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      PerR controls peroxide- and iron-responsive expression of oxidative stress defense genes in Helicobacter hepaticus

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          Abstract

          Chronic intestinal and hepatic colonization with the microaerophilic murine pathogen Helicobacter hepaticus can lead to a range of inflammatory diseases of the lower digestive tract. Colonization is associated with an active cellular immune response and production of oxygen radicals. During colonization, H. hepaticus needs to cope with and respond to oxidative stress, and here we report on the role of the H. hepaticus PerR-regulator (HH0942) in the expression of the peroxidase-encoding katA (HH0043) and ahpC (HH1564) genes. Transcription of katA and ahpC was induced by hydrogen peroxide, and by iron restriction of growth media. This iron- and hydrogen peroxide-responsive regulation of katA and ahpC was mediated at the transcriptional level, from promoters directly upstream of the genes. Inactivation of the perR gene resulted in constitutive, iron-independent high-level expression of the katA and ahpC transcripts and corresponding proteins. Finally, inactivation of the katA gene resulted in increased sensitivity of H. hepaticus to hydrogen peroxide and reduced aerotolerance. In H. hepaticus, iron metabolism and oxidative stress defense are intimately connected via the PerR regulatory protein. This regulatory pattern resembles that observed in the enteric pathogen Campylobacter jejuni, but contrasts with the pattern observed in the closely related human gastric pathogen Helicobacter pylori.

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          Most cited references 36

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          The struggle for iron - a metal at the host-pathogen interface.

          Iron holds a central position at the host-pathogen interface because mammalian and microbial cells have an essential demand for the metal, which is required for many metabolic processes. In addition, cross-regulatory interactions between iron homeostasis and immune function are evident. While iron affects the secretion of cytokines and the activity of transcription factors orchestrating immune responses, immune cell-derived mediators and acute-phase proteins control both systemic and cellular iron homeostasis. Additionally, immune-mediated strategies aim at restricting the supply of the essential nutrient iron to pathogens, which represents an effective strategy of host defence. On the other hand, microbes have evoked multiple strategies to utilize iron because a sufficient supply of this metal is linked to pathogen proliferation, virulence and persistence. The control over iron homeostasis is a central battlefield in host-pathogen interplay influencing the course of an infectious disease in favour of either the mammalian host or the pathogenic invader. This review summarizes our current knowledge on the combat of host cells and pathogens for the essential nutrient iron focusing on the immune-regulatory roles of iron on cell-mediated immunity necessary to control intracellular microbes, the host's mechanisms of iron restriction and on the counter-acting iron-acquisition strategies employed by intracellular microbes. © 2010 Blackwell Publishing Ltd.
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            The PerR transcription factor senses H2O2 by metal-catalysed histidine oxidation.

            The sensing of reactive oxygen species is essential for cellular responses to oxidative stress. The sensing of peroxides is typically mediated by redox-active cysteines in sensors such as the bacterial OxyR, OhrR, and Hsp33 proteins. Bacillus subtilis PerR is the prototype for a widespread family of metal-dependent peroxide sensors that regulate inducible peroxide-defence genes. Here we show that PerR senses peroxides by metal-catalysed oxidation. PerR contains two metal-binding sites: a structural Zn2+ site and a regulatory divalent metal ion site that preferentially binds Fe2+ or Mn2+ (ref. 5). Protein oxidation, catalysed by a bound ferrous ion, leads to the rapid and direct incorporation of one oxygen atom into histidine 37 (H37) or H91, two of the residues that coordinate the bound Fe2+. This mechanism accounts for the ability of PerR to sense low levels of hydrogen peroxide in vivo. The reduction of hydrogen peroxide by metal ions to generate highly reactive hydroxyl radicals underlies the genotoxic effects of peroxides, and has been shown to contribute to enzyme inactivation, but has not previously been shown to provide a regulatory mechanism for peroxide sensing.
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              Functional specialization within the Fur family of metalloregulators.

              The ferric uptake regulator (Fur) protein, as originally described in Escherichia coli, is an iron-sensing repressor that controls the expression of genes for siderophore biosynthesis and iron transport. Although Fur is commonly thought of as a metal-dependent repressor, Fur also activates the expression of many genes by either indirect or direct mechanisms. In the best studied model systems, Fur functions as a global regulator of iron homeostasis controlling both the induction of iron uptake functions (under iron limitation) and the expression of iron storage proteins and iron-utilizing enzymes (under iron sufficiency). We now appreciate that there is a tremendous diversity in metal selectivity and biological function within the Fur family which includes sensors of iron (Fur), zinc (Zur), manganese (Mur), and nickel (Nur). Despite numerous studies, the mechanism of metal ion sensing by Fur family proteins is still controversial. Other family members use metal catalyzed oxidation reactions to sense peroxide-stress (PerR) or the availability of heme (Irr).
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                Author and article information

                Journal
                1886
                122234
                European Journal of Microbiology and Immunology
                EuJMI
                Akadémiai Kiadó, co-published with Springer Science+Business Media B.V., Formerly Kluwer Academic Publishers B.V.
                2062-509X
                2062-8633
                1 September 2011
                : 1
                : 3
                : 215-222
                Affiliations
                [ 1 ] Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
                [ 2 ] Department of Internal Medicine, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
                [ 3 ] Department of Pediatrics, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
                [ 4 ] Laboratory of Microbiology, Wageningen University, Wageningen, The Netherlands
                [ 5 ] Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands
                [ 6 ] Laboratory of Pediatric Infectious Diseases, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
                [ 7 ] Institute of Food Research, Norwich, UK
                [ 8 ] Laboratory of Microbiology, Wageningen University, Dreijenplein 10, 6703 HB, Wageningen, The Netherlands
                Author notes
                [* ] +31-317-483742, +31-317-483829, clara.belzer@ 123456wur.nl
                Article
                5
                10.1556/EuJMI.1.2011.3.5
                3906617
                24516727
                Categories
                Original Articles

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