Modulation of Gamma Interferon Receptor 1 byMycobacterium tuberculosis: a Potential Immune Response Evasive Mechanism

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Abstract
Mycobacterium tuberculosisinhibits gamma interferon (IFN-γ)-mediated antimycobacterial action by adopting diverse mechanisms. IFN-γ binds to its receptor, IFN-γR, in order to initiate proper signaling. We have observed reduced surface expression levels of IFN-γ receptor 1 (IFN-γR1) in untreated pulmonary tuberculosis patients compared to those in healthy individuals (P< 0.01). Following antitubercular therapy, the expression of IFN-γR1 was restored in these patients. To delineate the mechanism by whichM. tuberculosismodulates IFN-γR1, in vitro experiments were designed, wherein the down modulation of IFN-γR1 surface expression was observed for CD14+cells in peripheral blood mononuclear cells (PBMCs) cocultured with liveM. tuberculosiscompared to that for uninfected cells (P< 0.01). No modulation of IFN-γR1 expression was observed for CD14+cells in PBMCs infected withMycobacterium smegmatis. A time-dependent decrease in IFN-γR1 mRNA expression was observed for PBMCs infected withM. tuberculosis. Similar down modulation of IFN-γR1 protein and mRNA expression in phorbol myristate acetate-differentiated THP-1 cells (pdTHP-1) byM. tuberculosiswas observed (P< 0.01). Using reporter gene analysis of 5′ deletion constructs of the IFN-γR1 gene (IFNGR1) promoter, the decrease in IFN-γR1 mRNA inM. tuberculosis-infected pdTHP-1 cells was shown to be due to the decreased transcription ofIFNGR1. By immunoblotting and electrophoretic mobility shift assays, the down regulation of stimulating protein 1 (Sp1) expression and its recruitment on the phorbol ester-responsive element of theIFNGR1promoter inM. tuberculosis-infected pdTHP-1 cells was observed. This down regulation of Sp1 in pdTHP-1 cells cocultured withM. tuberculosismay be responsible for the down regulation of IFN-γR1 expression, thereby potentially altering its receptivity to IFN-γ.

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