title: Interferon regulatory factor 2 protects mice from lethal viral neuroinvasion.
abstract: The host responds to virus infection by activating type I interferon (IFN) signaling leading to expression of IFN-stimulated genes (ISGs). Dysregulation of the IFN response results in inflammatory diseases and chronic infections. In this study, we demonstrate that IFN regulatory factor 2 (IRF2), an ISG and a negative regulator of IFN signaling, influences alphavirus neuroinvasion and pathogenesis. A Sindbis virus strain that in wild-type (WT) mice only causes disease when injected into the brain leads to lethal encephalitis in Irf2-/-mice after peripheral inoculation. Irf2-/-mice fail to control virus replication and recruit immune infiltrates into the brain. Reduced B cells and virus-specific IgG are observed in the Irf2-/-mouse brains despite the presence of peripheral neutralizing antibodies, suggesting a defect in B cell trafficking to the central nervous system (CNS). B cell-deficient μMT mice are significantly more susceptible to viral infection, yet WT B cells and serum are unable to rescue the Irf2-/-mice. Collectively, our data demonstrate that proper localization of B cells and local production of antibodies in the CNS are required for protection. The work advances our understanding of host mechanisms that affect viral neuroinvasion and their contribution to immunity against CNS infections.
authors.affiliation: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065.
authors.forename: Melody M H
authors.initials: MM
authors.lastname: Li
authors.affiliation: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065.
authors.forename: Leonia
authors.initials: L
authors.lastname: Bozzacco
authors.affiliation: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065.
authors.forename: Hans-Heinrich
authors.initials: HH
authors.lastname: Hoffmann
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Breton
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065.
authors.forename: Jakob
authors.initials: J
authors.lastname: Loschko
authors.affiliation: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065.
authors.forename: Jing W
authors.initials: JW
authors.lastname: Xiao
authors.affiliation: Tri-Institutional Laboratory of Comparative Pathology, Memorial Sloan-Kettering Cancer Center, The Rockefeller University, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Monette
authors.affiliation: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
authors.affiliation: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065 macdonm@rockefeller.edu.
authors.forename: Margaret R
authors.initials: MR
authors.lastname: MacDonald
mesh_terms: D018354:Alphavirus Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000818:Animals; D000914:Antibodies, Viral / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D001927:Brain Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology*; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology; D050836:Interferon Regulatory Factor-2 / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D012845:Sindbis Virus / Q000276:immunology*
chemical_list: D000914:Antibodies, Viral; D007074:Immunoglobulin G; D050836:Interferon Regulatory Factor-2; C494230:Irf2 protein, mouse