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Early expression of IFN-alpha/beta and iNOS in the brains of Venezuelan equine encephalitis virus-infected mice.

Abstract
To investigate the roles of type I interferon (IFN-alpha/beta) and other mediators of innate immune responses (e.g., inducible nitric oxide synthase [iNOS]) in early dissemination of Venezuelan equine encephalitis virus (VEE) infection, we used mice with targeted deletions in either their IFN-alpha/beta-receptor (IFNAR-1-/-) or interferon regulatory factor 2 (IRF-2-/-) genes. Following footpad infection, both IFNAR-1-/- and IRF-2-/- mice were more susceptible than control mice to VEE. The IFNAR-1-/- mice also exhibit accelerated VEE dissemination to serum, spleen, and brain, and compared with control mice, they evidenced faster kinetics in the upregulation of proinflammatory genes. In contrast, in IRF-2-/- mice, iNOS gene induction was completely absent following peripheral virulent VEE infection. In evaluating the role of cells involved in iNOS production, primary microglial cell cultures were found to be highly permissive to VEE infection. Moreover, VEE infection increased levels of nitric oxide (NO) in resting microglial cultures but decreased NO production in IFN-gamma-stimulated microglia. Thus, these findings suggest that reactive nitrogen species play an important contributory role in VEE dissemination and survival of the host. Our results further suggest the necessity for a carefully balanced host response that follows a middle course between immunopathology and insufficient inflammatory response to VEE infection.
AuthorsB A Schoneboom, J S Lee, F B Grieder
JournalJournal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research (J Interferon Cytokine Res) Vol. 20 Issue 2 Pg. 205-15 (Feb 2000) ISSN: 1079-9907 [Print] United States
PMID10714557 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • DNA-Binding Proteins
  • Interferon Regulatory Factor-2
  • Interferon Type I
  • Irf2 protein, mouse
  • Membrane Proteins
  • RNA, Messenger
  • Receptors, Interferon
  • Repressor Proteins
  • Transcription Factors
  • Receptor, Interferon alpha-beta
  • Nitric Oxide
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Nos2 protein, rat
Topics
  • Animals
  • Brain (enzymology, immunology, virology)
  • Cells, Cultured
  • Cricetinae
  • DNA-Binding Proteins (genetics)
  • Encephalitis Virus, Venezuelan Equine (pathogenicity, physiology)
  • Encephalomyelitis, Venezuelan Equine (enzymology, genetics, immunology)
  • Interferon Regulatory Factor-2
  • Interferon Type I (genetics)
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia (immunology, virology)
  • Nitric Oxide (biosynthesis)
  • Nitric Oxide Synthase (genetics)
  • Nitric Oxide Synthase Type II
  • RNA, Messenger (genetics, metabolism)
  • Rats
  • Receptor, Interferon alpha-beta
  • Receptors, Interferon (genetics)
  • Repressor Proteins
  • Transcription Factors
  • Up-Regulation
  • Virulence
  • Virus Replication

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