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Infection and Immunity, November 2004, p. 6603-6614, Vol. 72, No. 11
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.11.6603-6614.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Prolonged Toll-Like Receptor Signaling by Mycobacterium tuberculosis and Its 19-Kilodalton Lipoprotein Inhibits Gamma Interferon-Induced Regulation of Selected Genes in Macrophages

Rish K. Pai,1,{dagger} Meghan E. Pennini,1,{dagger} Aaron A. R. Tobian,1 David H. Canaday,2 W. Henry Boom,2 and Clifford V. Harding1*

Department of Pathology, Case Western Reserve University,1 Division of Infectious Diseases and Tuberculosis Research Unit, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio2

Received 4 March 2004/ Returned for modification 4 May 2004/ Accepted 14 June 2004

Infection of macrophages with Mycobacterium tuberculosis or exposure to M. tuberculosis 19-kDa lipoprotein for >16 h inhibits gamma interferon (IFN-{gamma})-induced major histocompatibility complex class II (MHC-II) expression by a mechanism involving Toll-like receptors (TLRs). M. tuberculosis was found to inhibit murine macrophage MHC-II antigen (Ag) processing activity induced by IFN-{gamma} but not by interleukin-4 (IL-4), suggesting inhibition of IFN-{gamma}-induced gene regulation. We designed an approach to test the ability of M. tuberculosis-infected cells to respond to IFN-{gamma}. To model chronic infection with M. tuberculosis with accompanying prolonged TLR signaling, macrophages were infected with M. tuberculosis or incubated with M. tuberculosis 19-kDa lipoprotein for 24 h prior to the addition of IFN-{gamma}. Microarray gene expression studies were then used to determine whether prolonged TLR signaling by M. tuberculosis broadly inhibits IFN-{gamma} regulation of macrophage gene expression. Of 347 IFN-{gamma}-induced genes, M. tuberculosis and 19-kDa lipoprotein inhibited induction of 42 and 36%, respectively. Key genes or gene products were also examined by quantitative reverse transcription-PCR and flow cytometry, confirming and extending the results obtained by microarray studies. M. tuberculosis inhibited IFN-{gamma} induction of genes involved in MHC-II Ag processing, Ag presentation, and recruitment of T cells. These effects were largely dependent on myeloid differentiation factor 88, implying a role for TLRs. Thus, prolonged TLR signaling by M. tuberculosis inhibits certain macrophage responses to IFN-{gamma}, particularly those related to MHC-II Ag presentation. This inhibition may promote M. tuberculosis evasion of T-cell responses and persistence of infection in tuberculosis.

* Corresponding author. Mailing address: Department of Pathology, BRB 925, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106-4943. Phone: (216) 368-5059. Fax: (216) 368-1300. E-mail: cvh3{at}po.cwru.edu.

Editor: F. C. Fang

{dagger} R.K.P. and M.E.P. contributed equally to this study.

Infection and Immunity, November 2004, p. 6603-6614, Vol. 72, No. 11
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.11.6603-6614.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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