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Infection and Immunity, April 2004, p. 2067-2074, Vol. 72, No. 4
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.4.2067-2074.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Mycobacterium tuberculosis Lipomannan Induces Apoptosis and Interleukin-12 Production in Macrophages

D. N. Dao,¹ L. Kremer,² Y. Guérardel,^3, A. Molano,⁴ W. R. Jacobs Jr.,¹ S. A. Porcelli,⁴ and V. Briken^4*

Howard Hughes Medical Institute,¹ Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461,⁴ Laboratoire des Mécanismes Moléculaires de la Pathogénie Microbienne, INSERM U447, Institut Pasteur de Lille/IBL, BP245-59019 Lille Cedex,² Laboratoire de Glycobiologie Structurale et Fonctionnelle, CNRS UMR8576, Université des Sciences et Technologies de Lille, F-59655 Villeneuve d'Ascq Cedex, France³

Received 17 September 2003/ Returned for modification 14 October 2003/ Accepted 19 November 2003

The mycobacterial cell wall component lipoarabinomannan (LAM) has been described as a virulence factor of Mycobacterium tuberculosis, and modification of the terminal arabinan residues of this compound with mannose caps (producing mannosyl-capped LAM [ManLAM]) in M. tuberculosis or with phosphoinositol caps (producing phosphoinositol-capped LAM [PILAM]) in Mycobacterium smegmatis has been implicated in various functions associated with these lipoglycans. A structure-function analysis was performed by using LAMs and their biosynthetic precursor lipomannans (LMs) isolated from different mycobacterial species on the basis of their capacity to induce the production of interleukin-12 (IL-12) and/or apoptosis of macrophage cell lines. Independent of the mycobacterial species, ManLAMs did not induce IL-12 gene expression or apoptosis of macrophages, whereas PILAMs induced IL-12 secretion and apoptosis. Interestingly, uncapped LAM purified from Mycobacterium chelonae did not induce IL-12 secretion or apoptosis. Furthermore, LMs, independent of their mycobacterial origins, were potent inducers of IL-12 and apoptosis. The precursor of LM, phosphatidyl-myo-inositol dimannoside, had no activity, suggesting that the mannan core of LM was required for the activity of LM. The specific interaction of LM with Toll-like receptor 2 (TLR-2) but not with TLR-4 suggested that these responses were mediated via the TLR-2 signaling pathway. Our experiments revealed an important immunostimulatory activity of the biosynthetic LAM precursor LM. The ratio of LAM to LM in the cell wall of mycobacteria may be an important determinant of virulence, and enzymes that modify LM could provide targets for development of antituberculosis drugs and for derivation of attenuated strains of M. tuberculosis.

Editor: D. L. Burns

Present address: Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan, Republic of China.

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