Cholesterol and fatty acids grease the wheels of Mycobacterium tuberculosis pathogenesis

Wilburn, Kaley M; Fieweger, Rachael A; VanderVen, Brian C.

doi:10.1093/femspd/fty021

Cited by 145 publications

(194 citation statements)

References 129 publications

Supporting

Mentioning

189

Contrasting

Unclassified

Order By: Relevance

“…Fatty acids and cholesterol metabolism are essential for mycobacteria to grow in macrophages and infect human and animals (29). However, the degradation of fatty acids and cholesterol results in accumulation of propionyl-CoA (30)(31)(32).…”

Section: Discussionmentioning

confidence: 99%

The Nitrogen Regulator GlnR Directly Controls Transcription of the prpDBC Operon Involved in Methylcitrate Cycle in Mycobacterium smegmatis

Liu

Shen

et al. 2019

J Bacteriol

View full text Add to dashboard Cite

Mycobacterium tuberculosis utilizes fatty acids of the host as the carbon source. Metabolism of odd-chain fatty acids by Mycobacterium tuberculosis produces propionyl coenzyme A (propionyl-CoA). The methylcitrate cycle is essential for mycobacteria to utilize the propionyl-CoA to persist and grow on these fatty acids. In M. smegmatis, methylcitrate synthase, methylcitrate dehydratase, and methylisocitrate lyase involved in the methylcitrate cycle are encoded by prpC, prpD, and prpB, respectively, in operon prpDBC. In this study, we found that the nitrogen regulator GlnR directly binds to the promoter region of the prpDBC operon and inhibits its transcription. The binding motif of GlnR was identified by bioinformatic analysis and validated using DNase I footprinting and electrophoretic mobility shift assays. The GlnR-binding motif is separated by a 164-bp sequence from the binding site of PrpR, a pathway-specific transcriptional activator of methylcitrate cycle, but the binding affinity of GlnR to prpDBC is much stronger than that of PrpR. Deletion of glnR resulted in faster growth in propionate or cholesterol medium compared with the wild-type strain. The ΔglnR mutant strain also showed a higher survival rate in macrophages. These results illustrated that the nitrogen regulator GlnR regulates the methylcitrate cycle through direct repression of the transcription of the prpDBC operon. This finding not only suggests an unprecedented link between nitrogen metabolism and the methylcitrate pathway but also reveals a potential target for controlling the growth of pathogenic mycobacteria. IMPORTANCE The success of mycobacteria survival in macrophage depends on its ability to assimilate fatty acids and cholesterol from the host. The cholesterol and fatty acids are catabolized via β-oxidation to generate propionyl coenzyme A (propionyl-CoA), which is then primarily metabolized via the methylcitrate cycle. Here, we found a typical GlnR binding box in the prp operon, and the affinity is much stronger than that of PrpR, a transcriptional activator of methylcitrate cycle. Furthermore, GlnR repressed the transcription of the prp operon. Deletion of glnR significantly enhanced the growth of Mycobacterium tuberculosis in propionate or cholesterol medium, as well as viability in macrophages. These findings provide new insights into the regulatory mechanisms underlying the cross talk of nitrogen and carbon metabolisms in mycobacteria.

show abstract

Section: Discussionmentioning

confidence: 99%

The Nitrogen Regulator GlnR Directly Controls Transcription of the prpDBC Operon Involved in Methylcitrate Cycle in Mycobacterium smegmatis

Liu

Shen

et al. 2019

J Bacteriol

View full text Add to dashboard Cite

show abstract

“…Current evidence suggests that fatty acids from host origin are used by Mtb as an energy source for persistence and virulence. Furthermore, the catabolism of hostderived lipids can be used by Mtb to regulate its replication and drug tolerance [53]. In axenic media such as Sauton's, the primary carbon source for the bacillus is glycerol [54] allowing the growth of Mtb [55].…”

Section: Main Transcriptomic Changes Between Ut127 and Ut205mentioning

confidence: 99%

Differential determinants of virulence in twoMycobacterium tuberculosisColombian clinical isolates of the LAM09 family

et al. 2019

View full text Add to dashboard Cite

The heterogeneity of the clinical outcome of Mycobacterium tuberculosis (Mtb) infection may be due in part to different strategies used by circulating strains to cause disease. This heterogeneity is one of the main limitations to eradicate tuberculosis disease. In this study, we have compared the transcriptional response of two closely related Colombian clinical isolates (UT127 and UT205) of the LAM family under two axenic media conditions. These clinical isolates are phenotypically different at the level of cell death, cytokine production, growth kinetics upon in vitro infection of human tissue macrophages, and membrane vesicle secretion upon culture in synthetic medium. Using RNA-seq, we have identified different pathways that account for two different strategies to cope with the stressful condition of a carbon-poor media such as Sauton's. We showed that the clinical isolate UT205 focus mainly in the activation of virulence systems such as the ESX-1, synthesis of diacyl-trehalose, polyacyltrehalose, and sulfolipids, while UT127 concentrates its efforts mainly in the survival mode by the activation of the DNA replication, cell division, and lipid biosynthesis. This is an example of two Mtb isolates that belong to the same family and lineage, and even though they have a very similar genome, its transcriptional regulation showed important differences. This results in summary highlight the necessity to reach a better understanding of the heterogeneity in the behavior of these circulating Mtb strains which may help us to design better treatments and vaccines and to identify new targets for drugs.

show abstract

“…We hypothesized that nutrient-starved mycobacteria might buffer the costs of TMM synthesis by enlisting such pathways. As the recycling mechanism for mycolic acids is still controversial (Dunphy et al, 2010; Wilburn et al, 2018), we focused on the role of trehalose uptake.…”

Section: Resultsmentioning

confidence: 99%

“…TDM can also be degraded by TDM hydrolase (TDMH) into TMM and free mycolic acids, the latter of which are an important component of biofilm extracellular matrix in mycobacteria (Holmes et al, 2019; Ojha et al, 2010). While a salvage mechanism for mycolic acids is still under debate (Cantrell et al, 2013; Dunphy et al, 2010; Forrellad et al, 2014; Wilburn et al, 2018), recapture of trehalose occurs via the LpqY-SugABC transporter (Kalscheuer et al, 2010b). Depending on the specific environmental demand, mycobacteria may funnel reclaimed trehalose back to central carbon metabolism, to generate intermediates for glycolysis or the pentose phosphate pathway, or store it in the cytoplasm, possibly as a stress protectant or compatible solute (Eoh et al, 2017; Lee et al, 2019; Nobre et al, 2014; Shleeva et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Trehalose recycling promotes energy-efficient mycomembrane reorganization in nutrient-limited mycobacteria

Pohane

Carr

Garhyan

et al. 2019

Preprint

View full text Add to dashboard Cite

2The mycomembrane layer of the mycobacterial cell envelope is a barrier to 3 environmental, immune and antibiotic insults. We find that there is mycomembrane 4 remodeling along the periphery of nutrient-starved, non-replicating mycobacterial cells. 5Remodeling is supported by recycling of trehalose, a non-mammalian disaccharide that 6 shuttles long-chain mycolate lipids to the mycomembrane. In the absence of trehalose 7 recycling, mycomembrane synthesis continues but mycobacteria experience ATP 8 depletion, enhanced respiration and redox stress. Redox stress from depletion of the 9 trehalose pool is suppressed in a mutant that lacks the OtsAB de novo trehalose 10 synthesis pathway. Our data suggest that trehalose recycling alleviates the energetic 11 burden of mycomembrane remodeling. Loss of trehalose salvage is known to attenuate 12

show abstract

Cholesterol and fatty acids grease the wheels of Mycobacterium tuberculosis pathogenesis

Cited by 145 publications

References 129 publications

The Nitrogen Regulator GlnR Directly Controls Transcription of the prpDBC Operon Involved in Methylcitrate Cycle in Mycobacterium smegmatis

The Nitrogen Regulator GlnR Directly Controls Transcription of the prpDBC Operon Involved in Methylcitrate Cycle in Mycobacterium smegmatis

Differential determinants of virulence in twoMycobacterium tuberculosisColombian clinical isolates of the LAM09 family

Trehalose recycling promotes energy-efficient mycomembrane reorganization in nutrient-limited mycobacteria

Contact Info

Product

Resources

About