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Infection and Immunity, May 2007, p. 2500-2510, Vol. 75, No. 5
0019-9567/07/$08.00+0     doi:10.1128/IAI.01743-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Modulation of Gamma Interferon Receptor 1 by Mycobacterium tuberculosis: a Potential Immune Response Evasive Mechanism{triangledown}

Amit Singhal,1 Anand Jaiswal,2 Virendra K. Arora,2 and Hanumanthappa K. Prasad1*

TB Immunology Laboratory, Department of Biotechnology, All India Institute of Medical Sciences, New Delhi 110029, India,1 LRS Hospital of Tuberculosis and Allied Disease, Mehrauli, New Delhi 110055, India2

Received 1 November 2006/ Returned for modification 1 December 2006/ Accepted 20 February 2007

Mycobacterium tuberculosis inhibits gamma interferon (IFN-{gamma})-mediated antimycobacterial action by adopting diverse mechanisms. IFN-{gamma} binds to its receptor, IFN-{gamma}R, in order to initiate proper signaling. We have observed reduced surface expression levels of IFN-{gamma} receptor 1 (IFN-{gamma}R1) in untreated pulmonary tuberculosis patients compared to those in healthy individuals (P < 0.01). Following antitubercular therapy, the expression of IFN-{gamma}R1 was restored in these patients. To delineate the mechanism by which M. tuberculosis modulates IFN-{gamma}R1, in vitro experiments were designed, wherein the down modulation of IFN-{gamma}R1 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-{gamma}R1 expression was observed for CD14+ cells in PBMCs infected with Mycobacterium smegmatis. A time-dependent decrease in IFN-{gamma}R1 mRNA expression was observed for PBMCs infected with M. tuberculosis. Similar down modulation of IFN-{gamma}R1 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-{gamma}R1 gene (IFNGR1) promoter, the decrease in IFN-{gamma}R1 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-{gamma}R1 expression, thereby potentially altering its receptivity to IFN-{gamma}.

* Corresponding author. Mailing address: TB Immunology Laboratory, Department of Biotechnology, All India Institute of Medical Sciences, New Delhi 110029, India. Phone: 91-11-26594994. Fax: 91-11-26589286. E-mail: hk_prasad{at}hotmail.com

{triangledown} Published ahead of print on 5 March 2007.

Editor: W. A. Petri, Jr.

Infection and Immunity, May 2007, p. 2500-2510, Vol. 75, No. 5
0019-9567/07/$08.00+0     doi:10.1128/IAI.01743-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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