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PMID: 12953091 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

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

The Journal of experimental medicine ·Vol. 198 ·No. 5 ·2003-09-01 ·Pages 693-704

Schnappinger D, Ehrt S, Voskuil MI, Liu Y, Mangan JA, Monahan IM, Dolganov G, Efron B, Butcher PD, Nathan C, Schoolnik GK

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.

MeSH Terms
Animals Gene Expression Regulation, Bacterial Macrophages/microbiology Mice Mycobacterium tuberculosis/genetics,metabolism Phagosomes/microbiology RNA, Bacterial/genetics Transcription, Genetic
Chemicals
RNA, Bacterial
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Schnappinger Dirk
Department of Microbiology and Immunology, Cornell University, 1300 York Avenue, New York, NY 10021, USA. [email protected]
Ehrt Sabine
Voskuil Martin I
Liu Yang
Mangan Joseph A
Monahan Irene M
Dolganov Gregory
Efron Brad
Butcher Philip D
Nathan Carl
Schoolnik Gary K
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20030846
Email
[email protected]
Published
2003-09-01
Pages
693-704
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2194186
Subset
IM
Grants
NHLBI NIH HHS · HL 68525 · United States
NIAID NIH HHS · R01 AI044826 · United States
NIAID NIH HHS · AI 44826 · United States
NHLBI NIH HHS · R01 HL068525 · United States
NHLBI NIH HHS · HL 61241 · United States
External Links
PubMed source DOI: 10.1084/jem.20030846 PMC Full Text View journal details
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