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      Mycobacterial P 1-Type ATPases Mediate Resistance to Zinc Poisoning in Human Macrophages

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          Summary

          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.

          Highlights

          ► Zinc accumulates in the M. tuberculosis ( Mtb) phagosome in macrophages (Mϕ) ► Mtb P 1-type ATPases, including CtpC, are induced upon exposure to zinc inside Mϕ ► CtpC enables Mtb resistance to zinc poisoning and intracellular survival in Mϕ ► P 1-type zinc efflux ATPase ZntA null E. coli is highly susceptible to Mϕ killing

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          Most cited references40

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          Nutritional immunity beyond iron: a role for manganese and zinc.

          Vertebrates sequester iron from invading pathogens, and conversely, pathogens express a variety of factors to steal iron from the host. Recent work has demonstrated that in addition to iron, vertebrates sequester zinc and manganese both intracellularly and extracellularly to protect against infection. Intracellularly, vertebrates utilize the ZIP/ZnT families of transporters to manipulate zinc levels, as well as Nramp1 to manipulate manganese levels. Extracellularly, the S100 protein calprotectin sequesters manganese and potentially zinc to inhibit microbial growth. To circumvent these defenses, bacteria possess high affinity transporters to import specific nutrient metals. Limiting the availability of zinc and manganese as a mechanism to defend against infection expands the spectrum of nutritional immunity and further establishes metal sequestration as a key defense against microbial invaders. Copyright 2009 Elsevier Ltd. All rights reserved.
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            Mammalian zinc transporters: nutritional and physiologic regulation.

            Research advances defining how zinc is transported into and out of cells and organelles have increased exponentially within the past five years. Research has progressed through application of molecular techniques including genomic analysis, cell transfection, RNA interference, kinetic analysis of ion transport, and application of cell and animal models including knockout mice. The knowledge base has increased for most of 10 members of the ZnT family and 14 members of the Zrt-, Irt-like protein (ZIP) family. Relative to the handling of dietary zinc is the involvement of ZnT1, ZIP4, and ZIP5 in intestinal zinc transport, involvement of ZIP10 and ZnT1 in renal zinc reabsorption, and the roles of ZIP5, ZnT2, and ZnT1 in pancreatic release of endogenous zinc. These events are major factors in regulation of zinc homeostasis. Other salient findings are the involvement of ZnT2 in lactation, ZIP14 in the hypozincemia of inflammation, ZIP6, ZIP7, and ZIP10 in metastatic breast cancer, and ZnT8 in insulin processing and as an autoantigen in diabetes.
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              A role for the ATP7A copper-transporting ATPase in macrophage bactericidal activity.

              Copper is an essential micronutrient that is necessary for healthy immune function. This requirement is underscored by an increased susceptibility to bacterial infection in copper-deficient animals; however, a molecular understanding of its importance in immune defense is unknown. In this study, we investigated the effect of proinflammatory agents on copper homeostasis in RAW264.7 macrophages. Interferon-gamma was found to increase expression of the high affinity copper importer, CTR1, and stimulate copper uptake. This was accompanied by copper-stimulated trafficking of the ATP7A copper exporter from the Golgi to vesicles that partially overlapped with phagosomal compartments. Silencing of ATP7A expression attenuated bacterial killing, suggesting a role for ATP7A-dependent copper transport in the bactericidal activity of macrophages. Significantly, a copper-sensitive mutant of Escherichia coli lacking the CopA copper-transporting ATPase was hypersensitive to killing by RAW264.7 macrophages, and this phenotype was dependent on ATP7A expression. Collectively, these data suggest that copper-transporting ATPases, CopA and ATP7A, in both bacteria and macrophage are unique determinants of bacteria survival and identify an unexpected role for copper at the host-pathogen interface.
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                Author and article information

                Journal
                Cell Host Microbe
                Cell Host Microbe
                Cell Host & Microbe
                Cell Press
                1931-3128
                1934-6069
                15 September 2011
                15 September 2011
                : 10
                : 3
                : 248-259
                Affiliations
                [1 ]Centre National de la Recherche Scientifique, Institut de Pharmacologie et de Biologie Structurale, 31000 Toulouse, France
                [2 ]Université de Toulouse, Université Paul Sabatier, Institut de Pharmacologie et de Biologie Structurale, 31000 Toulouse, France
                [3 ]Aix Marseille Université, Faculté des Sciences de Luminy, Centre d'Immunologie de Marseille-Luminy, F-13288 Marseille, France
                [4 ]Inserm, U631, Centre d'Immunologie de Marseille-Luminy, F-13288 Marseille, France
                [5 ]CNRS, UMR6102, Centre d'Immunologie de Marseille-Luminy, F-13288 Marseille, France
                [6 ]Key Laboratory of Medical Molecular Virology, Fudan University, 200032 Shanghai, China
                [7 ]Institut Pasteur, Unité de Génétique Mycobactérienne, 75015 Paris, France
                [8 ]Brighton and Sussex Medical School, University of Sussex, Brighton BN1 9PX, UK
                [9 ]Department of Biotechnology and Bioscience, University of Milano-Bicocca, 20126 Milan, Italy
                [10 ]Centre for Infection, Division of Clinical Sciences, St. George's University of London, London SW17 0RE, UK
                [11 ]Singapore Immunology Network, 138648 Singapore, Singapore
                Author notes
                []Corresponding author olivier.neyrolles@ 123456ipbs.fr
                [12]

                These authors contributed equally to this work

                Article
                CHOM614
                10.1016/j.chom.2011.08.006
                3221041
                21925112
                e96e870d-2ceb-494c-8b0d-599f78ae0737
                © 2011 Elsevier Inc.

                This document may be redistributed and reused, subject to certain conditions.

                History
                : 18 April 2011
                : 22 July 2011
                : 23 August 2011
                Categories
                Article

                Microbiology & Virology
                Microbiology & Virology

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