The Journal of Experimental Medicine
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Published online 14 February 2005 doi:10.1084/jem.20041668
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 4, 535-543
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ARTICLE

 Mycobacterium tuberculosis controls host innate immune activation through cyclopropane modification of a glycolipid effector molecule

Vivek Rao2, Nagatoshi Fujiwara3, Steven A. Porcelli3, and Michael S. Glickman1,2

1 Division of Infectious Diseases, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10021
2 Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10021
3 Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461

CORRESPONDENCE Michael S. Glickman: glickmam{at}mskcc.org

Mycobacterium tuberculosis (Mtb) infection remains a global health crisis. Recent genetic evidence implicates specific cell envelope lipids in Mtb pathogenesis, but it is unclear whether these cell envelope compounds affect pathogenesis through a structural role in the cell wall or as pathogenesis effectors that interact directly with host cells. Here we show that cyclopropane modification of the Mtb cell envelope glycolipid trehalose dimycolate (TDM) is critical for Mtb growth during the first week of infection in mice. In addition, TDM modification by the cyclopropane synthase pcaA was both necessary and sufficient for proinflammatory activation of macrophages during early infection. Purified TDM isolated from a cyclopropane-deficient pcaA mutant was hypoinflammatory for macrophages and induced less severe granulomatous inflammation in mice, demonstrating that the fine structure of this glycolipid was critical to its proinflammatory activity. These results established the fine structure of lipids contained in the Mtb cell envelope as direct effectors of pathogenesis and identified temporal control of host immune activation through cyclopropane modification of TDM as a critical pathogenic strategy of Mtb.

Abbreviations used: Mtb, Mycobacterium tuberculosis; TDM, trehalose dimycolate.

V. Rao and N. Fujiwara contributed equally to this work.

N. Fujiwara's present address is Department of Host Defense, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.


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