Lipid Inclusions in Mycobacterial Infections

Stehr, Matthias; Elamin, Ayssar A.; Singh, Mahavir

doi:10.5772/54526

Cited by 12 publications

(32 citation statements)

References 118 publications

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“…7;9;15 Mycobacterial membrane and storage lipids are complex, composing the unique mycolic acid layer in the mycobacterial cell wall. 72;73 These membrane lipids are constantly broken down and recycled under normal growth conditions, matching with the genomic and proteomic expression patterns of LipW under normal growth conditions.…”

Section: Discussionmentioning

confidence: 99%

“…4 This interplay between nutrient cycles and TB infection is exemplified in the lipid filled granulomas that demarcate a TB infection. 4;6;7 In these granulomas, Mtb accumulates large congregations of lipid inclusions and foamy macrophages that facilitate the lipid degradation and nutrient scavenging pathways required to sustain a long-term Mtb infection. 1;4;6;7 …”

mentioning

confidence: 99%

“…11;12 Expression of serine hydrolases also cycle with nutrient starvation and triacylglyerol (TAG) utilization and are colocalized with lipid inclusions and foamy macrophages. 7–9;13–15 Although the ability of Mtb to shift carbon sources makes targeting a particular nutrient pathway unlikely to completely inhibit growth, nonselective inhibitors of serine hydrolases downregulate TAG utilization and impede the reactivation of dormant Mtb infections. 1;4;16–18 …”

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confidence: 99%

“…17;21;22 Many Lip family members are, however, likely still connected to metabolism and energy utilization in Mtb , as 11 Lip genes are located adjacent or proximal to triacylglycerol synthetase (tgs) genes in the Mtb genome. 7 …”

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confidence: 99%

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Structural Basis for the Strict Substrate Selectivity of the Mycobacterial Hydrolase LipW

et al. 2016

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The complex life cycle of Mycobacterium tuberculosis requires diverse energy mobilization and utilization strategies facilitated by a battery of lipid metabolism enzymes. Among lipid metabolism enzymes, the Lip family of mycobacterial serine hydrolases is essential to lipid scavenging, metabolic cycles, and reactivation from dormancy. Based on the homologous rescue strategy for mycobacterial drug targets, we have characterized the three-dimensional structure of full length LipW from Mycobacterium marinum, the first structure of a catalytically active Lip family member. LipW contains a deep, expansive substrate-binding pocket with only a narrow, restrictive active site, suggesting tight substrate selectivity for short, unbranched esters. Structural alignment reinforced this strict substrate selectivity of LipW, as the binding pocket of LipW aligned most closely with the bacterial acyl esterase superfamily. Detailed kinetic analysis of two different LipW homologues confirmed this strict substrate selectivity, as each homologue selected for unbranched propionyl ester substrates, irrespective of the alcohol portion of the ester. Using comprehensive substitutional analysis across the binding pocket, the strict substrate selectivity of LipW for propionyl esters was assigned to a narrow funnel in the acyl-binding pocket capped by a key hydrophobic valine residue. The polar, negatively charged alcohol-binding pocket also contributed to substrate orientation and stabilization of rotameric states in the catalytic serine. Together the structural, enzymatic, and substitutional analysis of LipW provide a connection between the structure and metabolic properties of a Lip family hydrolase that refines its biological function in active and dormant tuberculosis infection.

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Section: Discussionmentioning

confidence: 99%

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Structural Basis for the Strict Substrate Selectivity of the Mycobacterial Hydrolase LipW

et al. 2016

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“…Inclusions may also be sinks for nutrients, leading to lower bacterial replication rates (6). M. tuberculosis lipid inclusions are observed during growth arrest in mouse lung (13) and under in vitro stress conditions (6,10,12,14,15,(27)(28)(29). Bacteria form lipid inclusions by rerouting metabolic carbon fluxes from biomass generation pathways to storage pathways (13).…”

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Multiscale Model of Mycobacterium tuberculosis Infection Maps Metabolite and Gene Perturbations to Granuloma Sterilization Predictions

et al. 2016

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cGranulomas are a hallmark of tuberculosis. Inside granulomas, the pathogen Mycobacterium tuberculosis may enter a metabolically inactive state that is less susceptible to antibiotics. Understanding M. tuberculosis metabolism within granulomas could contribute to reducing the lengthy treatment required for tuberculosis and provide additional targets for new drugs. Two key adaptations of M. tuberculosis are a nonreplicating phenotype and accumulation of lipid inclusions in response to hypoxic conditions. To explore how these adaptations influence granuloma-scale outcomes in vivo, we present a multiscale in silico model of granuloma formation in tuberculosis. The model comprises host immunity, M. tuberculosis metabolism, M. tuberculosis growth adaptation to hypoxia, and nutrient diffusion. We calibrated our model to in vivo data from nonhuman primates and rabbits and apply the model to predict M. tuberculosis population dynamics and heterogeneity within granulomas. We found that bacterial populations are highly dynamic throughout infection in response to changing oxygen levels and host immunity pressures. Our results indicate that a nonreplicating phenotype, but not lipid inclusion formation, is important for long-term M. tuberculosis survival in granulomas. We used virtual M. tuberculosis knockouts to predict the impact of both metabolic enzyme inhibitors and metabolic pathways exploited to overcome inhibition. Results indicate that knockouts whose growth rates are below ϳ66% of the wild-type growth rate in a culture medium featuring lipid as the only carbon source are unable to sustain infections in granulomas. By mapping metabolite-and gene-scale perturbations to granuloma-scale outcomes and predicting mechanisms of sterilization, our method provides a powerful tool for hypothesis testing and guiding experimental searches for novel antituberculosis interventions.T uberculosis (TB), caused by inhalation of the pathogen Mycobacterium tuberculosis, is a leading cause of death worldwide (1, 2). The main sites of infection during TB are lung granulomas, dense collections of immune cells and bacteria that develop following infection (3). Understanding M. tuberculosis dynamics within granulomas could aid in development of new antibiotic therapies, since M. tuberculosis growth rates, heterogeneity, and dynamics can affect antibiotic efficacy (3-7).Two in vitro-observed adaptations of M. tuberculosis, suspected to be important in the ability of M. tuberculosis to persist in the host lung, are (i) the adoption of a nonreplicating phenotype and (ii) the accumulation of lipid inclusions, aggregates of neutral lipids inside bacteria (8-13). Hypoxia is known to be a trigger for the transition to a nonreplicating phenotype and the formation of lipid inclusions (9,12,14,15).The in vivo role of the nonreplicating phenotype remains controversial. It has been suggested that M. tuberculosis acquires the nonreplicating phenotype in response to stresses present in the host (such as hypoxia) and that this phenotype allows M. tubercul...

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Rv2037c, a stress induced conserved hypothetical protein of Mycobacterium tuberculosis, is a phospholipase: Role in cell wall modulation and intracellular survival

Kumari

Saini

Kaur

et al. 2020

International Journal of Biological Macromolecules

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Lipid Inclusions in Mycobacterial Infections

Cited by 12 publications

References 118 publications

Structural Basis for the Strict Substrate Selectivity of the Mycobacterial Hydrolase LipW

Structural Basis for the Strict Substrate Selectivity of the Mycobacterial Hydrolase LipW

Multiscale Model of Mycobacterium tuberculosis Infection Maps Metabolite and Gene Perturbations to Granuloma Sterilization Predictions

Rv2037c, a stress induced conserved hypothetical protein of Mycobacterium tuberculosis, is a phospholipase: Role in cell wall modulation and intracellular survival

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