Comprehensive analysis of iron utilization by Mycobacterium tuberculosis

Zhang, Lei; Hendrickson, R. Curtis; Meikle, Virginia; Lefkowitz, Elliot J.; Ioerger, Thomas R.; Niederweis, Michael

doi:10.1371/journal.ppat.1008337

Cited by 75 publications

(81 citation statements)

References 83 publications

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“…Another important cluster of proteins involved in mycobacterial secretion and induced by MTS1338 are those of the ESX-3 secretion system. ESX-3 is essential for iron homeostasis and survival of mycobacteria in vivo [68], which is consistent with the significance of iron uptake for MTb virulence revealed in animal models [3,69] and patients with TB [70]. Iron is an essential element for MTb, which expresses over 40 enzymes requiring iron as a cofactor.…”

Section: Discussionsupporting

confidence: 81%

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Mycobacterium tuberculosis Small RNA MTS1338 Confers Pathogenic Properties to Non-Pathogenic Mycobacterium smegmatis

et al. 2021

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Small non-coding RNAs play a key role in bacterial adaptation to various stresses. Mycobacterium tuberculosis small RNA MTS1338 is upregulated during mycobacteria infection of macrophages, suggesting its involvement in the interaction of the pathogen with the host. In this study, we explored the functional effects of MTS1338 by expressing it in non-pathogenic Mycobacterium smegmatis that lacks the MTS1338 gene. The results indicated that MTS1338 slowed the growth of the recombinant mycobacteria in culture and increased their survival in RAW 264.7 macrophages, where the MTS1338-expressing strain significantly (p < 0.05) reduced the number of mature phagolysosomes and changed the production of cytokines IL-1β, IL-6, IL-10, IL-12, TGF-β, and TNF-α compared to those of the control strain. Proteomic and secretomic profiling of recombinant and control strains revealed differential expression of proteins involved in the synthesis of main cell wall components and in the regulation of iron metabolism (ESX-3 secretion system) and response to hypoxia (furA, whiB4, phoP). These effects of MTS1338 expression are characteristic for M. tuberculosis during infection, suggesting that in pathogenic mycobacteria MTS1338 plays the role of a virulence factor supporting the residence of M. tuberculosis in the host.

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Section: Discussionsupporting

confidence: 81%

“…The ESX-3 system contributes to siderophore-mediated iron acquisition [ 71 ]. Furthermore, ESX-3 is involved in heme utilization by MTb [ 68 ], which is necessary for the function of many transcriptional regulators and cytochromes present in mycobacteria.…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis Small RNA MTS1338 Confers Pathogenic Properties to Non-Pathogenic Mycobacterium smegmatis

et al. 2021

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“…Lastly, it is worth pointing out that an efficient iron acquisition machinery for scavenging iron from tightly regulated host environment is an absolute requirement for all successful pathogens. For this, most of the pathogens have evolved high‐affinity iron‐binding proteins (Skaar, 2010; Zhang et al, 2020). For example, Mycobacterium secretes iron‐harvesting siderophore proteins, such as mycobactins and carboxymycobactins, that help it to acquire ferric iron from its surroundings (Knobloch et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Leishmaniainfection triggers hepcidin‐mediated proteasomal degradation of Nramp1 to increase phagolysosomal iron availability

Banerjee

Datta

2020

Cellular Microbiology

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Natural resistance–associated macrophage protein 1 (Nramp1) was originally discovered as a genetic determinant of resistance against multiple intracellular pathogens, including Leishmania. It encodes a transmembrane protein of the phago‐endosomal compartments, where it functions as an iron transporter. But the mechanism by which Nramp1 controls host–pathogen dynamics and determines final outcome of an infection is yet to be fully deciphered. Whether the expression of Nramp1 is altered in response to a pathogen attack is also unknown. To address these, Nramp1 status was examined in Leishmania major–infected murine macrophages. We observed that at 12 hrs post infection, there was drastic lowering of Nramp1 level accompanied by increased phagolysosomal iron content and enhanced intracellular parasite growth. Leishmania infection–induced Nramp1 downregulation was caused by ubiquitin‐proteasome degradation pathway, which in turn was found to be mediated by the iron‐regulatory peptide hormone hepcidin. Blocking of Nramp1 degradation with proteasome inhibitor or transcriptional agonist of hepcidin resulted in depletion of phagolysosomal iron pool that led to significant reduction of intracellular parasite burden. Interestingly, Nramp1 level was restored to normalcy after 30 hrs of infection with a concomitant drop in phagolysosomal iron, which is suggestive of a host counteractive response to deprive the pathogen of this essential micronutrient. Taken together, our study implicates Nramp1 as a central player in the host–pathogen battle for phagolysosomal iron. We also report Nramp1 as a novel target for hepcidin, and this ‘hepcidin‐Nramp1’ axis may have a broader role in regulating macrophage iron homeostasis.

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“…Future efforts should therefore be directed towards covering a wider and diverse region of experimental condition space. Towards this end, a recent TnSeq screen assaying iron uptake in M. tuberculosis [36] , as well as recent technical developments that couple TnSeq with random DNA barcoding (RB-TnSeq) allowing parallel screening across dozens of conditions [37] are very encouraging.…”

Section: Discussionmentioning

confidence: 99%

TheMycobacterium tuberculosistransposon sequencing database (MtbTnDB): a large-scale guide to genetic conditional essentiality

Jinich

Zaveri

DeJesus³

et al. 2021

Preprint

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Characterization of gene essentiality across different conditions is a useful approach for predicting gene function. Transposon sequencing (TnSeq) is a powerful means of generating genome-wide profiles of essentiality and has been used extensively in Mycobacterium tuberculosis (Mtb) genetic research. Over the past two decades, dozens of TnSeq screens have been published, yielding valuable insights into the biology of Mtb in vitro, inside macrophages, and in model host organisms. However, these Mtb TnSeq profiles are distributed across dozens of research papers within supplementary materials, which makes querying them cumbersome and assembling a complete and consistent synthesis of existing data challenging. Here, we address this problem by building a central repository of publicly available TnSeq screens performed in M. tuberculosis, which we call the Mtb transposon sequencing database (MtbTnDB). The MtbTnDB encompasses 64 published and unpublished TnSeq screens, and is standardized, open-access, and allows users easy access to data, visualizations, and functional predictions through an interactive web-app (www.mtbtndb.app). We also present evidence that (i) genes in the same genomic neighborhood tend to have similar TnSeq profiles, and (ii) clusters of genes with similar TnSeq profiles tend to be enriched for genes belonging to the same functional categories. Finally, we test and evaluate machine learning models trained on TnSeq profiles to guide functional annotation of orphan genes in Mtb. In addition to facilitating the exploration of conditional genetic essentiality in this important human pathogen via a centralized TnSeq data repository, the MtbTnDB will enable hypothesis generation and the extraction of meaningful patterns by facilitating the comparison of datasets across conditions. This will provide a basis for insights into the functional organization of Mtb genes as well as gene function prediction.

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Comprehensive analysis of iron utilization by Mycobacterium tuberculosis

Cited by 75 publications

References 83 publications

Mycobacterium tuberculosis Small RNA MTS1338 Confers Pathogenic Properties to Non-Pathogenic Mycobacterium smegmatis

Mycobacterium tuberculosis Small RNA MTS1338 Confers Pathogenic Properties to Non-Pathogenic Mycobacterium smegmatis

Leishmaniainfection triggers hepcidin‐mediated proteasomal degradation of Nramp1 to increase phagolysosomal iron availability

TheMycobacterium tuberculosistransposon sequencing database (MtbTnDB): a large-scale guide to genetic conditional essentiality

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