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

TitleTranscriptional Adaptation of Mycobacterium tuberculosis within Macrophages: Insights into the Phagosomal Environment.
Publication TypeJournal Article
Year of Publication2003
AuthorsSchnappinger D, Ehrt S, Voskuil MI, Liu Y, Mangan JA, Monahan IM, Dolganov G, Efron B, Butcher PD, Nathan C, Schoolnik GK
JournalJ Exp Med
Volume198
Issue5
Pagination693-704
Date Published2003 Sep 01
ISSN0022-1007
KeywordsAnimals, Gene Expression Regulation, Bacterial, Macrophages, Mice, Mycobacterium tuberculosis, Phagosomes, RNA, Bacterial, Transcription, Genetic
Abstract

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 beta-oxidation of fatty acids indicated that fatty acids furnish carbon and energy. Induction of sigmaE-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.

DOI10.1084/jem.20030846
Alternate JournalJ Exp Med
PubMed ID12953091
PubMed Central IDPMC2194186
Grant ListHL 68525 / HL / NHLBI NIH HHS / United States
R01 AI044826 / AI / NIAID NIH HHS / United States
AI 44826 / AI / NIAID NIH HHS / United States
R01 HL068525 / HL / NHLBI NIH HHS / United States
HL 61241 / HL / NHLBI NIH HHS / United States

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