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Infection and Immunity, October 2004, p. 5712-5721, Vol. 72, No. 10
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.10.5712-5721.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The Down-Regulation of Cathepsin G in THP-1 Monocytes after Infection with Mycobacterium tuberculosis Is Associated with Increased Intracellular Survival of Bacilli

Carlos A. Rivera-Marrero,1,2* Julie Stewart,2 William M. Shafer,2,3 and Jesse Roman1,2

Department of Medicine, Pulmonary, Allergy & Critical Care Division,1 Department of Microbiology & Immunology Emory University School of Medicine, Atlanta,3 Atlanta VA Medical Center Research Service, Decatur, Georgia2

Received 8 March 2004/ Returned for modification 13 May 2004/ Accepted 14 July 2004

Cathepsin G (CatG) is a serine protease found in the azurophilic granules of monocytes that is known to have antimicrobial properties, but its role in Mycobacterium tuberculosis infection is unknown. We found that M. tuberculosis infection of human THP-1 monocytic cells induced the down-regulation of CatG mRNA expression, as demonstrated by gene array analysis and reverse transcription-PCR. This was associated with a concomitant decrease in CatG protein and enzymatic activity. In contrast, the expression of lysosomal cathepsins B and D was up-regulated in infected cells. This effect was also observed when THP-1 cells were induced to differentiate into adherent macrophages by exposure to bacterial lipopolysaccharide (LPS). In agreement with this, CatG expression was null in adherent macrophages isolated from bronchoalveolar lavages and normal blood. We wanted to determine if the down-regulation of CatG would be relevant to M. tuberculosis infection. First, we found that addition of CatG to THP-1 cells prior to infection resulted in decreased bacillary viability, presumably due to extracellular killing of bacilli. However, pretreatment of cells with LPS, which decreases intracellular CatG expression, resulted in increased bacillary viability. Second, we found that CatG cationic peptides killed M. tuberculosis bacilli and were five- to sevenfold more bactericidal than full-length CatG. These observations suggest that M. tuberculosis infection of human monocytic cells results in a "cathepsin switch" with down-regulation of CatG rendering M. tuberculosis bacilli more viable. Therefore, the down-regulation of CatG in macrophages is advantageous to M. tuberculosis bacilli and possibly is an important mechanism by which M. tuberculosis is able to evade the host immune defenses.

* Corresponding author. Mailing address: Department of Medicine, Pulmonary Division., Atlanta VAMC (Mailstop 151), Room 12C 106, 1670 Clairmont Rd., Decatur, GA 30033. Phone: (404) 321-6111, ext. 7178. Fax: (404) 728-7750. E-mail: crivera{at}emory.edu.

Editor: A. D. O'Brien

Infection and Immunity, October 2004, p. 5712-5721, Vol. 72, No. 10
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.10.5712-5721.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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