title: Interferon-Regulatory Factor 5-Dependent Signaling Restricts Orthobunyavirus Dissemination to the Central Nervous System.
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 deoxynucleotidyltransferase-mediated 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.
  
  
  OBJECTIVE
  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 Irf3(-/-) Irf7(-/-) (DKO) mice infected with OROV was not as rapid or complete as observed in Ifnar(-/-) 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.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA Department of Genetics, Evolution and Bioagents, Institute of Biology, University of Campinas, Campinas, Brazil.
authors.forename: Jose Luiz
authors.initials: JL
authors.lastname: Proenca-Modena
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hyde
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, USA Department of Biochemistry and Immunology, University of São Paulo, Ribeirão Preto School of Medicine, Ribeirão Preto, Brazil.
authors.forename: Renata
authors.initials: R
authors.lastname: Sesti-Costa
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Lucas
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Amelia K
authors.initials: AK
authors.lastname: Pinto
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Richner
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Gorman
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Lazear
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, USA Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, USA Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, Missouri, USA diamond@wusm.wustl.edu.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
mesh_terms: D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000473:pathology / Q000821:virology; D002044:Bunyaviridae Infections / Q000276:immunology*; D002478:Cells, Cultured; D002490:Central Nervous System / Q000821:virology*; D003713:Dendritic Cells / Q000821:virology; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D054884:Host-Pathogen Interactions; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D007370:Interferon Type I / Q000378:metabolism; D008099:Liver / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008962:Models, Theoretical; D016851:Orthobunyavirus / Q000276:immunology* / Q000502:physiology; D015398:Signal Transduction; D013154:Spleen / Q000821:virology; D016019:Survival Analysis; D014779:Virus Replication
chemical_list: D050835:Interferon Regulatory Factors; D007370:Interferon Type I; C498178:Irf5 protein, mouse