Interferon regulatory factor IRF-7 induces the antiviral alpha interferon response and protects against lethal West Nile virus infection.

Abstract

Type I interferon (IFN-alpha/beta) comprises a family of immunomodulatory cytokines that are critical for controlling viral infections. In cell culture, many RNA viruses trigger IFN responses through the binding of RNA recognition molecules (RIG-I, MDA5, and TLR-3) and induction of interferon regulatory factor IRF-3-dependent gene transcription. Recent studies with West Nile virus (WNV) have shown that type I IFN is essential for restricting infection and that a deficiency of IRF-3 results in enhanced lethality. However, IRF-3 was not required for optimal systemic IFN production in vivo or in vitro in macrophages. To begin to define the transcriptional factors that regulate type I IFN after WNV infection, we evaluated IFN induction and virus control in IRF-7(-/-) mice. Compared to congenic wild-type mice, IRF-7(-/-) mice showed increased lethality after WNV infection and developed early and elevated WNV burdens in both peripheral and central nervous system tissues. As a correlate, a deficiency of IRF-7 blunted the systemic type I IFN response in mice. Consistent with this, IFN-alpha gene expression and protein production were reduced and viral titers were increased in IRF-7(-/-) primary macrophages, fibroblasts, dendritic cells, and cortical neurons. In contrast, in these cells the IFN-beta response remained largely intact. Our data suggest that the early protective IFN-alpha response against WNV occurs through an IRF-7-dependent transcriptional signal.

• Authors: Stephane Daffis, Melanie A Samuel, Mehul S Suthar, Brian C Keller, Michael Gale Jr, Michael S Diamond
• Journal: Journal of virology (J Virol) Vol. 82 Issue 17 Pg. 8465-75 (Sep 2008) ISSN: 1098-5514 [Electronic] United States
• PMID: 18562536 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Interferon Regulatory Factor-7
• Interferon-alpha
• RNA, Messenger
• RNA, Viral

Topics

• Animals
• Antiviral Agents (immunology, metabolism)
• Cells, Cultured
• Cerebral Cortex (cytology)
• Crosses, Genetic
• Dendritic Cells (virology)
• Embryo, Mammalian (cytology)
• Fibroblasts (virology)
• Interferon Regulatory Factor-7 (metabolism)
• Interferon-alpha (biosynthesis, genetics, immunology)
• L Cells
• Macrophages (metabolism, virology)
• Mice
• Mice, Congenic
• Mice, Inbred C57BL
• Mice, Knockout
• Neurons (virology)
• RNA, Messenger (analysis)
• RNA, Viral (analysis)
• Survival Analysis
• Viral Load
• Viremia
• West Nile Fever (immunology, prevention & control, virology)
• West Nile virus (genetics, growth & development, immunology, pathogenicity)