Key Points
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Pulmonary tuberculosis is a complex disease that is clinically manifested by the appearance of different types of granulomas including necrotic, caseous and liquefied lesions. Latent bacteria might be responsible for reactivation disease and are thought to reside in caseous granulomas.
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Several animal models have been used to investigate different aspects of human latent disease. So far, the non-human primate model has shown the most similarity to the heterogeneity of human pulmonary tuberculosis and the development of latent disease.
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The most thoroughly investigated in vitro model of latent persistence involves a hypoxic culture that is generated by gradual consumption of all the available oxygen in stirred, sealed tubes. Adaptation to hypoxic conditions is associated with the increased expression of several enzymes including nitrate reductase and glycine dehydrogenase.
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The signal for entry into a state of metabolic persistence may be different in humans and mice. In mice, the metabolic signal is probably provided by nitric oxide. In vitro models have shown that exposure to nitric oxide induces the transcription of a 48-gene regulon in Mycobacterium tuberculosis — the dormancy regulon — and the same regulon is upregulated in infected mice. Nitric oxide exposure shares many transcriptional similarities with hypoxia, but there are some important differences. Low concentrations of oxygen might be the predominant signal for the bacteria during the development of latency in humans.
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β-oxidation and gluconeogenesis are important for persistence of this pathogen in murine tissues. However, β-oxidation is unlikely to allow M. tuberculosis to maintain redox balance in the absence of external electron acceptors. It is possible that human caseous granulomas that harbour latent organisms are hypoxic, which might indicate that unless these lesions contain sufficient concentrations of nitrate as terminal electron acceptor, fatty acids may not be important during persistence in humans.
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M. tuberculosis may maintain an energized membrane by fermentation pathways. Transcriptional profiling of anaerobic cultures has revealed that transcription of a set of genes that might have a role in fermentation is induced under such conditions.
Abstract
Human tuberculosis is a complex disease caused by bacterial populations that are located in discrete lesions (microenvironments) in a single host. Some of these microenvironments are conducive to replication, whereas others restrict bacterial growth without necessarily sterilizing the infecting microorganisms. The physical and biochemical milieu in these lesions is poorly defined. None of the existing animal models for tuberculosis (except perhaps non-human primates) reproduce the diversity of disease progression that is seen in humans. Nonetheless, transcriptomics and studies using bacterial mutants have led to testable hypotheses about metabolic functions that are essential for viability in the absence of replication. A complete picture of bacterial metabolism must balance reducing equivalents while maintaining an energized membrane and basic cellular processes.
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Glossary
- GHON COMPLEX
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The primary lesion together with the draining and affected lymph nodes caused by initial infection by Mycobacterium tuberculosis.
- CASEUM
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The wet/semi-dry chalky paste that results from tissue necrosis in granulomas.
- REACTIVE NITROGEN INTERMEDIATES
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Oxides of nitrogen besides nitrite and nitrate that arise in cellular environments, including nitroxyl (NO2•) and nitrosonium ions (NO+), S-nitrosothiols (RSNO), nitric oxide (NO) and peroxynitrites (ONOO−).
- REACTIVE OXYGEN INTERMEDIATES
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The different oxidation states of oxygen in biological reactions that include hydrogen peroxide (H2O2), superoxide ([O2−]•), singlet oxygen (1O2•), ozone (O3), hydroxyl radical (•OH) and hypohalites (for example, ClO−).
- CLUSTERED STRAINS
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Isolates of M. tuberculosis obtained from different patients during a defined time period that share sufficient genotypic characteristics so that one can reasonably infer that the patients were infected from each other or a common source.
- FERMENTATION
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The metabolic process by which energy is derived from substrate-level phosphorylation by the partial oxidation of organic substrates using organic metabolic intermediates as electron donors and electron acceptors.
- STRINGENT RESPONSE
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The bacterial stress response triggered typically by nutritional starvation which leads to global metabolic and transcriptional changes, the most characteristic being the loss of stable RNA accumulation (tRNA and rRNA) and downregulation of protein synthesis. The stringent response is mediated by intracellular accumulation of phosphorylated derivatives of GTP or GDP, collectively termed (p)ppGpp.
- ACID-FAST BACTERIA
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Have cell wall characteristics that result in bacilli retaining the red dye carbol fuchsin after an acid wash.
- REDOX BALANCE
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This refers to the metabolic reactions that are possible or necessary to maintain the NADH:NAD+ ratio in a cell. The number of reactions that generate NADH (or another reduced cofactor such as FADH2) must be balanced by metabolic reactions that reoxidize an equivalent amount of the reduced cofactor.
- DISPROPORTIONATION
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An oxidation–reduction reaction in which the same molecule is both oxidized and reduced.
- MIDPOINT POTENTIAL
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The redox potential of a chemical species at which half of the molecules are reduced and half are oxidized. It measures the tendency to oxidize another compound and is measured relative to hydrogen.
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Boshoff, H., Barry, C. Tuberculosis — metabolism and respiration in the absence of growth. Nat Rev Microbiol 3, 70–80 (2005). https://doi.org/10.1038/nrmicro1065
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DOI: https://doi.org/10.1038/nrmicro1065
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