Mycobacterium tuberculosis inhibits IFN-γ transcriptional responses without inhibiting activation of STAT1

Li Min Ting, Anne C. Kim, Ashok Cattamanchi, Joel D. Ernst

Research output: Contribution to journalArticle

256 Scopus citations

Abstract

IFN-γ 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- γ signaling by M. tuberculosis and found that M. tuberculosis infection of human macrophages blocks several responses to IFN-γ, including killing of Toxoplasma gondii and induction of FcγRI. The inhibitory effect of M. tuberculosis is directed at transcription of IFN-γ-responsive genes, but does not affect proximal steps in the Janus kinase-STAT pathway, as STAT1α 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-γ-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-γ. 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-γ 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-γ 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.

Original languageEnglish (US)
Pages (from-to)3898-3906
Number of pages9
JournalJournal of Immunology
Volume163
Issue number7
StatePublished - Oct 1 1999

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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