (DKO) mice infected with OROV was not as rapid or complete as observed in\n            <jats:italic>Ifnar<\/jats:italic>\n            <jats:sup>\u2212\/\u2212<\/jats:sup>\n            mice, indicating that other transcriptional factors associated with an IFN response contribute to antiviral immunity against OROV. Here, we evaluated bunyavirus replication, tissue tropism, and cytokine production in primary cells and mice lacking IRF-5. We demonstrate an important role for IRF-5 in preventing neuroinvasion and the ensuing encephalitis caused by OROV and LACV.\n          <\/jats:p>","DOI":"10.1128\/jvi.02276-15","type":"journal-article","created":{"date-parts":[[2015,10,15]],"date-time":"2015-10-15T03:08:44Z","timestamp":1444878524000},"page":"189-205","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":44,"title":["Interferon-Regulatory Factor 5-Dependent Signaling Restricts Orthobunyavirus Dissemination to the Central Nervous System"],"prefix":"10.1128","volume":"90","author":[{"given":"Jose Luiz","family":"Proenca-Modena","sequence":"first","affiliation":[{"name":"Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA"},{"name":"Department of Genetics, Evolution and Bioagents, Institute of Biology, University of Campinas, Campinas, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer L.","family":"Hyde","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renata","family":"Sesti-Costa","sequence":"additional","affiliation":[{"name":"Department of Pathology &amp; Immunology, Washington University School of Medicine, St. Louis, Missouri, USA"},{"name":"Department of Biochemistry and Immunology, University of S\u00e3o Paulo, Ribeir\u00e3o Preto School of Medicine, Ribeir\u00e3o Preto, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiffany","family":"Lucas","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelia K.","family":"Pinto","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin M.","family":"Richner","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Gorman","sequence":"additional","affiliation":[{"name":"Department of Pathology &amp; Immunology, Washington University School of Medicine, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen M.","family":"Lazear","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA"},{"name":"Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Diamond","sequence":"additional","affiliation":[{"name":"Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA"},{"name":"Department of Pathology &amp; Immunology, Washington University School of Medicine, St. Louis, Missouri, USA"},{"name":"Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA"},{"name":"Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.19.1.623"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2007.01.014"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.02.015"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature03308"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0603255"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M400726200"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1205459"},{"key":"e_1_3_2_9_2","first-page":"6424","article-title":"Interferon regulatory factor 5, a novel mediator of cell cycle arrest and cell death","volume":"63","author":"Barnes BJ","year":"2003","unstructured":"Barnes BJ, Kellum MJ, Pinder KE, Frisancho JA, Pitha PM. 2003. 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