Interferon-regulatory factor 5-dependent signaling restricts orthobunyavirus dissemination to the central nervous system

Jose Luiz Proenca-Modena, Jennifer L. Hyde, Renata Sesti-Costa, Tiffany Lucas, Amelia K. Pinto, Justin M. Richner, Matthew J. Gorman, Helen M. Lazear, Michael S. Diamond

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

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 Irf3, Irf5, and Irf7 or in Irf5 alone. Deletion of Irf3, Irf5, and Irf7 together resulted in uncontrolled viral replication in the liver and spleen, hypercytokinemia, extensive liver injury, and an early-death phenotype. Remarkably, deletion of Irf5 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 Irf5-/- mice were associated with abundant viral antigen and terminal deoxynucleotidyltransferasemediated dUTP-biotin nick end labeling (TUNEL)-positive cells in several regions of the brain. Circulating dendritic cell (DC) subsets in Irf5-/- mice had higher levels of OROV RNA in vivo yet produced lower levels of type I IFN than wild-type (WT) cells. This result was supported by data obtained in vitro, 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.

Original languageEnglish
Pages (from-to)189-205
Number of pages17
JournalJournal of virology
Volume90
Issue number1
DOIs
StatePublished - Jan 1 2016

Fingerprint Dive into the research topics of 'Interferon-regulatory factor 5-dependent signaling restricts orthobunyavirus dissemination to the central nervous system'. Together they form a unique fingerprint.

  • Cite this

    Proenca-Modena, J. L., Hyde, J. L., Sesti-Costa, R., Lucas, T., Pinto, A. K., Richner, J. M., Gorman, M. J., Lazear, H. M., & Diamond, M. S. (2016). Interferon-regulatory factor 5-dependent signaling restricts orthobunyavirus dissemination to the central nervous system. Journal of virology, 90(1), 189-205. https://doi.org/10.1128/JVI.02276-15