The Journal of Experimental Medicine
Avanti Polar Lipids
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Published 2 September 2003. doi:10.1084/jem.20030846
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© Rockefeller University Press, 0022-1007/2003/9/693 $5.00
The Journal of Experimental Medicine, Volume 198, Number 5, 693-704

Transcriptional Adaptation of Mycobacterium tuberculosis within Macrophages : Insights into the Phagosomal Environment



Dirk Schnappinger3,4, Sabine Ehrt3, Martin I. Voskuil1, Yang Liu1, Joseph A. Mangan6, Irene M. Monahan6, Gregory Dolganov7, Brad Efron2, Philip D. Butcher6, Carl Nathan3,4,5 and Gary K. Schoolnik1

1 Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford Medical School
2 Department of Health Research and Policy, Stanford University, Stanford, CA 94305
3 Department of Microbiology and Immunology, Weill Medical College and Graduate Programs in
4 Molecular Biology, Weill Graduate School of Medical Sciences, Cornell University, New York, NY 10021
5 Immunology, Weill Graduate School of Medical Sciences, Cornell University, New York, NY 10021
6 Department of Medical Microbiology, St. George's Hospital Medical School, London SW17 ORE, United Kingdom
7 Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, San Francisco, CA 94143

Address correspondence to Dirk Schnappinger, Department of Microbiology and Immunology, Cornell University, 1300 York Avenue, New York, NY, 10021. Phone: (212) 746-3788; Fax: (212) 746-8587; email: dis2003{at}med.cornell.edu; or Gary K. Schoolnik, Department of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford Medical School, Beckman Center, Room 241, Stanford, CA 94305. Phone: (650) 723-8158; Fax: (650) 723-1399; email: schoolni{at}cmgm.stanford.edu

Little is known about the biochemical environment in phagosomes harboring an infectious agent. To assess the state of this organelle we captured the transcriptional responses of Mycobacterium tuberculosis (MTB) in macrophages from wild-type and nitric oxide (NO) synthase 2–deficient mice before and after immunologic activation. The intraphagosomal transcriptome was compared with the transcriptome of MTB in standard broth culture and during growth in diverse conditions designed to simulate features of the phagosomal environment. Genes expressed differentially as a consequence of intraphagosomal residence included an interferon {gamma}– and NO-induced response that intensifies an iron-scavenging program, converts the microbe from aerobic to anaerobic respiration, and induces a dormancy regulon. Induction of genes involved in the activation and ß-oxidation of fatty acids indicated that fatty acids furnish carbon and energy. Induction of {sigma}E-dependent, sodium dodecyl sulfate–regulated genes and genes involved in mycolic acid modification pointed to damage and repair of the cell envelope. Sentinel genes within the intraphagosomal transcriptome were induced similarly by MTB in the lungs of mice. The microbial transcriptome thus served as a bioprobe of the MTB phagosomal environment, showing it to be nitrosative, oxidative, functionally hypoxic, carbohydrate poor, and capable of perturbing the pathogen's cell envelope.

Key Words: microarray gene expression analysis • macrophage activation • inducible nitric oxide synthase • innate immunity • pathogenicity


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