Abstract
IFN-gamma activates macrophages to kill diverse intracellular pathogens, but does not activate human macrophages to kill virulent Mycobacterium tuberculosis. We tested the hypothesis that this is due to inhibition of IFN-gamma signaling by M. tuberculosis and found that M. tuberculosis infection of human macrophages blocks several responses to IFN-gamma, including killing of Toxoplasma gondii and induction of FcgammaRI. The inhibitory effect of M. tuberculosis is directed at transcription of IFN-gamma-responsive genes, but does not affect proximal steps in the Janus kinase-STAT pathway, as STAT1alpha tyrosine and serine phosphorylation, dimerization, nuclear translocation, and DNA binding are intact in M. tuberculosis-infected cells. In contrast, there is a marked decrease in IFN-gamma-induced association of STAT1 with the transcriptional coactivators CREB binding protein and p300 in M. tuberculosis-infected macrophages, indicating that M. tuberculosis directly or indirectly disrupts this protein-protein interaction that is essential for transcriptional responses to IFN-gamma. Gamma-irradiated M. tuberculosis and isolated cell walls reproduce the effects of live bacteria, indicating that the bacterial component(s) that initiates inhibition of IFN-gamma responses is constitutively expressed. Although lipoarabinomannan has been found to exert effects on macrophages, it does not account for the inhibitory effects of cell walls. These results indicate that one mechanism for M. tuberculosis to evade the human immune response is to inhibit the IFN-gamma signaling pathway, and that the mechanism of inhibition is distinct from that reported for Leishmania donovani or CMV, in that it targets the interaction of STAT1 with the basal transcriptional apparatus.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antibodies, Monoclonal / pharmacology
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Biological Transport
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CREB-Binding Protein
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Cell Nucleus / metabolism
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Cells, Cultured
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DNA-Binding Proteins / antagonists & inhibitors*
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DNA-Binding Proteins / metabolism*
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Humans
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Interferon-Stimulated Gene Factor 3
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Interferon-gamma / antagonists & inhibitors*
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Interferon-gamma / physiology*
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Macrophages / immunology
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Macrophages / metabolism
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Macrophages / microbiology
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Macrophages / parasitology
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Mycobacterium tuberculosis / growth & development
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Mycobacterium tuberculosis / immunology*
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Nuclear Proteins / metabolism
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Phosphorylation
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RNA, Messenger / biosynthesis
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Receptors, IgG / antagonists & inhibitors
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Receptors, IgG / biosynthesis
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Receptors, IgG / genetics
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STAT1 Transcription Factor
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Serine / metabolism
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Signal Transduction / immunology
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Subcellular Fractions / immunology
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Subcellular Fractions / microbiology
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Toxoplasma / growth & development
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Toxoplasma / immunology
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Trans-Activators / antagonists & inhibitors*
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Trans-Activators / metabolism*
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / metabolism
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Transcription, Genetic / immunology*
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Transcriptional Activation / immunology
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Transforming Growth Factor beta / antagonists & inhibitors
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Transforming Growth Factor beta / immunology
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Tyrosine / antagonists & inhibitors
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Tyrosine / metabolism
Substances
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Antibodies, Monoclonal
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DNA-Binding Proteins
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Interferon-Stimulated Gene Factor 3
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Nuclear Proteins
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RNA, Messenger
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Receptors, IgG
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STAT1 Transcription Factor
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STAT1 protein, human
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Trans-Activators
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Transcription Factors
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Transforming Growth Factor beta
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gamma interferon activation factor
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Tyrosine
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Serine
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Interferon-gamma
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CREB-Binding Protein
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CREBBP protein, human