title: STAT1-independent control of a neurotropic measles virus challenge in primary neurons and infected mice.
abstract: Neurons are chiefly nonrenewable; thus, cytolytic immune strategies to clear or control neurotropic viral infections could have lasting neurologic consequences. IFN-γ is a potent antiviral cytokine that is critical for noncytolytic clearance of multiple neurotropic viral infections, including measles virus (MV); however, the downstream pathways through which IFN-γ functions in neurons have not been defined. Unlike most cell types studied to date in which IFN-γ affects gene expression via rapid and robust activation of STAT1, basal STAT1 levels in primary hippocampal neurons are constitutively low, resulting in attenuated STAT1 activation and consequently slower kinetics of IFN-γ-driven STAT1-dependent gene expression. Given this altered expression and activation of STAT1 in neurons, we sought to determine whether STAT1 was required for IFN-γ-mediated protection from infection in neurons. To do so, we evaluated the consequences of MV challenge of STAT1-deficient mice and primary hippocampal neurons explanted from these mice. Surprisingly, the absence of STAT1 did not restrict the ability of IFN-γ to control viral infection either in vivo or ex vivo. Moreover, the canonical IFN-γ-triggered STAT1 gene expression profile was not induced in STAT1-deficient neurons, suggesting that IFN-γ regulates neuronal STAT1-independent pathways to control viral replication.
authors.affiliation: Program in Immune Cell Development and Host Defense, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Lauren A
authors.initials: LA
authors.lastname: O'Donnell
authors.forename: Stephen
authors.initials: S
authors.lastname: Conway
authors.forename: R Wesley
authors.initials: RW
authors.lastname: Rose
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Nicolas
authors.forename: Michael
authors.initials: M
authors.lastname: Slifker
authors.forename: Siddharth
authors.initials: S
authors.lastname: Balachandran
authors.forename: Glenn F
authors.initials: GF
authors.lastname: Rall
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006624:Hippocampus / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D008457:Measles / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D008459:Measles virus / Q000276:immunology* / Q000472:pathogenicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D050794:STAT1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D007371:Interferon-gamma