Iron Supplementation Therapy, A Friend and Foe of Mycobacterial Infections?

Abstract

Iron is an essential element that is required for oxygen transfer, redox, and metabolic activities in mammals and bacteria. Mycobacteria, some of the most prevalent infectious agents in the world, require iron as growth factor. Mycobacterial-infected hosts set up a series of defense mechanisms, including systemic iron restriction and cellular iron distribution, whereas mycobacteria have developed sophisticated strategies to acquire iron from their hosts and to protect themselves from iron's harmful effects. Therefore, it is assumed that host iron and iron-binding proteins, and natural or synthetic chelators would be keys targets to inhibit mycobacterial proliferation and may have a therapeutic potential. Beyond this hypothesis, recent evidence indicates a host protective effect of iron against mycobacterial infections likely through promoting remodeled immune response. In this review, we discuss experimental procedures and clinical observations that highlight the role of the immune response against mycobacteria under various iron availability conditions. In addition, we discuss the clinical relevance of our knowledge regarding host susceptibility to mycobacteria in the context of iron availability and suggest future directions for research on the relationship between host iron and the immune response and the use of iron as a therapeutic agent.

Keywords: immunity; iron; mycobacteria.

Figure 1

Schematic representation of the cell envelope of Mycobacterium tuberculosis (adapted from [2]). The cell envelope of M. tuberculosis includes an inner cell membrane (CM), a network of peptidoglycan (PG) with covalently attached macromolecules: AG, PIM₂, PIM₆, LM, and Man-LAM; an outer membrane (OM) composed of mycolic acid (MA), attached to TDM, DAT, PAT, PDIM, and SL-1; and an outmost layer of polysaccharides and proteins. AG: arabinogalactan; DAT: diacyltrehalose; LM: lipomannan; Man-LAM: mannose-capped lipoarabinomannan; PAT: poliacyltrehalose; PDIM: phthiocerol dimycocerosate; PIM₂: phospho-myo-inositol-dimannoside; PIM₆: phospho-myo-inositol-hexamannoside; MmpL: mycobacterial membrane protein large; TDM: trehalose dimycolate; SL-1: sulphoglycolipid.

Figure 2

Series of reactive oxygen species generated in response to intracellular mycobacteria infection. Macrophages and neutrophils produce reactive oxygen species to kill intracellular microbes in a series of reaction which can be initiated by the conversion of NADPH to NADP ⁺ via the NADPH oxidase (NOX) and the production of superoxide O₂⁻ in presence of O₂. O₂⁻ can enter in the phagosome and later in the mycobacteria through porins or crosses the outer membrane that is partially permeabilized by antimicrobial peptides. O₂⁻ is a substrate for superoxide dismutase (SodCI, SodA) to produce H₂O₂ which can freely diffuse across membranes. The hydroxyl radical (OH^•) is produced from H₂O₂ and superoxide via Fenton reaction. Mycobacteria produce the catalase KatG to detoxify H₂O₂. The production of NO from arginine metabolism via nitric oxide synthase (NOS2) can generate nitric oxide which in presence of O₂⁻ produce ONOO⁻ and NO₂⁻, which present some toxic proprieties against mycobacteria.

Figure 3

Structure of exochelin siderophore of M. smegmatis with its iron chelation proprieties. The iron-chelating residues of exochelin with their interaction with iron molecule is shown in red circle (adapted from [29]).

Figure 4

Structure of mycobactin and carboxymycobactin siderophores of pathogenic mycobacteria. This figure represents mycobactin and carboxymycobactin from M. tuberculosis with the iron-chelating residues circled in red.

Figure 5

Heme-iron and siderophore-mediated iron acquisition of Mycobacterium tuberculosis in macrophage phagosome (adapted from [55]). M. tuberculosis has both heme and non-heme iron uptake pathways. M. tuberculosis secretes and express on its outer membrane PPE36/37 which can bind to heme and induce heme importation across the outer membrane. Then heme is linked to Rv0265c which facilitate heme transport to the cytosol using an unknown heme importer. In the cytosol, heme is degraded by the heme-degrading protein MhuD and iron is extracted from heme. It is also possible than heme can also be exported from cytosol through MmpL3/11 transporters and then linked to Rv0203 and later exported outside the bacteria. M. tuberculosis can also acquire iron through the siderophore-mediated iron acquisition system. M. tuberculosis desferricarboxymycobactin competes with host iron transferrin to acquire iron in phagosome. Iron is then bound to mycobactin which transports iron across the inner membrane through the IrtAB transporter complex. Once in the cytosol, iron is dissociated from mycobactin which is then exported from the cytosol through MmpS4/L4 and MmpS5/L5 complex.

Figure 6

Mycobacterial stress sensors (adapted from [75]) Mammalian host cell generates radicals and gases as a mechanism to counter mycobacterial infection. M. tuberculosis senses these potentially damaging stresses and responds by adjusting its energy metabolism, physiology and signaling and counters the damage by detoxification processes. M. tuberculosis possesses sensing mechanisms such as the Dos dormancy regulon and the WhiB3 redox sensor detecting environmental gases and alterations in its intracellular redox state. The Dos regulon senses O₂, NO, and CO through the DosS and DosT heme proteins which transduce the signal to DosR leading to the induction of 48-member Dos dormancy regulon. WhiB3 functions as a regulator of cellular metabolism, which responds to O₂ and NO through its Fe–S cluster and integrates it with intermediary metabolic pathways. WhiB3 is an intracellular redox regulator that dissipates reductive stress generated by utilization of host fatty acids through β-oxidation.

Figure 7

Suggested model of biphasic effect of iron supplementation during mycobacterial infection. A moderate concentration of iron supplementation can have a benefit effect for host during mycobacterial infection (shown in green). However, at high concentration of iron supplementation, iron can be beneficial for mycobacteria promoting growth and virulence (shown in red).