Competition for zinc binding in the host-pathogen interaction

Cerasi, Mauro; Ammendola, Serena; Battistoni, Andrea

doi:10.3389/fcimb.2013.00108

Cited by 103 publications

(85 citation statements)

References 98 publications

(110 reference statements)

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“…For example, zinc is an essential cofactor for enzymatic reactions, DNA synthesis, and gene expression (2). One study has shown that over 3% of Escherichia coli proteins contain zinc (3).…”

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confidence: 99%

Dual Zinc Transporter Systems in Vibrio cholerae Promote Competitive Advantages over Gut Microbiome

et al. 2015

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Zinc is an essential trace metal required for numerous cellular processes in all forms of life. In order to maintain zinc homeostasis, bacteria have developed several transport systems to regulate its uptake. In this study, we investigated zinc transport systems in the enteric pathogen Vibrio cholerae, the causative agent of cholera. Bioinformatic analysis predicts that two gene clusters, VC2081 to VC2083 (annotated as zinc utilization genes znuABC) and VC2551 to VC2555 (annotated as zinc-regulated genes zrgABCDE), are regulated by the putative zinc uptake regulator Zur. Using promoter reporter and biochemical assays, we confirmed that Zur represses znuABC and zrgABCDE promoters in a Zn 2؉ -dependent manner. Under Zn 2؉ -limiting conditions, we found that mutations in either the znuABC or zrgABCDE gene cluster affect bacterial growth, with znuABC mutants displaying a more severe growth defect, suggesting that both ZnuABC and ZrgABCDE are involved in Zn 2؉ uptake and that ZnuABC plays the predominant role. Furthermore, we reveal that ZnuABC and ZrgABCDE are important for V. cholerae colonization in both infant and adult mouse models, particularly in the presence of other intestinal microbiota. Collectively, our studies indicate that these two zinc transporter systems play vital roles in maintaining zinc homeostasis during V. cholerae growth and pathogenesis. Metal ions are required for many crucial biological processes and are necessary for the survival of living organisms, including bacteria (1). For example, zinc is an essential cofactor for enzymatic reactions, DNA synthesis, and gene expression (2). One study has shown that over 3% of Escherichia coli proteins contain zinc (3). Bacteria have therefore evolved sophisticated systems to control their intracellular zinc concentrations in response to zinc fluctuations in the environment. One system utilized by nearly all bacteria is ZnuABC, a high-affinity zinc uptake system belonging to the ATP binding cassette (ABC) transporter family (4). Three proteins constitute this system: ZnuA, a periplasmic Zn 2ϩ binding protein that captures and delivers zinc to ZnuB, which serves as an inner membrane channel, and ZnuC, an ATPase that provides the energy needed for zinc transport (4). On the other hand, zinc levels in bacteria need to be tightly regulated, as excess zinc has deleterious effects on cells, such as prevention of Mn 2ϩ intracellular accumulation (5) and inhibition of enzymes (6). Zinc transport genes are generally controlled by Zur, a member of the Fur protein family of metal-dependent transcriptional regulators (7). Under zinc-replete conditions, Zur binds free Zn 2ϩ . The Zur-Zn complex then binds to the promoter of znuABC, thus blocking the binding of RNA polymerase (8). Under zinc-deficient conditions, the zinc binding sites of Zur are unoccupied, leading to the destabilization of Zur and the inability to bind and repress znuABC transcription, thus allowing zinc acquisition. In some bacteria, in addition to repressing Zn 2ϩ uptake transporters, Zur can a...

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“…For example, zinc is an essential cofactor for enzymatic reactions, DNA synthesis, and gene expression (2). One study has shown that over 3% of Escherichia coli proteins contain zinc (3).…”

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confidence: 99%

Dual Zinc Transporter Systems in Vibrio cholerae Promote Competitive Advantages over Gut Microbiome

et al. 2015

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“…Over the course of infection, M. tuberculosis can exist in various environments and thus is exposed to a wide range of metals (39)(40)(41). In order to determine whether iron-and zinc-mediated regulation of EsxG and EsxH might influence virulence, we infected murine BMDMs with M. tuberculosis that was pregrown for 3 days in Sauton's medium with iron and zinc or without iron and zinc to test conditions that maximize the difference in EsxG-EsxH secretion.…”

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confidence: 99%

Role of Metal-Dependent Regulation of ESX-3 Secretion in Intracellular Survival of Mycobacterium tuberculosis

et al. 2016

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bMore people die every year from Mycobacterium tuberculosis infection than from infection by any other bacterial pathogen. Type VII secretion systems (T7SS) are used by both environmental and pathogenic mycobacteria to secrete proteins across their complex cell envelope. In the nonpathogen Mycobacterium smegmatis, the ESX-1 T7SS plays a role in conjugation, and the ESX-3 T7SS is involved in metal homeostasis. In M. tuberculosis, these secretion systems have taken on roles in virulence, and they also are targets of the host immune response. ESX-3 secretes a heterodimer composed of EsxG (TB9.8) and EsxH (TB10.4), which impairs phagosome maturation in macrophages and is essential for virulence in mice. Given the importance of EsxG and EsxH during infection, we examined their regulation. With M. tuberculosis, the secretion of EsxG and EsxH was regulated in response to iron and zinc, in accordance with the previously described transcriptional response of the esx-3 locus to these metals. While iron regulated the esx-3 expression in both M. tuberculosis and M. smegmatis, there is a significant difference in the dynamics of this regulation. In M. smegmatis, the esx-3 locus behaved like other iron-regulated genes such as mbtB. In M. tuberculosis, both iron and zinc modestly repressed esx-3 expression. Diminished secretion of EsxG and EsxH in response to these metals altered the interaction of M. tuberculosis with macrophages, leading to impaired intracellular M. tuberculosis survival. Our findings detail the regulatory differences of esx-3 in M. tuberculosis and M. smegmatis and demonstrate the importance of metal-dependent regulation of ESX-3 for virulence in M. tuberculosis. T he intracellular pathogen Mycobacterium tuberculosis survives within phagocytic immune cells such as macrophages and dendritic cells (1).M. tuberculosis evades degradation by the endolysosomal pathway, growing in an early endosome-like compartment or escaping into the cytosol (2, 3). Acidified lysosomes are just one obstacle for the bacilli to overcome as the host also regulates metals such as iron, zinc, copper, and manganese to create an uninhabitable microenvironment (4). These metals are essential but at the same time can be toxic, so both host and pathogen tightly regulate them. For example, macrophages can increase zinc levels in M. tuberculosis-containing phagosomes to induce toxicity (5). Calprotectin, on the other hand, is released at sites of infection to bind and withhold zinc and manganese from bacteria (6). Similarly, host iron is bound to glycoproteins such as transferrin and lactoferrin, and during infection the host further limits available iron by reducing plasma iron levels via ferroportins (7-9). In addition, lipocalin 2-mediated sequestration of iron has been shown to be an important antimycobacterial innate immune response (10). To compete for iron, M. tuberculosis produces siderophores, mycobactin and carboxymycobactin, which are highaffinity iron chelators (11). Since iron is a strong redox catalyst that can be toxic to cel...

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Section: Microbial Adaptation To Host Defenses: Metallo-transporters mentioning

confidence: 99%

“…Staats et al (2013) present the role of Zn in bacteria-host relationship and how this metal represents a very promising target for the development of novel antimicrobial strategies. Cerasi et al (2013) emphasize the role of Zn in the host-fungi relationships and the impact of Zn bioavailability on the expression of virulence genes.Lastly, metallo-regulation of bacterial gene expression is discussed in relation to virulence. Porcheron et al (2013) review the enterobacterial metallo-transporters and their regulation, discussing strain-specific differences.…”

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confidence: 99%

Metal economy in host-microbe interactions

2015

Frontiers Research Topics

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This Research Topic presents knowledge on transition metal metabolism in various infections from the dual perspective of offender and defender. HOST NUTRITIONAL IMMUNITY: DEPRIVING OR POISONINGTo date, the implication of divalent metals have been described in two different immune strategies that aim to fight microbial invaders. One consists in depriving microbes of essential divalent metals whereas the other aims at overloading invaders with toxic concentrations of metal. The contributions in this section present, in different situations, various aspects of this metal economy at the host-microbe interface.Two papers deal with metal homeostasis as hosts interact with bacteria. Diaz-Ochoa et al. (2014) review immunological mechanisms to sequester Fe, Mn, and Zn in the inflamed gut and strategies of commensals and pathogens to evade mucosal defenses and obtain such nutrients. Lisher and Giedroc (2013) detail chemical and structural mechanisms to capture Mn, an antioxidant used by pathogens to adapt to human hosts, and the impact of Fe and Zn on Mn bioavailability during infections.The most coveted metal, iron is key to nutritional immunity and microbial virulence. Using amoeba as model phagocyte, Bozzaro et al. (2013) present the tug of war between a bacterial predator, sequestering intracellular iron to resist invasion, and pathogens which elude such defense mechanisms. On mammalian defense against intracellular bacteria and protozoan parasites, Silva-Gomes et al. (2013) outline divergent approaches: iron-withholding to prevent microbial replication or iron-based oxidative injury to kill invaders.Host may also target invaders with toxic doses of Cu and Zn, normally kept at low concentrations. Neyrolles et al. (2013) present an opinion article on bacterial Zn and Cu poisoning in the context of Mycobacterium tuberculosis infection. Chaturvedi and Henderson (2014) summarize the specific properties of copper and its toxic effect on bacteria cells. Arguello et al. (2013) review how bacteria integrate homeostatic mechanisms to avoid Cu toxicity by sensing and regulating ion chelation, chaperoning and membrane transport. MICROBIAL ADAPTATION TO HOST DEFENSES: METALLO-TRANSPORTERS OR EXPORTERSTo overcome host resistance to infection, numerous mechanisms have been selected through the course of microbial evolution, in particular transporters that can feed the bacteria even at low metal concentration or, on the contrary, metallo-exporters that can expel metals outside the cell to avoid toxic accumulation. The articles in this section describe the microbial transport arsenal, and its regulation, which play major roles to influence metal economy at the host-microbe interface.Bacterial and fungal strategies to acquire Fe is the subject of four contributions. Liu and Biville (2013) discuss erythrocyte parasitism by Bartonella, transmitted by arthropod vectors and relying principally on heme capture and oxidative stress defense to cause persistent infections. Runyen-Janecky (2013) highlights some of the recent findings on heme i...

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Competition for zinc binding in the host-pathogen interaction

Cited by 103 publications

References 98 publications

Dual Zinc Transporter Systems in Vibrio cholerae Promote Competitive Advantages over Gut Microbiome

Dual Zinc Transporter Systems in Vibrio cholerae Promote Competitive Advantages over Gut Microbiome

Role of Metal-Dependent Regulation of ESX-3 Secretion in Intracellular Survival of Mycobacterium tuberculosis

Metal economy in host-microbe interactions

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