Abstract
IFNs, which transduce pivotal signals through Stat1 and Stat2, effectively suppress the replication of Legionella pneumophila in primary murine macrophages. Although the ability of IFN-γ to impede L. pneumophila growth is fully dependent on Stat1, IFN-αβ unexpectedly suppresses L. pneumophila growth in both Stat1- and Stat2-deficient macrophages. New studies demonstrating that the robust response to IFN-αβ is lost in Stat1-Stat2 double-knockout macrophages suggest that Stat1 and Stat2 are functionally redundant in their ability to direct an innate response toward L. pneumophila. Because the ability of IFN-αβ to signal through Stat1-dependent complexes (i.e., Stat1-Stat1 and Stat1-Stat2 dimers) has been well characterized, the current studies focus on how Stat2 is able to direct a potent response to IFN-αβ in the absence of Stat1. These studies reveal that IFN-αβ is able to drive the formation of a Stat2 and IFN regulatory factor 9 complex that drives the expression of a subset of IFN-stimulated genes, but with substantially delayed kinetics. These observations raise the possibility that this pathway evolved in response to microbes that have devised strategies to subvert Stat1-dependent responses.
Copyright © 2015 by The American Association of Immunologists, Inc.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bone Marrow Cells / immunology
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Bone Marrow Cells / microbiology
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Bone Marrow Cells / pathology
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Gene Expression Regulation
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Host-Pathogen Interactions
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Interferon-Stimulated Gene Factor 3, gamma Subunit / genetics
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Interferon-Stimulated Gene Factor 3, gamma Subunit / immunology*
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Interferon-gamma / genetics
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Interferon-gamma / immunology
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Legionella pneumophila / immunology
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Legionellosis / genetics
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Legionellosis / immunology*
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Legionellosis / microbiology
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Legionellosis / pathology
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Macrophages / immunology*
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Macrophages / microbiology
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Macrophages / pathology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Primary Cell Culture
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Protein Multimerization
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Receptor, Interferon alpha-beta / genetics
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Receptor, Interferon alpha-beta / immunology*
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STAT1 Transcription Factor / deficiency
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STAT1 Transcription Factor / genetics
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STAT1 Transcription Factor / immunology*
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STAT2 Transcription Factor / deficiency
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STAT2 Transcription Factor / genetics
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STAT2 Transcription Factor / immunology*
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Signal Transduction
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Time Factors
Substances
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IRF9 protein, mouse
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Ifnar1 protein, mouse
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Interferon-Stimulated Gene Factor 3, gamma Subunit
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STAT1 Transcription Factor
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STAT2 Transcription Factor
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Stat1 protein, mouse
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Stat2 protein, mouse
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Receptor, Interferon alpha-beta
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Interferon-gamma