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Transcriptional Adaptation of Mycobacterium tuberculosis within Macrophages
Open accessAbstract
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 γ– 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 β-oxidation of fatty acids indicated that fatty acids furnish carbon and energy. Induction of σE-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.
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“Several studies have reported that nuo is down-regulated in M. tuberculosis during mouse lung infection (18), survival in macrophages (19), in both non-replicating persistence (NRP)-1 (1% oxygen saturation) and NRP-2 (0.06% oxygen saturation) relative to aerated mid-log growth (18), and upon starvation in vitro (20).”
From Energetics of Respiration and Oxidative Phosphorylation in Mycobacteria (2014) · cites this paper as [19]
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“In contrast, fumarate reductase, nitrate reductase and NDH-2 are all upregulated under these conditions (19).”
From Energetics of Respiration and Oxidative Phosphorylation in Mycobacteria (2014) · cites this paper as [19]
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“Transcriptional analysis of M. tuberculosis in the macrophage (phagosomal environment) has revealed that NDH-1, menaquinol-cytochrome c oxidoreductase and the ATP synthase are all down-regulated when compared to cells growing exponentially, suggesting that there is a reduced need for energy generation during bacteriostasis i.e., the growth state of intraphagosomal M. tuberculosis (19).”
From Energetics of Respiration and Oxidative Phosphorylation in Mycobacteria (2014) · cites this paper as [19]
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“In M. tuberculosis, the atp operon is downregulated during growth in macrophages (19), the mouse lung and in cells exposed to NO or hypoxia (18).”
From Energetics of Respiration and Oxidative Phosphorylation in Mycobacteria (2014) · cites this paper as [19]
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“the fight of the host against the pathogen in M. tuberculosis infection involves several levels including containment of the microbe, generation of radicals and a hostile, acidic environment, deprivation from essential nutrients, formation of anti-mycobacterial peptides and cytokines which strengthen host responses by attracting other immune cells, down to cell damage and suicidal activities of MO”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [5]
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“Accordingly, transcriptional analysis of macrophages and M. tuberculosis has demonstrated that Mycobacteria regulate a myriad of genes to secure a sufficient supply of iron within the cell, whereas macrophages aim to restrict the availability of this metal by different mechanisms (5).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [5]
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Metadata
- Authors
- Schnappinger, D., Ehrt, S., Voskuil, M. I., Liu, Y., Mangan, J. A., Monahan, I. M., Dolganov, G., Efron, B., Butcher, P. D., Nathan, C., & Schoolnik, G. K.
- Affiliations
- Cornell University (US)
- 3Department of Microbiology and Immunology, Weill Medical College and Graduate Programs in
- Stanford Medicine (US)
- St George's, University of London (GB)
- University of California, San Francisco (US)
- Stanford University (US)
- Corresponding author
- Schnappinger, Dirk
- ORCID
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2003-09-01
- Volume
- 198
- Issue
- 5
- Pages
- 693-704
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2194186
- OpenAlex
- W2007097682
- Cited by
- 1,420
- References
- 58
- Citations by year
- 2026: 26 · 2025: 35 · 2024: 46 · 2023: 32 · 2022: 55 · 2021: 41 · 2020: 37 · 2019: 68 · 2018: 63 · 2017: 65 · 2016: 61 · 2015: 96 · 2014: 90 · 2013: 75 · 2012: 96
- FWCI
- 31.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- St George's Online Research Archive (St George's University of London) (acceptedVersion)
- Funders
- Hearst Foundations
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- Defense Advanced Research Projects Agency
- Advanced Research Projects Agency
- Medical Research Council
- National Heart, Lung, and Blood Institute (R01HL068525, HL 61241, HL68525, R01HL061241)
- National Institute of Allergy and Infectious Diseases (R01AI044826, AI-44826)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Health Sciences › Medicine › Epidemiology › Mycobacterium research and diagnosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- Mycobacterium tuberculosis, macrophages, nitric oxide synthase 2, interferon-gamma, iron scavenging, anaerobic respiration, fatty acid beta-oxidation, sigma E, cell envelope damage, hypoxia, nitrosative stress, tuberculosis pathogenesis
- MeSH terms
- Animals, Macrophages, Mycobacterium tuberculosis, Phagosomes, RNA, Bacterial, Transcription, Genetic, Gene Expression Regulation, Bacterial, Mice
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