title: hsp70 and a novel axis of type I interferon-dependent antiviral immunity in the measles virus-infected brain.
abstract: The major inducible 70-kDa heat shock protein (hsp70) is host protective in a mouse model of measles virus (MeV) brain infection. Transgenic constitutive expression of hsp70 in neurons, the primary target of MeV infection, abrogates neurovirulence in neonatal H-2(d) congenic C57BL/6 mice. A significant level of protection is retained after depletion of T lymphocytes, implicating innate immune mechanisms. The focus of the present work was to elucidate the basis for hsp70-dependent innate immunity using this model. Transcriptome analysis of brains from transgenic (TG) and nontransgenic (NT) mice 5 days after infection identified type I interferon (IFN) signaling, macrophage activation, and antigen presentation as the main differences linked to survival. The pivotal role of type I IFN in hsp70-mediated protection was demonstrated in mice with a genetically disrupted type I IFN receptor (IFNAR(-/-)), where IFNAR(-/-) eliminated the difference in survival between TG and NT mice. Brain macrophages, not neurons, are the predominant source of type I IFN in the virus-infected brain, and in vitro studies provided a mechanistic basis by which MeV-infected neurons can induce IFN-β in uninfected microglia in an hsp70-dependent manner. MeV infection induced extracellular release of hsp70 from mouse neuronal cells that constitutively express hsp70, and extracellular hsp70 induced IFN-β transcription in mouse microglial cells through Toll-like receptors 2 and 4. Collectively, our results support a novel axis of type I IFN-dependent antiviral immunity in the virus-infected brain that is driven by hsp70.
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA.
authors.forename: Mi Young
authors.initials: MY
authors.lastname: Kim
authors.forename: Yaoling
authors.initials: Y
authors.lastname: Shu
authors.forename: Thomas
authors.initials: T
authors.lastname: Carsillo
authors.forename: Jianying
authors.initials: J
authors.lastname: Zhang
authors.forename: Lianbo
authors.initials: L
authors.lastname: Yu
authors.forename: Cornelia
authors.initials: C
authors.lastname: Peterson
authors.forename: Sonia
authors.initials: S
authors.lastname: Longhi
authors.forename: Sarah
authors.initials: S
authors.lastname: Girod
authors.forename: Stefan
authors.initials: S
authors.lastname: Niewiesk
authors.forename: Michael
authors.initials: M
authors.lastname: Oglesbee
mesh_terms: D000818:Animals; D001921:Brain / Q000276:immunology* / Q000473:pathology / Q000821:virology; D004195:Disease Models, Animal; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology*; D007370:Interferon Type I / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D008297:Male; D008457:Measles / Q000276:immunology* / Q000821:virology; D008459:Measles virus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency; D015398:Signal Transduction; D016019:Survival Analysis; D059467:Transcriptome
chemical_list: D018840:HSP70 Heat-Shock Proteins; C508032:Ifnar1 protein, mouse; D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta