The Stringent Response of
            <i>Mycobacterium tuberculosis</i>
            Is Required for Long-Term Survival

Primm, Todd P.; Andersen, Susan J.; Mizrahi, Valerie; Avarbock, David; Rubin, Harvey; Barry, Clifton E.

doi:10.1128/jb.182.17.4889-4898.2000

Cited by 314 publications

(373 citation statements)

References 80 publications

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“…EmbR (Rv1267c), a putative transcriptional regulator of arabinan cell wall metabolism (60), and Rv3058c, a probable transcriptional factor that belongs to TetR family (61), were detected only in the control and R24 (five-fold increase at R24). Under unfavorable conditions, bacteria shift their metabolic activities by stringent response (62). In accordance with this hypothesis, Rv2583c, a GTP pyrophosphokinase (RelA) involved in stringent response in MTB was detected only at NRP2.…”

Section: Validation Of Quantitative Proteomic Data By Qpcr-tosupporting

confidence: 56%

Profiling the Proteome of Mycobacterium tuberculosis during Dormancy and Reactivation

Gopinath

Raghunandanan

Gomez

et al. 2015

Molecular & Cellular Proteomics

114

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Tuberculosis, caused by Mycobacterium tuberculosis, still remains a major global health problem. The main obstacle in eradicating this disease is the ability of this pathogen to remain dormant in macrophages, and then reactivate later under immuno-compromised conditions. The physiology of hypoxic nonreplicating M. tuberculosis is well-studied using many in vitro dormancy models. However, the physiological changes that take place during the shift from dormancy to aerobic growth (reactivation) have rarely been subjected to a detailed investigation. In this study, we developed an in vitro reactivation system by re-aerating the virulent laboratory strain of M. tuberculosis that was made dormant employing Wayne's dormancy model, and compared the proteome profiles of dormant and reactivated bacteria using label-free onedimensional LC/MS/MS analysis. The proteome of dormant bacteria was analyzed at nonreplicating persistent stage 1 (NRP1) and stage 2 (NRP2), whereas that of reactivated bacteria was analyzed at 6 and 24 h post reaeration. Proteome of normoxially grown bacteria served as the reference. In total, 1871 proteins comprising 47% of the M. tuberculosis proteome were identified, and many of them were observed to be expressed differentially or uniquely during dormancy and reactivation. The number of proteins detected at different stages of dormancy (764 at NRP1, 691 at NRP2) and reactivation (768 at R6 and 983 at R24) was very low compared with that of the control (1663). The number of unique proteins identified during normoxia, NRP1, NRP2, R6, and R24 were 597, 66, 56, 73, and 94, respectively. We analyzed various biological functions during these conditions. Fluctuation in the relative quantities of proteins involved in energy metabolism during dormancy and reactivation was the most significant observation we made in this study. Proteins that are up-regulated or uniquely expressed during reactivation from dormancy offer to be attractive targets for therapeutic intervention to

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Section: Validation Of Quantitative Proteomic Data By Qpcr-tosupporting

confidence: 56%

Profiling the Proteome of Mycobacterium tuberculosis during Dormancy and Reactivation

Gopinath

Raghunandanan

Gomez

et al. 2015

Molecular & Cellular Proteomics

114

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“…1), and leucine biosynthesis (31) are also essential pathways (Sassetti et al 2003). Finally, the ppGpp metabolic pathway (81) is essential for long-term survival of mycobacteria under starvation conditions (Primm et al 2000). All these pathways of M. tuberculosis have high RPI values.…”

Section: Discussionmentioning

confidence: 99%

Insights on the Evolution of Metabolic Networks of Unicellular Translationally Biased Organisms from Transcriptomic Data and Sequence Analysis

Carbone

Madden

2005

J Mol Evol

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Abstract. Codon bias is related to metabolic functions in translationally biased organisms, and two facts are argued about. First, genes with high codon bias describe in meaningful ways the metabolic characteristics of the organism; important metabolic pathways corresponding to crucial characteristics of the lifestyle of an organism, such as photosynthesis, nitrification, anaerobic versus aerobic respiration, sulfate reduction, methanogenesis, and others, happen to involve especially biased genes. Second, gene transcriptional levels of sets of experiments representing a significant variation of biological conditions strikingly confirm, in the case of Saccharomyces cerevisiae, that metabolic preferences are detectable by purely statistical analysis: the high metabolic activity of yeast during fermentation is encoded in the high bias of enzymes involved in the associated pathways, suggesting that this genome was affected by a strong evolutionary pressure that favored a predominantly fermentative metabolism of yeast in the wild. The ensemble of metabolic pathways involving enzymes with high codon bias is rather well defined and remains consistent across many species, even those that have not been considered as translationally biased, such as Helicobacter pylori, for instance, reveal some weak form of translational bias for this genome. We provide numerical evidence, supported by experimental data, of these facts and conclude that the metabolic networks of translationally biased genomes, observable today as projections of eons of evolutionary pressure, can be analyzed numerically and predictions of the role of specific pathways during evolution can be derived. The new concepts of Comparative Pathway Index, used to compare organisms with respect to their metabolic networks, and Evolutionary Pathway Index, used to detect evolutionarily meaningful bias in the genetic code from transcriptional data, are introduced.

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“…In E. coli, the two proteins RelA and SpoT regulate the concentration of (p)ppGpp, a global transcriptional activator of numerous metabolic pathways under starvation conditions (19). RelA is important for the virulence of Listeria monocytogenes (20), for the activation of quorum sensing in Pseudomonas aeruginosa (21), and for long-term survival of Mycobacterium tuberculosis (22). In Brucella spp.…”

Section: Resultsmentioning

confidence: 99%

The analysis of the intramacrophagic virulome ofBrucella suisdeciphers the environment encountered by the pathogen inside the macrophage host cell

Köhler

Foulongne

Ouahrani‐Bettache

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

235

234

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The pathogen Brucella suis resides and multiplies within a phagocytic vacuole of its host cell, the macrophage. The resulting complex relationship has been investigated by the analysis of the set of genes required for virulence, which we call intramacrophagic virulome. Ten thousand two hundred and seventy-two miniTn5 mutants of B. suis constitutively expressing gfp were screened by fluorescence microscopy for lack of intracellular multiplication in human macrophages. One hundred thirty-one such mutants affected in 59 different genes could be isolated, and a function was ascribed to 53 of them. We identified genes involved in (i) global adaptation to the intracellular environment, (ii) amino acid, and (iii) nucleotide synthesis, (iv) sugar metabolism, (v) oxidoreduction, (vi) nitrogen metabolism, (vii) regulation, (viii) disulphide bond formation, and (ix) lipopolysaccharide biosynthesis. Results led to the conclusion that the replicative compartment of B. suis is poor in nutrients and characterized by low oxygen tension, and that nitrate may be used for anaerobic respiration. Intramacrophagic virulome analysis hence allowed the description of the nature of the replicative vacuole of the pathogen in the macrophage and extended our understanding of the niche in which B. suis resides. We propose calling this specific compartment ''brucellosome.'' I nteractions between microorganisms and their hosts extend from acute infections to persistent infectious diseases or symbiosis. This type of interaction can result from a million years of coevolution and coadaptation of the two organisms. Thus, the biology of the interaction can be read, at least partially, in the genome of the microorganism. In the specific case of pathogenic bacteria, deciphering of the genes involved in the interaction and analysis of their functions will shed light on the environment encountered by the parasite in the host and will contribute to the understanding of the complex relationship between two organisms. As a name for the whole set of genes required for virulence, i.e., involved in the invasion of the host by the bacteria and their adaptation to the environment provided by this host, we propose virulome. In this study, we will perform a thorough analysis of the intramacrophagic virulome of Brucella suis.Brucella spp. is an ␣ proteobacteriaceae that induces a persistent disease in some mammals, resulting in abortion. In humans, initial septicemia may be followed by a subacute or a chronic infection (1). Brucella spp. is phyletically related as well to plant symbionts such as rhizobiaceae, as to rickettsiae, which generate an acute infectious disease (2). In terms of virulence, brucellae occupy an intermediate position where the adaptation results in a mild disease that allows them to persist in mammal hosts. It is usually considered that, for a facultative intracellular bacterium such as Brucella spp., which multiplies in trophoblasts or macrophages (3), one of the challenges is to rapidly adapt to the intracellular settings but also to resis...

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The Stringent Response of Mycobacterium tuberculosis Is Required for Long-Term Survival

Cited by 314 publications

References 80 publications

Profiling the Proteome of Mycobacterium tuberculosis during Dormancy and Reactivation

Profiling the Proteome of Mycobacterium tuberculosis during Dormancy and Reactivation

Insights on the Evolution of Metabolic Networks of Unicellular Translationally Biased Organisms from Transcriptomic Data and Sequence Analysis

The analysis of the intramacrophagic virulome ofBrucella suisdeciphers the environment encountered by the pathogen inside the macrophage host cell

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