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Infection and Immunity, May 2003, p. 2487-2497, Vol. 71, No. 5
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.5.2487-2497.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Inhibition of Response to Alpha Interferon by Mycobacterium tuberculosis

Savita Prabhakar,1 Yaming Qiao,1 Yoshihiko Hoshino,2 Michael Weiden,2 Antony Canova,1 Elena Giacomini,3 Eliana Coccia,3 and Richard Pine1*

Public Health Research Institute, Newark, New Jersey 07103,1 Department of Medicine, Division of Pulmonary and Critical Care Medicine, New York University School of Medicine, New York, New York 10016,2 Department of Infectious, Parasitic, and Immune-Mediated Diseases, Division of Immunology, Istituto Superiore di Sanità, 00161 Rome, Italy3

Received 22 August 2002/ Returned for modification 25 October 2002/ Accepted 10 February 2003

We previously reported that infection by Mycobacterium tuberculosis, the causative agent of tuberculosis, leads to secretion of alpha/beta interferon (IFN-{alpha}/ß). While IFN-{alpha}/ß ordinarily stimulates formation of signal transducer and stimulator of transcription-1 (STAT-1) homodimers and IFN-stimulated gene factor-3 (ISGF-3), only ISGF-3 is found in infected human monocytes and macrophages. We have now investigated the basis for this unusual profile of transcription factor activation and its consequences for regulation of transcription, as well as the impact of infection on response to IFN-{alpha}. After infection, IFN-{alpha} stimulation of STAT-1 homodimers is inhibited in monocytes and macrophages, while stimulation of ISGF-3 increases in monocytes but tends to decline in macrophages. Effects of infection on the abundance of ISGF-3 subunits, STAT-1, STAT-2, and interferon regulatory factor 9, and on tyrosine phosphorylation of STAT-1 and STAT-2 explain the observed changes in DNA-binding activity, which correlate with increased or inhibited transcription of genes regulated by ISGF-3 and STAT-1. Infection by Mycobacterium bovis BCG does not inhibit IFN-{alpha}-stimulated tyrosine phosphorylation of STAT-1, formation of homodimers, or transcription of genes regulated by STAT-1 homodimers, suggesting that inhibition of the response to IFN-{alpha}/ß by M. tuberculosis is an aspect of pathogenicity. Thus, this well-known feature of infection by pathogenic viruses may also be a strategy employed by pathogenic bacteria.

* Corresponding author. Mailing address: Public Health Research Institute, 225 Warren St., Newark, NJ 07103. Phone: (973) 854-3320. Fax: (973) 854-3321. E-mail: rpine{at}phri.org.

Editor: S. H. E. Kaufmann

Infection and Immunity, May 2003, p. 2487-2497, Vol. 71, No. 5
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.5.2487-2497.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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