• Iron In Melioidosis

    From ironjustice@21:1/5 to All on Fri Jan 12 18:24:52 2018
    Burkholderia pseudomallei modulates host iron homeostasis to facilitate iron availability and intracellular survival
    Imke H. E. Schmidt , Claudia Gildhorn, Martha A. L. Böning, Vera A. Kulow, Ivo Steinmetz , Antje Bast
    Published: January 12, 2018https://doi.org/10.1371/journal.pntd.0006096 Abstract
    The control over iron homeostasis is critical in host-pathogen-interaction. Iron plays not only multiple roles for bacterial growth and pathogenicity, but also for modulation of innate immune responses. Hepcidin is a key regulator of host iron metabolism
    triggering degradation of the iron exporter ferroportin. Although iron overload in humans is known to increase susceptibility to Burkholderia pseudomallei, it is unclear how the pathogen competes with the host for the metal during infection. This study
    aimed to investigate whether B. pseudomallei, the causative agent of melioidosis, modulates iron balance and how regulation of host cell iron content affects intracellular bacterial proliferation.

    Principal findings
    Upon infection of primary macrophages with B. pseudomallei, expression of ferroportin was downregulated resulting in higher iron availability within macrophages. Exogenous modification of iron export function by hepcidin or iron supplementation by ferric
    ammonium citrate led to increased intracellular iron pool stimulating B. pseudomallei growth, whereas the iron chelator deferoxamine reduced bacterial survival. Iron-loaded macrophages exhibited a lower expression of NADPH oxidase, iNOS, lipocalin 2,
    cytokines and activation of caspase-1. Infection of mice with the pathogen caused a diminished hepatic ferroportin expression, higher iron retention in the liver and lower iron levels in the serum (hypoferremia). In vivo administration of ferric ammonium
    citrate tended to promote the bacterial growth and inflammatory response, whereas limitation of iron availability significantly ameliorated bacterial clearance, attenuated serum cytokine levels and improved survival of infected mice.

    Our data indicate that modulation of the cellular iron balance is likely to be a strategy of B. pseudomallei to improve iron acquisition and to restrict antibacterial immune effector mechanisms and thereby to promote its intracellular growth. Moreover,
    we provide evidence that changes in host iron homeostasis can influence susceptibility to melioidosis, and suggest that iron chelating drugs might be an additional therapeutic option.

    Author summary
    Iron is an essential nutrient for many bacterial pathogens. A sufficient availability is linked to bacterial proliferation and pathogenicity. The host requires iron for cellular functions including innate immune defense mechanisms. Consequently, the
    control over iron homeostasis plays an important role in the course of infection. Burkholderia pseudomallei is an environmental bacterium ubiquitous in soil and water surfaces causing the disease melioidosis with a wide range of signs and symptoms
    including localized, pulmonary, or bloodstream infections. Conditions with increased iron stores, such as thalassemia, are considered to increase the risk to acquire melioidosis. Here we show that infection with the pathogen triggers downregulation of
    the major cellular iron exporter inducing intracellular iron retention and stimulation of bacterial proliferation. Experimental iron overload appears to predispose to infection with B. pseudomallei, whereas iron deficiency confers relative resistance to
    melioidosis. These effects of changed iron metabolism on the course of infection may be ascribed to modifications in the host immune response and direct effects on bacterial growth, respectively. Thus, the B. pseudomallei-driven alteration of cellular
    iron traffic leading to increased iron availability can promote its intracellular growth, and treatment with iron chelators together with antibiotics might be an appropriate strategy to control infection.


    Citation: Schmidt IHE, Gildhorn C, Böning MAL, Kulow VA, Steinmetz I, Bast A (2018) Burkholderia pseudomallei modulates host iron homeostasis to facilitate iron availability and intracellular survival. PLoS Negl Trop Dis 12(1): e0006096. https://doi.org/

    Editor: Pamela L. C. Small, University of Tennessee, UNITED STATES

    Received: March 28, 2017; Accepted: November 4, 2017; Published: January 12, 2018

    Copyright: © 2018 Schmidt et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and
    source are credited.

    Data Availability: All relevant data are within the paper and its Supporting Information files.

    Funding: IHES was supported by grants from the Graduate College 840 and Research Training Group 1870 (Deutsche Forschungsgemeinschaft, DFG). CG was supported by a grant from the European Social Fund (ESF). The funders had no role in study design, data
    collection and analysis, decision to publish, or preparation of the manuscript.

    Competing interests: The authors have declared that no competing interests exist.

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