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Complex lipid determines tissue-specific replication of Mycobacterium tuberculosis in mice

Nature volume 402, pages 79–83 (1999)Cite this article

Abstract

Tuberculosis is the leading cause of death in the world resulting from a single bacterial infection1. Despite its enormous burden on world health, little is known about the molecular mechanisms of pathogenesis of Mycobacterium tuberculosis. Bacterial multiplication and concomitant tissue damage within an infected host, including experimentally infected mice, occurs primarily in the lungs—the favoured niche of M. tuberculosis2. Although it has been proposed that the distinctive cell wall of M. tuberculosis is important for virulence, rigorous genetic proof has been lacking. Here, using signature-tagged mutagenesis, we isolated three attenuated M. tuberculosis mutants that cannot synthesize or transport a complex, cell wall-associated lipid called phthiocerol dimycocerosate (PDIM) which is found only in pathogenic mycobacteria3,4. Two mutants have transposon insertions affecting genes implicated in PDIM synthesis; the third has a disruption in a gene encoding a large transmembrane protein required for proper subcellular localization of PDIM. Synthesis and transport of this complex lipid is only required for growth in the lung; all three mutants are unaffected for growth in the liver and spleen. This clearly shows that a lipid is required for M. tuberculosis virulence.

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Figure 1: Three related, avirulent mutants of M. tuberculosis isolated by STM mutagenesis.
Figure 2: The three giv mutants cannot synthesize or transport PDIM.
Figure 3: PDIM synthesis and export is required for M. tuberculosis replication in mouse lungs but not in the liver or spleen.
Figure 4: Model for synthesis and export of PDIM.

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Acknowledgements

We thank P. Brennan for valuable discussions and for purified PDIM; M. Glickman, J. McKinney, R. Morbidoni and P. Draper for helpful discussions; P. Walter, M. Glickman and J. Blanchard for critical review of the manuscript and encouragement; D. Chatterjee, J. Torrelles, D. Dick and M. Scherman for mass spectrum and NMR analysis; R. Russell for valuable discussions and assistance with histopathology; and R. McAdam and S. Quan for the inverse PCR protocol. J.S.C. is a Fellow of The Jane Coffin Childs Memorial Fund for Medical Research.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, 10461, New York, USA

    Jeffery S. Cox, Bing Chen & William R. Jacobs Jr

  2. Department of Microbiology, Colorado State University, Ft. Collins, 80523, Colorado, USA

    Michael McNeil

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  1. Jeffery S. Cox
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Correspondence to William R. Jacobs Jr.

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Cox, J., Chen, B., McNeil, M. et al. Complex lipid determines tissue-specific replication of Mycobacterium tuberculosis in mice. Nature 402, 79–83 (1999). https://doi.org/10.1038/47042

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