Modulation of gamma interferon receptor 1 by Mycobacterium tuberculosis: a potential immune response evasive mechanism.
Mycobacterium tuberculosis inhibits gamma interferon (IFN-gamma)-mediated antimycobacterial action by adopting diverse mechanisms. IFN-gamma binds to its receptor, IFN-gammaR, in order to initiate proper signaling. We have observed reduced surface expression levels of IFN-gamma receptor 1 (IFN-gammaR1) in untreated pulmonary tuberculosis patients compared to those in healthy individuals (P < 0.01). Following antitubercular therapy, the expression of IFN-gammaR1 was restored in these patients. To delineate the mechanism by which M. tuberculosis modulates IFN-gammaR1, in vitro experiments were designed, wherein the down modulation of IFN-gammaR1 surface expression was observed for CD14+ cells in peripheral blood mononuclear cells (PBMCs) cocultured with live M. tuberculosis compared to that for uninfected cells (P < 0.01). No modulation of IFN-gammaR1 expression was observed for CD14+ cells in PBMCs infected with Mycobacterium smegmatis. A time-dependent decrease in IFN-gammaR1 mRNA expression was observed for PBMCs infected with M. tuberculosis. Similar down modulation of IFN-gammaR1 protein and mRNA expression in phorbol myristate acetate-differentiated THP-1 cells (pdTHP-1) by M. tuberculosis was observed (P < 0.01). Using reporter gene analysis of 5' deletion constructs of the IFN-gammaR1 gene (IFNGR1) promoter, the decrease in IFN-gammaR1 mRNA in M. tuberculosis-infected pdTHP-1 cells was shown to be due to the decreased transcription of IFNGR1. 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 the IFNGR1 promoter in M. tuberculosis-infected pdTHP-1 cells was observed. This down regulation of Sp1 in pdTHP-1 cells cocultured with M. tuberculosis may be responsible for the down regulation of IFN-gammaR1 expression, thereby potentially altering its receptivity to IFN-gamma.
Singhal
Amit
A
TB Immunology Laboratory, Department of Biotechnology, All India Institute of Medical Sciences, New Delhi 110029, India.
Jaiswal
Anand
A
Arora
Virendra K
VK
Prasad
Hanumanthappa K
HK
D002460:Cell Line; D002478:Cells, Cultured; D015536:Down-Regulation; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000382:microbiology; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000254:growth & development / Q000472:pathogenicity*; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism*; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000382:microbiology; D000096743:Interferon gamma Receptor
D018950:Lipopolysaccharide Receptors; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor