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- Title
TheMycobacterium tuberculosisSigD sigma factor controls the expression of ribosome-associated gene products in stationary phase and is required for full virulence.
- Authors
Calamita, Heather; Ko, Chiew; Tyagi, Sandeep; Yoshimatsu, Tetsuyuki; Morrison, Norman E.; Bishai, William R.
- Abstract
During infectionMycobacterium tuberculosisis exposed to several environmental conditions depending on the stage and severity of the disease. To survive,M. tuberculosisuses alternate sigma factors to regulate its gene expression in response to the changing host environment. In order to better understand the way in which stress response genes are regulated, the extracytoplasmic sigma factor genesigDwas deleted and subsequently complemented in the CDC1551 strain ofM. tuberculosis. TheΔ sigDmutant strain exhibited anin vitrogrowth rate in rich medium identical to that of both thesigD-complemented and wild-type CDC1551 strains. Additionally, no differences were observed in short-term intracellular growth between the mutant, complemented, and wild-type bacteria within the J774A.1 macrophage cell line. However, tumour necrosis factor (TNF)-α levels in macrophages infected with theΔ sigDmutant were decreased as compared to levels observed in macrophages infected with the wild-type bacteria. In time-to-death studies, C3H mice infected with theΔ sigDmutant exhibited a mortality delay compared to those infected with either the complemented or wild-type strains. Although mice infected with theΔ sigDmutant died at a reduced rate, the bacillary loads in the lungs and spleen of these mice were comparable to those seen in mice infected with either the complemented or wild-type strains. Microarray analysis of theΔ sigDmutant relative to wild type revealed that SigD directs the expression of a small set of ribosomal genes and adenosine triphosphate transporters whose expression is normally induced during stationary phase growthin vitro. Altered expression of a subset of these genes was confirmed by quantitative reverse transcription polymerase chain reaction analysis. Promoter-like elements resembling the consensus sequence AGAAAG-N16−20-CGTTAA were found upstream of 19 of the genes underexpressed in theΔ sigDmutant suggesting this may be the recognition sequence for theM. tuberculosisSigD-holoenzyme, EσD. These data indicate that theM. tuberculosisSigD sigma factor governs the expression of a small set of ribosomal genes typically expressed in stationary phase duringin vitrogrowth and that loss ofsigDreduces macrophage TNF-α secretion as well as the lethality ofM. tuberculosisinfection in mice.
- Subjects
MYCOBACTERIUM tuberculosis; GENE expression; GENES; MACROPHAGES; TUMORS; GENETIC regulation
- Publication
Cellular Microbiology, 2005, Vol 7, Issue 2, p233
- ISSN
1462-5814
- Publication type
Article
- DOI
10.1111/j.1462-5822.2004.00454.x