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As few studies have evaluated the importance of\n                    <jats:italic>Ifitm3 in vivo<\/jats:italic>\n                    in restricting viral pathogenesis, we investigated its significance as an antiviral gene against West Nile virus (WNV), an encephalitic flavivirus, in cells and mice.\n                    <jats:italic>Ifitm3<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice were more vulnerable to lethal WNV infection, and this was associated with greater virus accumulation in peripheral organs and central nervous system tissues. As no difference in viral burden in the brain or spinal cord was observed after direct intracranial inoculation, Ifitm3 likely functions as an antiviral protein in nonneuronal cells. Consistent with this,\n                    <jats:italic>Ifitm3<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    fibroblasts but not dendritic cells resulted in higher yields of WNV in multistep growth analyses. Moreover, transcomplementation experiments showed that Ifitm3 inhibited WNV infection independently of Ifitm1, Ifitm2, Ifitm5, and Ifitm6. Beyond a direct effect on viral infection in cells, analysis of the immune response in WNV-infected\n                    <jats:italic>Ifitm3<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice showed decreases in the total number of B cells, CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells, and antigen-specific CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells. Finally, bone marrow chimera experiments demonstrated that Ifitm3 functioned in both radioresistant and radiosensitive cells, as higher levels of WNV were observed in the brain only when Ifitm3 was absent from both compartments. Our analyses suggest that Ifitm3 restricts WNV pathogenesis likely through multiple mechanisms, including the direct control of infection in subsets of cells.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>IMPORTANCE<\/jats:bold>\n                    As part of the mammalian host response to viral infections, hundreds of interferon-stimulated genes (ISGs) are induced. The inhibitory activity of individual ISGs varies depending on the specific cell type and viral pathogen. Among ISGs, the genes encoding interferon-induced transmembrane protein (\n                    <jats:italic>IFITM<\/jats:italic>\n                    ) have been reported to inhibit multiple families of viruses in cell culture. However, few reports have evaluated the impact of\n                    <jats:italic>IFITM<\/jats:italic>\n                    genes on viral pathogenesis\n                    <jats:italic>in vivo<\/jats:italic>\n                    . In this study, we characterized the antiviral activity of Ifitm3 against West Nile virus (WNV), an encephalitic flavivirus, using mice with a targeted gene deletion of\n                    <jats:italic>Ifitm3<\/jats:italic>\n                    . Based on extensive virological and immunological analyses, we determined that Ifitm3 protects mice from WNV-induced mortality by restricting virus accumulation in peripheral organs and, subsequently, in central nervous system tissues. Our data suggest that Ifitm3 restricts WNV pathogenesis by multiple mechanisms and functions in part by controlling infection in different cell types.\n                  <\/jats:p>","DOI":"10.1128\/jvi.00581-16","type":"journal-article","created":{"date-parts":[[2016,7,6]],"date-time":"2016-07-06T21:38:44Z","timestamp":1467841124000},"page":"8212-8225","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":94,"title":["The Interferon-Stimulated Gene\n                    <i>Ifitm3<\/i>\n                    Restricts West Nile Virus Infection and Pathogenesis"],"prefix":"10.1128","volume":"90","author":[{"given":"Matthew J.","family":"Gorman","sequence":"first","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subhajit","family":"Poddar","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Farzan","sequence":"additional","affiliation":[{"name":"Department of Immunobiology and Microbial Sciences, The Scripps Research Institute, Jupiter, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael S.","family":"Diamond","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA"},{"name":"Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA"},{"name":"Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA"},{"name":"The 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":"10.1186\/1471-2164-13-155"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0049265"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002909"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1320856111"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V76.12.2583.2583"},{"key":"e_1_3_2_7_2","doi-asserted-by":"crossref","first-page":"2207","DOI":"10.4049\/jimmunol.145.7.2207","article-title":"TAPA-1, the target of an antiproliferative antibody, is associated on the cell surface with the Leu-13 antigen","volume":"145","author":"Takahashi S","year":"1990","unstructured":"Takahashi S, Doss C, Levy S, Levy R. 1990. 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