Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Mycobacterial p(1)-type ATPases mediate resistance to zinc poisoning in human macrophages.

ABSTRACT: Mycobacterium tuberculosis thrives within macrophages by residing in phagosomes and preventing them from maturing and fusing with lysosomes. A parallel transcriptional survey of intracellular mycobacteria and their host macrophages revealed signatures of heavy metal poisoning. In particular, mycobacterial genes encoding heavy metal efflux P-type ATPases CtpC, CtpG, and CtpV, and host cell metallothioneins and zinc exporter ZnT1, were induced during infection. Consistent with this pattern of gene modulation, we observed a burst of free zinc inside macrophages, and intraphagosomal zinc accumulation within a few hours postinfection. Zinc exposure led to rapid CtpC induction, and ctpC deficiency caused zinc retention within the mycobacterial cytoplasm, leading to impaired intracellular growth of the bacilli. Thus, the use of P(1)-type ATPases represents a M. tuberculosis strategy to neutralize the toxic effects of zinc in macrophages. We propose that heavy metal toxicity and its counteraction might represent yet another chapter in the host-microbe arms race. [Data is also available from http://bugs.sgul.ac.uk/E-BUGS-122]

ORGANISM(S): Mycobacterium tuberculosis

SUBMITTER: Adam Witney

PROVIDER: E-BUGS-122 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Mycobacterial p(1)-type ATPases mediate resistance to zinc poisoning in human macrophages.

Botella Hélène H Peyron Pascale P Levillain Florence F Poincloux Renaud R Poquet Yannick Y Brandli Irène I Wang Chuan C Tailleux Ludovic L Tilleul Sylvain S Charrière Guillaume M GM Waddell Simon J SJ Foti Maria M Lugo-Villarino Geanncarlo G Gao Qian Q Maridonneau-Parini Isabelle I Butcher Philip D PD Castagnoli Paola Ricciardi PR Gicquel Brigitte B de Chastellier Chantal C Neyrolles Olivier O

Cell host & microbe 20110901 3

Mycobacterium tuberculosis thrives within macrophages by residing in phagosomes and preventing them from maturing and fusing with lysosomes. A parallel transcriptional survey of intracellular mycobacteria and their host macrophages revealed signatures of heavy metal poisoning. In particular, mycobacterial genes encoding heavy metal efflux P-type ATPases CtpC, CtpG, and CtpV, and host cell metallothioneins and zinc exporter ZnT1, were induced during infection. Consistent with this pattern of gene ...[more]

PMID: 21925112

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Project description:Obesity is considered as a major public health concern with strong economic and social burdens. Exposure to pollutants such as heavy metals can contribute to the development of obesity and its associated metabolic disorders, including type 2 diabetes and cardiovascular diseases. Adipose tissue is an endocrine and paracrine organ that plays a key role in the development of these diseases and is one of the main target of heavy metal accumulation. In this study, we determined by inductively coupled plasma mass spectrometry cadmium concentrations in human subcutaneous and visceral adipose tissues, ranging between 2.5 nM and 2.5 µM. We found a positive correlation between cadmium levels and age, sex and smoking status and a negative correlation between cadmium and body mass index. Based on cadmium adipose tissue concentrations found in humans, we investigated the effects of cadmium exposure, at concentrations between 1 nM and 10 µM, on adipose-derived human mesenchymal stem cells differentiated into mature adipocytes in vitro. Transcriptomic analysis highlighted that such exposure altered the expression of genes involved in trace element homeostasis and heavy metal detoxification, such as Solute Carrier Family transporters and metallothioneins. This effect correlated with zinc level alteration in cells and cellular media. Interestingly, dysregulation of zinc homeostasis and transporters has been particularly associated with the development of obesity and type 2 diabetes. Moreover, we found that cadmium exposure induces the pro-inflammatory state of the adipocytes by enhancing the expression of genes such as IL-6, IL-1B and CCL2, cytokines also induced in obesity. Finally, cadmium modulates various adipocyte functions such as the insulin response signaling pathway and lipid homeostasis. Collectively, our data identified some of the cellular mechanisms by which cadmium alters adipocyte functions, thus highlighting new facets of its potential contribution to the progression of metabolic disorders.

Dataset Information

Mycobacterial p(1)-type ATPases mediate resistance to zinc poisoning in human macrophages.

Publications

Mycobacterial p(1)-type ATPases mediate resistance to zinc poisoning in human macrophages.

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