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Journal of Bacteriology, August 2009, p. 5232-5239, Vol. 191, No. 16
0021-9193/09/$08.00+0     doi:10.1128/JB.00452-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

igr Genes and Mycobacterium tuberculosis Cholesterol Metabolism{triangledown} ,{dagger}

Jennifer C. Chang,1,2,{ddagger} Maurine D. Miner,1 Amit K. Pandey,5 Wendy P. Gill,1,3,§ Nada S. Harik,4 Christopher M. Sassetti,5 and David R. Sherman1,2*

Seattle Biomedical Research Institute, Seattle, Washington 98109,1 Interdisciplinary Program of Pathobiology, Department of Global Health, University of Washington, Seattle, Washington 98195,2 Division of Infectious Diseases, University of Washington, Seattle, Washington 98195,3 Division of Pediatric Infectious Diseases, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72202,4 Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, Massachusetts 016555

Received 1 April 2009/ Accepted 7 June 2009

Recently, cholesterol was identified as a physiologically important nutrient for Mycobacterium tuberculosis survival in chronically infected mice. However, it remained unclear precisely when cholesterol is available to the bacterium and what additional bacterial functions are required for its metabolism. Here, we show that the igr locus, which we previously found to be essential for intracellular growth and virulence of M. tuberculosis, is required for cholesterol metabolism. While igr-deficient strains grow identically to the wild type in the presence of short- and long-chain fatty acids, the growth of these bacteria is completely inhibited in the presence of cholesterol. Interestingly, this mutant is still able to respire under cholesterol-dependent growth inhibition, suggesting that the bacteria can metabolize other carbon sources during cholesterol toxicity. Consistent with this hypothesis, we found that the growth-inhibitory effect of cholesterol in vitro depends on cholesterol import, as mutation of the mce4 sterol uptake system partially suppresses this effect. In addition, the {Delta}igr mutant growth defect during the early phase of disease is completely suppressed by mutating mce4, implicating cholesterol intoxication as the primary mechanism of attenuation. We conclude that M. tuberculosis metabolizes cholesterol throughout infection.

* Corresponding author. Mailing address: Seattle Biomedical Research Institute, 307 Westlake Ave N, Ste 500. Seattle, WA 98109. Phone: (206) 256-7200. Fax: (206) 256-7229. E-mail: david.sherman{at}sbri.org

{triangledown} Published ahead of print on 19 June 2009.

{dagger} Supplemental material for this article may be found at http://jb.asm.org/.

{ddagger} Present address: Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, Chicago, IL 60607.

§ Present address: Infectious Disease Consultants, Denver, CO 80218.

Journal of Bacteriology, August 2009, p. 5232-5239, Vol. 191, No. 16
0021-9193/09/$08.00+0     doi:10.1128/JB.00452-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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