Modulation of Iron Metabolism in Response to Infection: Twists for All Tastes

Gomes, Ana Cordeiro; Moreira, Ana C.; Mesquita, Gonçalo; Gomes, Maria Salomé

doi:10.3390/ph11030084

Cited by 37 publications

(38 citation statements)

References 149 publications

(176 reference statements)

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“…They recycle senescent red blood cells and nurse the formation of new ones [11][12][13] , thus participating in the major systemic iron fluxes occurring in higher vertebrates. Macrophages are also a first line of defence against pathogens, and they modulate iron availability as part of host protective mechanisms 12,[14][15][16] .…”

mentioning

confidence: 99%

H-Ferritin is essential for macrophages’ capacity to store or detoxify exogenously added iron

Mesquita

Silva

Gomes

et al. 2020

Sci Rep

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Macrophages are central cells both in the immune response and in iron homeostasis. Iron is both essential and potentially toxic. Therefore, iron acquisition, transport, storage, and release are tightly regulated, by several important proteins. Cytosolic ferritin is an iron storage protein composed of 24 subunits of either the L-or the H-type chains. H-ferritin differs from L-ferritin in the capacity to oxidize fe 2+ to fe 3+ . In this work, we investigated the role played by H-ferritin in the macrophages' ability to respond to immune stimuli and to deal with exogenously added iron. We used mice with a conditional deletion of the H-ferritin gene in the myeloid lineage to obtain bone marrow-derived macrophages. These macrophages had normal viability and gene expression under basal culture conditions. However, when treated with interferon-gamma and lipopolysaccharide they had a lower activation of Nitric Oxide Synthase 2. Furthermore, H-ferritin-deficient macrophages had a higher sensitivity to ironinduced toxicity. This sensitivity was associated with a lower intracellular iron accumulation but a higher production of reactive oxygen species. These data indicate that H-ferritin modulates macrophage response to immune stimuli and that it plays an essential role in protection against iron-induced oxidative stress and cell death.Since macrophages and iron metabolism are tightly connected and H-ferritin is crucial for iron storage inside the cells, we hypothesized that H-ferritin has a key role in macrophages viability, development, activation, and iron handling. To test this hypothesis, we used mice with a conditional deletion of the H-ferritin gene (Fth1) in the myeloid lineage, generated from the H-ferritin-loxP mice created by Lukas Kuhn and collaborators 17 . We obtained bone marrow-derived macrophages (BMDM) from these mice and found that although in vitro macrophage differentiation proceeded normally, H-ferritin-deficient BMDM had subtle alterations in their response to immune stimulation and a marked increase in susceptibility to oxidative stress and cell death induced by exogenously added iron. Scientific RepoRtS |(2020) 10:3061 | https://doi.

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confidence: 99%

H-Ferritin is essential for macrophages’ capacity to store or detoxify exogenously added iron

Mesquita

Silva

Gomes

et al. 2020

Sci Rep

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“…Another experimental study supporting this is by Ellison et al who proved that there is minimal transcriptional response after iron depletion in rickettsial culture exposed to iron chelator 24 hours after in vitro treatment [30]. Moreover, it is observed that Orientia tsutsugamushi infect human monocytic cells and increases expression of Interferon type-1 genes resulting in a M1 type of Monocyte-macrophage phenotype which sequesters iron within macrophages [31,32].…”

Section: Discussionmentioning

confidence: 84%

Hyperferritinemia in pediatric scrub typhus: A prospective observational study

Williams

Menon

Bhatia

et al. 2020

Preprint

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Background: Hyperferritinemia is increasingly associated with mortality in sepsis. Studies estimating the prevalence of hyperferritinemia in pediatric scrub typhus is limited.Methods: We conducted a prospective observational study from a tertiary care teaching hospital in North India where 72 children with confirmed scrub typhus;17(24%)-PCR positive, 68(94%)-IgM ELISA positive and 13(18%)-both PCR and ELISA positive. Serum ferritin was measured in 62 children to identify the prevalence of hyperferritinemia and determine its association with mortality. Results: Hyperferritinemia (>500µg/L) was seen in 72.6% [n=45] children; 26(42%) were mild (500-2000µg/L), 13(21%) were moderate (2000-10000µg/L) and 6(9.7%) were severe (>10000µg/L). A biphasic pattern of hyperferritinemia was seen with two peaks when plotted against duration since symptoms onset; one between 2 and 3 days (early onset hyperferritinemia) and second peak between 12 and14 days (late onset hyperferritinemia). Early onset hyperferritinemia had more survivors than late onset hyperferritinemia. Non survivors had significantly higher PRISM III, PELOD-2, hyperlactatemia, hypoalbuminemia, organ dysfunction, need for mechanical ventilation and need of RRT. Ferritin had poor sensitivity and specificity in predicting survival with AUC of 0.56. Organ dysfunction and risk scores as PRISM III, PELOD 2 and VIS at admission were better predictors with AUC(95%CI) of 0.72(0.56,0.89), 0.77(0.63,0.92) and 0.90(0.78,1.0) respectively.Conclusions: Hyperferritinemia is common in scrub typhus. A distinct biphasic response was observed with worse outcome in late onset hyperferritinemia. Organ dysfunction and risk scores were better predictors of mortality than ferritin.

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“…Given that pathogens fundamentally need iron to survive and proliferate, iron chelators have been suggested as a plausible strategy to treat infections, including mycobacteriosis [198]. We have previously shown that the addition of iron chelators to M. avium, in axenic cultures, in macrophage cultures, or in vivo, led to significant decreases in mycobacterial growth [199,200].…”

Section: Iron Chelatorsmentioning

confidence: 97%

“…Given the host's need for iron for their own metabolic needs, one important concern related to iron chelation therapies is the development of adequate cell-targeting strategies that may guarantee iron depletion in the pathogen without a concomitant deficiency in the host [198]. From the data available so far, chelators alone don't seem to exhibit a strong enough antimycobacterial activity, but they may have a role as an adjunct therapy, together with conventional antibiotics.…”

Section: Iron Chelatorsmentioning

confidence: 99%

Looking beyond Typical Treatments for Atypical Mycobacteria

2020

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The genus Mycobacterium comprises not only the deadliest of bacterial pathogens, Mycobacterium tuberculosis, but several other pathogenic species, including M. avium and M. abscessus. The incidence of infections caused by atypical or nontuberculous mycobacteria (NTM) has been steadily increasing, and is associated with a panoply of diseases, including pulmonary, soft-tissue, or disseminated infections. The treatment for NTM disease is particularly challenging, due to its long duration, to variability in bacterial susceptibility profiles, and to the lack of evidence-based guidelines. Treatment usually consists of a combination of at least three drugs taken from months to years, often leading to severe secondary effects and a high chance of relapse. Therefore, new treatment approaches are clearly needed. In this review, we identify the main limitations of current treatments and discuss different alternatives that have been put forward in recent years, with an emphasis on less conventional therapeutics, such as antimicrobial peptides, bacteriophages, iron chelators, or host-directed therapies. We also review new forms of the use of old drugs, including the repurposing of non-antibacterial molecules and the incorporation of antimicrobials into ionic liquids. We aim to stimulate advancements in testing these therapies in relevant models, in order to provide clinicians and patients with useful new tools with which to treat these devastating diseases.

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Modulation of Iron Metabolism in Response to Infection: Twists for All Tastes

Cited by 37 publications

References 149 publications

H-Ferritin is essential for macrophages’ capacity to store or detoxify exogenously added iron

H-Ferritin is essential for macrophages’ capacity to store or detoxify exogenously added iron

Hyperferritinemia in pediatric scrub typhus: A prospective observational study

Looking beyond Typical Treatments for Atypical Mycobacteria

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