Iron metabolism and the innate immune response to infection

Johnson, Erin E.; Wessling‐Resnick, Marianne

doi:10.1016/j.micinf.2011.10.001

Cited by 221 publications

(169 citation statements)

References 111 publications

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“…Although Fe 2+ in phagolysosomes can produce hydroxyl radicals via Fenton reaction, thus potentially killing bacteria, depletion of the iron pool from the phagosome deprives pathogenic bacteria of metal ions that are critical for their survival. Invasive bacteria, such as Legionella pneumophila, Mycobacterium tuberculosis or Salmonella enterica serovar Typhimurium are known to absorb large amounts of iron, while at the same time they are resistant to oxygen radicals (Henard and Vazquez-Torres, 2011;Johnson and Wessling-Resnick, 2012;Kortman et al, 2012;Moalem et al, 2004;Robey and Cianciotto, 2002;Slauch, 2011). Recently, we also showed that L. pneumophila hinders recruitment of the V-H + -ATPase, but not Nramp1, in the Legionella-containing vacuole in a process apparently involving inhibition of phosphatidylinositol-3-phosphate formation.…”

Section: Introductionmentioning

confidence: 89%

The Nramp (Slc11) proteins regulate development, resistance to pathogenic bacteria and iron homeostasis in Dictyostelium discoideum

Peracino

Buracco

Bozzaro

2013

Journal of Cell Science

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SummaryThe Dictyostelium discoideum genome harbors two genes encoding members of the Nramp superfamily, which is conserved from bacteria (MntH proteins) to humans (Slc11 proteins). Nramps are proton-driven metal ion transporters with a preference for iron and manganese. Acquisition of these metal cations is vital for all cells, as they act as redox cofactors and regulate key cellular processes, such as DNA synthesis, electron transport, energy metabolism and oxidative stress. Dictyostelium Nramp1 (Slc11a1), like its mammalian ortholog, mediates resistance to infection by invasive bacteria. We have extended the analysis to the nramp2 gene, by generating single and double nramp1/nramp2 knockout mutants and cells expressing GFP fusion proteins. In contrast to Nramp1, which is recruited to phagosomes and macropinosomes, the Nramp2 protein is localized exclusively in the membrane of the contractile vacuole, a vesicular tubular network regulating cellular osmolarity. Both proteins colocalize with the V-H + -ATPase, which can provide the electrogenic force for vectorial transport. Like nramp1, nramp2 gene disruption affects resistance to Legionella pneumophila. Disrupting both genes additionally leads to defects in development, with strong delay in cell aggregation, formation of large streams and multi-tipped aggregates. Single and double mutants display differential sensitivity to cell growth under conditions of iron overload or depletion. The data favor the hypothesis that Nramp1 and Nramp2, under control of the V-H + -ATPase, synergistically regulate iron homeostasis, with the contractile vacuole possibly acting as a store for metal cations.

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Section: Introductionmentioning

confidence: 89%

The Nramp (Slc11) proteins regulate development, resistance to pathogenic bacteria and iron homeostasis in Dictyostelium discoideum

Peracino

Buracco

Bozzaro

2013

Journal of Cell Science

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“…Individuals with hemochromatosis are susceptible to infections (Vibrio, Yersinia, E. coli), but the overexpression of ferroportin reduces iron in macrophages such that resistance to obligate intracellular pathogens is observed (Mycobacteria, Salmonella, Legionella) (76). In vitro studies show that overexpression of ferroportin disrupts M. tuberculosis growth (77), diminishes growth of Salmonella (78), and reduces HIV replication (79).…”

Section: Roles Of Other Transportersmentioning

confidence: 99%

“…In vitro studies show that overexpression of ferroportin disrupts M. tuberculosis growth (77), diminishes growth of Salmonella (78), and reduces HIV replication (79). Conversely, studies of flatiron mice, which have ferroportin deficiency (70,76,80), demonstrate that loss of its export activity confers greater susceptibility to intracellular pathogens (81). Macrophages from these mice support greater growth of Chlamydophila psittaci, and this effect was lost upon iron chelation (81).…”

Section: Roles Of Other Transportersmentioning

confidence: 99%

Nramp1 and Other Transporters Involved in Metal Withholding during Infection

Wessling‐Resnick

2015

Journal of Biological Chemistry

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112

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During the course of infection, many natural defenses are set up along the boundaries of the host-pathogen interface. Key among these is the host response to withhold metals to restrict the growth of invading microbes. This simple act of nutritional warfare, starving the invader of an essential element, is an effective means of limiting infection. The physiology of metal withholding is often referred to as "nutritional immunity," and the mechanisms of metal transport that contribute to this host response are the focus of this review.The rationale for host metal withholding against invading pathogens seems intuitive; restriction of any nutrient required for pathogen survival should combat infection. But why metals? The answer to this question becomes crystal clear when one recognizes that iron is required for nearly all life forms, including pathogenic bacteria, with a few rare exceptions that rely on manganese instead (1-7). Iron is essential for ATP production and other metabolic pathways, but its concentration is limited to avoid production of ROS 2 catalyzed by excess levels of this redox-active metal (8). In some organisms, manganese can substitute for redox-active iron to protect against oxidative stress (9, 10). Moreover, most pathogens require manganese to produce their own superoxide dismutase activity to thwart oxidative killing mechanisms exerted by the host (11-13). Iron and manganese have similar ionic radii, have a divalent charge state under physiological conditions, have similar coordination chemistries, and have cellular concentrations in the micromolar range. Consequently, it comes as no surprise that these two metals also share membrane transporters, despite their different cellular functions and distributions. Restriction of iron and/or manganese provides a broad-spectrum metabolic "antidote" against all pathogenic infections, and the common transport pathways used by these metals present selective targets to limit their availability. Although many other immune responses contribute to the fight against infection, metal withholding represents a major force in host defense with combat controlled through transport.The concept of nutritional immunity through metal withholding is largely based on the observations that the iron content of the human diet profoundly affects infectious diseases such as malaria, brucellosis, and tuberculosis (14, 15). Iron overload states such as sickle cell anemia and ␤-thalassemia increase the risk of infection (16 -18). Hereditary hemochromatosis, an inherited disorder of iron metabolism, is also linked to susceptibility to some pathogens (17, 19 -22). Iron deficiency, on the other hand, is associated with decreased survival of individuals infected with HIV and other agents (23). Still, high iron is positively associated with viral load and mortality in HIV (24 -26), suggesting that an optimal balance of iron is necessary. In general terms, low iron status is protective, whereas elevated iron levels promote infection (27, 28). The complexity of host-pathogen interact...

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“…In mammals, T. brucei lives as a trypomastigote in the bloodstream and tissue fluids [Bitter et al, 1998;Subramanya, 2009;Taylor and Kelly, 2010;Johnson and Wessling-Resnick, 2012]. As an extracellular parasite, it depends on endocytosis to take up nutrients from the host blood [Subramanya, 2009].…”

Section: Use Of Host Transferrin By T Bruceimentioning

confidence: 99%