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Role of Iron in Bacterial Pathogenesis

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Front. Cell. Infect. Microbiol. | doi: 10.3389/fcimb.2018.00344

Editorial: The Role of Iron in Bacterial Pathogenesis

  • 1Department of Basic Medical Sciences, College of Medicine, Qatar University, Qatar
  • 2Department of Bioengineering Sciences, Microbiology Unit, VIB-VUB Center for Structural Biology, Vrije Universiteit Brussel, Belgium

Iron is the 4th most abundant element on earth and it is needed by most organisms, including bacteria. It exists in two oxidation states, Fe2+ and Fe3+, reason why it is involved in many oxido-reduction reactions (Andrews et al., 2013). Ferric iron (Fe3+) is the dominant form in oxygenated environments, and has a very low solubility, which presents a problem for microorganisms with an aerobic lifestyle (Andrews et al., 2013). Conversely, in anaerobic environments or in micro-aerobic conditions at low pH, the soluble ferrous iron (Fe2+) is the most abundant form (Andrews et al., 2003). Bacterial pathogens are facing a problem because free iron is not available since it is bound to heme or by circulating proteins such as transferrin of lactoferrin (Finkelstein et al., 1983, Cornelissen & Sparling, 1994). Pathogens use different strategies to obtain iron from the host, via the production of extracellular Fe3+ chelating molecules termed siderophores (either their own or produced by other microorganisms), via the uptake of heme, and via the uptake of Fe2+ (Feo system) (Andrews et al., 2013). A single pathogen can adapt its iron uptake strategy in function of the type of infection (acute or chronic) and the availability or not of ferrous iron (Cornelis & Dingemans, 2013). In this issue, several authors present several facets around iron uptake in different bacterial pathogens. Yersinia pestis produces the yersiniabactin siderophore under aerobic conditions and the Feo Fe2+ uptake system under microaerobic conditions (Fetherston et al., 2012). The feo operon of Y. pestis is peculiar since it is repressed by Fe via the Fur repressor only under microaerobic, but not under aerobic conditions, unless the promotor region gets truncated. The other facet of the host-pathogen battle for iron is the host response to the bacterial pathogen. As shown, again for Y. pestis, a live vaccine induces an iron nutritional immunity via the production by the host of hemopexin and transferrin iron binding proteins.
Some pathogenic bacteria infect fish, such as Vibrio anguillarum and Photobacterium damsellae, both belonging to the Vibrionaceae. Citrate is probably the simplest siderophore and is produced by the citrate synthase and excreted by P. damsellae strains unable to produce the vibrioferrin siderophore, establishing a link between the cellular metabolism and iron uptake. In their review article, Li and Ma describe the ways by which different V. anguillarum pathogenic strains take up iron either via the production of siderophores (anguibactin, vanchrobactin), uptake of xenosiderophores enterobactin or ferrichrome, or uptake of heme or ferrous iron. Burkholderia represents a genus of β-proteobacteria with 90 species, including the B. cepacia complex (BCC), which cause infections in the lungs of patients with cystic fibrosis and B. pseudomallei, which causes meloidiosis. Butt and Thomas reviewed the different iron uptake strategies of these highly adaptable bacteria, including the production of siderophores (ornibactins, cepaciachelin, pyochelin, malleobactin), the uptake of heme and of ferrous iron. Francisella tulariensis is the causative agent of tularemia and is able to replicate in macrophages. F. tulariensis can take up the siderophore rhizoferrin, but relies on the Feo system for the uptake of ferrous iron. The uptake of rhizoferrin does however not need the TonB protein as in other bacteria while the uptake of Fe2+ involves an outer membrane protein termed FupA, which is also unusual. Inhibition of the uptake of iron by bacteria involves among other approaches the use of gallium-protoporphyrin IX as shown in the case of Pseudomonas aeruginosa. GaPPX is a heme analog that can be taken up via outer membrane heme receptors, inhibiting the growth of P. aeruginosa under conditions of iron limitation. Once in the cell, GaPPX was shown to target the aerobic respiration.
Bacterial pathogens sense iron-limiting conditions and respond accordingly by upregulating iron acquisition mechanisms and virulence genes (Zughaier et al., 2014). Mouméne et al report that the intracellular bacteria Ehrlichia ruminantium upregulates type 4 secretion system (T4SS) and virulence genes under iron depletion via the newly identified master regulatory Protein ExrR. Ferric uptake regulator (Fur) is a transcription factor that upregulates virulence factors in bacteria during iron depletion. Guo et al used unmarked gene deletion system to investigate the role of Fur in the virulence of Riemerella anatipestifer, an avian pathogen. Using RNA-seq analysis they determined fur regulated genes and identified putative fur binding sequences. Their study further demonstrated that deleting fur gene led to reduction of virulence in vivo. In response to infection the host limits the bioavailability of iron by up-regulating expression of hepcidin, the master iron-regulating hormone, which limits iron uptake from the gut and retains iron in macrophages. Nairz and colleagues investigated the role of dietary iron enrichment in host-pathogen interactions during Salmonella Typhimurium infection in mice with hereditary hemochromatosis (genetic Hfe-deficiency) compared to wild type. They observed that Salmonella infection induced hepcidin and hypofferemia in Hfe-independent manner. However, iron overload increased the number of bacteria in mice. Further, Salmonella infection in mice responded to iron-depleting conditions in the host and upregulated iron acquisition genes.
Malhotra et al report that Mycobacterium tuberculosis (M.tb) utilize its highly conserved glycolytic enzyme GAPDH to acquire iron from the host by binding lactoferrin with high affinity. M.tb sequester iron from lactoferrin bound to GAPDH on the surface of bacteria. Sharma and Bisht provide a perspective on the role of iron storing proteins in the emergence of antibiotic resistance. Based on their previous observation that iron storing proteins bacterioferritin (Rv1876) and ferritin (Rv3841) were overexpressed in aminoglycosides resistant isolates of M.tb, They used a computational approach (STRING analysis) to predict protein partners that interact with bacterioferrin and ferritin. Among the identified partners is the hypothetical transmembrane protein Rv1877, which is predicted to be involved in drug resistance, therefore Rv1877 may be a potential drug discovery target.

Keywords: iron depletion, Virulence Factors, Host defense against pathogenic bacteria, Iron-regulated genes, siderophore

Received: 22 Aug 2018; Accepted: 11 Sep 2018.

Edited by:

John S. Gunn, The Ohio State University, United States

Reviewed by:

Kevin Mason, The Ohio State University, United States  

Copyright: © 2018 Zughaier and Cornelis. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Susu M. Zughaier, College of Medicine, Qatar University, Department of Basic Medical Sciences, Doha, Qatar, szughaier@qu.edu.qa
Prof. Pierre Cornelis, VIB-VUB Center for Structural Biology, Vrije Universiteit Brussel, Department of Bioengineering Sciences, Microbiology Unit, Brussels, 1050, Brussels, Belgium, pcornel@vub.ac.be