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1.
Iron Metabolism at the Interface between Host and Pathogen: From Nutritional Immunity to Antibacterial Development.
Marchetti, M, De Bei, O, Bettati, S, Campanini, B, Kovachka, S, Gianquinto, E, Spyrakis, F, Ronda, L
International journal of molecular sciences. 2020;(6)
Abstract
Nutritional immunity is a form of innate immunity widespread in both vertebrates and invertebrates. The term refers to a rich repertoire of mechanisms set up by the host to inhibit bacterial proliferation by sequestering trace minerals (mainly iron, but also zinc and manganese). This strategy, selected by evolution, represents an effective front-line defense against pathogens and has thus inspired the exploitation of iron restriction in the development of innovative antimicrobials or enhancers of antimicrobial therapy. This review focuses on the mechanisms of nutritional immunity, the strategies adopted by opportunistic human pathogen Staphylococcus aureus to circumvent it, and the impact of deletion mutants on the fitness, infectivity, and persistence inside the host. This information finally converges in an overview of the current development of inhibitors targeting the different stages of iron uptake, an as-yet unexploited target in the field of antistaphylococcal drug discovery.
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2.
Plants in the real world: An introduction to the JBC Reviews thematic series.
Jez, JM
The Journal of biological chemistry. 2020;(45):15376-15377
Abstract
The deep relationship between plants and humans predates civilization, and our reliance on plants as sources of food, feed, fiber, fuels, and pharmaceuticals continues to increase. Understanding how plants grow and overcome challenges to their survival is critical for using these organisms to meet current and future demands for food and other plant-derived materials. This thematic review series on "plants in the real world" presents a set of eight reviews that highlight advances in understanding plant health, including the role of thiamine (vitamin B1), iron, and the plant immune system; how plants use ethylene and ubiquitin systems to control growth and development; and how new gene-editing approaches, the redesign of plant cell walls, and deciphering herbicide resistance evolution can lead to the next generation of crops.
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3.
Global look at nutritional and functional iron deficiency in infancy.
Zimmermann, MB
Hematology. American Society of Hematology. Education Program. 2020;(1):471-477
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Abstract
Iron-deficiency anemia (IDA) affects many infants in low- and middle-income countries (LMICs) and may impair cognitive development and adaptive immunity. Effective interventions to improve iron intakes for infants in LMICs are urgently needed. However, absorption of oral iron fortificants and supplements is low, usually <10%, and most of the iron passes into the colon unabsorbed. In randomized controlled trials, provision of iron to infants in LMICs adversely affects their gut microbiome and increases pathogenic Escherichia coli, gut inflammation, and diarrhea. To minimize these detrimental effects of iron, it is important to provide the lowest effective dosage and maximize fractional iron absorption. Prebiotic galacto-oligosaccharides and apo-lactoferrin may prove useful in iron formulations in LMICs because they increase absorption of fortificant iron and at the same time may mitigate the adverse effects of unabsorbed iron on the infant gut. Providing well-absorbed iron early in infancy may improve immune function. Recent data from a Kenyan birth cohort suggest IDA at the time of infant vaccination impairs the response to diphtheria, pertussis, and pneumococcus vaccines. A randomized trial follow-up study reported that providing iron to Kenyan infants at the time of measles vaccination increased antimeasles immunoglobulin G (IgG), seroconversion, and IgG avidity. Because IDA is so common among infants in LMICs and because the vaccine-preventable disease burden is so high, even if IDA only modestly reduces immunogenicity of vaccines, its prevention could have major benefits.
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Iron Deficiency Anemia at Time of Vaccination Predicts Decreased Vaccine Response and Iron Supplementation at Time of Vaccination Increases Humoral Vaccine Response: A Birth Cohort Study and a Randomized Trial Follow-Up Study in Kenyan Infants.
Stoffel, NU, Uyoga, MA, Mutuku, FM, Frost, JN, Mwasi, E, Paganini, D, van der Klis, FRM, Malhotra, IJ, LaBeaud, AD, Ricci, C, et al
Frontiers in immunology. 2020;:1313
Abstract
Background: Iron deficiency may impair adaptive immunity and is common among African infants at time of vaccination. Whether iron deficiency impairs vaccine response and whether iron supplementation improves humoral vaccine response is uncertain. Methods: We performed two studies in southern coastal Kenya. In a birth cohort study, we followed infants to age 18 mo and assessed whether anemia or iron deficiency at time of vaccination predicted vaccine response to three-valent oral polio, diphtheria-tetanus-whole cell pertussis-Haemophilus influenzae type b vaccine, ten-valent pneumococcal-conjugate vaccine and measles vaccine. Primary outcomes were anti-vaccine-IgG and seroconversion at age 24 wk and 18 mo. In a randomized trial cohort follow-up, children received a micronutrient powder (MNP) with 5 mg iron daily or a MNP without iron for 4 mo starting at age 7.5 mo and received measles vaccine at 9 and 18 mo; primary outcomes were anti-measles IgG, seroconversion and avidity at age 11.5 mo and 4.5 y. Findings: In the birth cohort study, 573 infants were enrolled and 303 completed the study. Controlling for sex, birthweight, anthropometric indices and maternal antibodies, hemoglobin at time of vaccination was the strongest positive predictor of: (A) anti-diphtheria and anti-pertussis-IgG at 24 wk (p = 0.0071, p = 0.0339) and 18 mo (p = 0.0182, p = 0.0360); (B) anti-pertussis filamentous hemagglutinin-IgG at 24 wk (p = 0.0423); and (C) anti-pneumococcus 19 IgG at 18 mo (p = 0.0129). Anemia and serum transferrin receptor at time of vaccination were the strongest predictors of seroconversion against diphtheria (p = 0.0484, p = 0.0439) and pneumococcus 19 at 18 mo (p = 0.0199, p = 0.0327). In the randomized trial, 155 infants were recruited, 127 and 88 were assessed at age 11.5 mo and 4.5 y. Compared to infants that did not receive iron, those who received iron at time of vaccination had higher anti-measles-IgG (p = 0.0415), seroconversion (p = 0.0531) and IgG avidity (p = 0.0425) at 11.5 mo. Interpretation: In Kenyan infants, anemia and iron deficiency at time of vaccination predict decreased response to diphtheria, pertussis and pneumococcal vaccines. Primary response to measles vaccine may be increased by iron supplementation at time of vaccination. These findings argue that correction of iron deficiency during early infancy may improve vaccine response.
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How Severe Anaemia Might Influence the Risk of Invasive Bacterial Infections in African Children.
Abuga, KM, Muriuki, JM, Williams, TN, Atkinson, SH
International journal of molecular sciences. 2020;(18)
Abstract
Severe anaemia and invasive bacterial infections are common causes of childhood sickness and death in sub-Saharan Africa. Accumulating evidence suggests that severely anaemic African children may have a higher risk of invasive bacterial infections. However, the mechanisms underlying this association remain poorly described. Severe anaemia is characterized by increased haemolysis, erythropoietic drive, gut permeability, and disruption of immune regulatory systems. These pathways are associated with dysregulation of iron homeostasis, including the downregulation of the hepatic hormone hepcidin. Increased haemolysis and low hepcidin levels potentially increase plasma, tissue and intracellular iron levels. Pathogenic bacteria require iron and/or haem to proliferate and have evolved numerous strategies to acquire labile and protein-bound iron/haem. In this review, we discuss how severe anaemia may mediate the risk of invasive bacterial infections through dysregulation of hepcidin and/or iron homeostasis, and potential studies that could be conducted to test this hypothesis.
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Iron metabolism and lymphocyte characterisation during Covid-19 infection in ICU patients: an observational cohort study.
Bolondi, G, Russo, E, Gamberini, E, Circelli, A, Meca, MCC, Brogi, E, Viola, L, Bissoni, L, Poletti, V, Agnoletti, V
World journal of emergency surgery : WJES. 2020;(1):41
Abstract
BACKGROUND Iron metabolism and immune response to SARS-CoV-2 have not been described yet in intensive care patients, although they are likely involved in Covid-19 pathogenesis. METHODS We performed an observational study during the peak of pandemic in our intensive care unit, dosing D-dimer, C-reactive protein, troponin T, lactate dehydrogenase, ferritin, serum iron, transferrin, transferrin saturation, transferrin soluble receptor, lymphocyte count and NK, CD3, CD4, CD8 and B subgroups of 31 patients during the first 2 weeks of their ICU stay. Correlation with mortality and severity at the time of admission was tested with the Spearman coefficient and Mann-Whitney test. Trends over time were tested with the Kruskal-Wallis analysis. RESULTS Lymphopenia is severe and constant, with a nadir on day 2 of ICU stay (median 0.555 109/L; interquartile range (IQR) 0.450 109/L); all lymphocytic subgroups are dramatically reduced in critically ill patients, while CD4/CD8 ratio remains normal. Neither ferritin nor lymphocyte count follows significant trends in ICU patients. Transferrin saturation is extremely reduced at ICU admission (median 9%; IQR 7%), then significantly increases at days 3 to 6 (median 33%, IQR 26.5%, p value 0.026). The same trend is observed with serum iron levels (median 25.5 μg/L, IQR 69 μg/L at admission; median 73 μg/L, IQR 56 μg/L on days 3 to 6) without reaching statistical significance. Hyperferritinemia is constant during intensive care stay: however, its dosage might be helpful in individuating patients developing haemophagocytic lymphohistiocytosis. D-dimer is elevated and progressively increases from admission (median 1319 μg/L; IQR 1285 μg/L) to days 3 to 6 (median 6820 μg/L; IQR 6619 μg/L), despite not reaching significant results. We describe trends of all the abovementioned parameters during ICU stay. CONCLUSIONS The description of iron metabolism and lymphocyte count in Covid-19 patients admitted to the intensive care unit provided with this paper might allow a wider understanding of SARS-CoV-2 pathophysiology.
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Iron Status of Burkinabé Adolescent Girls Predicts Malaria Risk in the Following Rainy Season.
Brabin, L, Roberts, SA, Tinto, H, Gies, S, Diallo, S, Brabin, B
Nutrients. 2020;(5)
Abstract
High levels of storage iron may increase malaria susceptibility. This risk has not been investigated in semi-immune adolescents. We investigated whether baseline iron status of non-pregnant adolescent girls living in a high malaria transmission area in Burkina Faso affected malaria risk during the following rainy season. For this prospective study, we analysed data from an interim safety survey, conducted six months into a randomised iron supplementation trial. We used logistic regression to model the risk of P. falciparum infection prevalence by microscopy, the pre-specified interim safety outcome, in relation to iron status, nutritional indicators and menarche assessed at recruitment. The interim survey was attended by 1223 (82%) of 1486 eligible participants, 1084 (89%) of whom were <20 years at baseline and 242 (22%) were pre-menarcheal. At baseline, prevalence of low body iron stores was 10%. At follow-up, 38% of adolescents had predominantly asymptomatic malaria parasitaemias, with no difference by menarcheal status. Higher body iron stores at baseline predicted an increased malaria risk in the following rainy season (OR 1.18 (95% CI 1.05, 1.34, p = 0.007) after adjusting for bed net use, age, menarche, and body mass index. We conclude that routine iron supplementation should not be recommended without prior effective malaria control.
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8.
Immunity, Inflammation and Heart Failure: Their Role on Cardiac Function and Iron Status.
Perticone, M, Zito, R, Miceli, S, Pinto, A, Suraci, E, Greco, M, Gigliotti, S, Hribal, ML, Corrao, S, Sesti, G, et al
Frontiers in immunology. 2019;:2315
Abstract
Aims: Heart failure is a clinical syndrome characterized by subclinical systemic inflammation and immune system activation associated with iron deficiency. No data exist on the various activations of immune-mediated mechanisms of inflammation in heart failure patients with reduced/preserved ejection fraction. We aimed to (1) investigate possible differences in inflammatory parameters and oxidative stress, and (2) detect a different iron status between groups. Materials and Methods: We enrolled 50 consecutive Caucasian outpatients with heart failure. All patients underwent echocardiographic measurements, laboratory determinations, evaluation of iron status and Toll-like receptors, and NF-κB expression in peripheral blood mononuclear cells, as well as pro-inflammatory cytokines. All statistical calculations were made using SPSS for Mac version 21.0. Results: Patients with reduced ejection fraction showed significantly lower hemoglobin levels (12.3 ± 1.4 vs. 13.6 ± 1.4 g/dl), serum iron (61.4 ± 18.3 vs. 93.7 ± 33.7 mcg/dl), transferrin iron binding capacity (20.7 ± 8.4 vs. 31.1 ± 15.6 %), and e-GFR values (78.1 ± 36.1 vs. 118.1 ± 33.9 ml/min/1.73 m2) in comparison to patients with preserved ejection fraction, while unsaturated iron binding capacity (272.6 ± 74.9 vs. 221.7 ± 61.4 mcg/dl), hepcidin (4.61 ± 0.89 vs. 3.28 ± 0.69 ng/ml), and creatinine (1.34 ± 0.55 vs. 1.03 ± 0.25 mg/dl) were significantly higher in the same group. When considering inflammatory parameters, patients with reduced ejection fraction showed significantly higher expression of both Toll-like receptors-2 (1.90 ± 0.97 vs. 1.25 ± 0.76 MFI) and Toll-like receptors-4 (4.54 ± 1.32 vs. 3.38 ± 1.62 MFI), respectively, as well as a significantly higher activity of NF-κB (2.67 ± 0.60 vs. 1.07 ± 0.30). Furthermore, pro-inflammatory cytokines, interleukin-1, and interleukin-6, was significantly higher in patients with reduced ejection fraction, while the protective cytokine interleukin-10 was significantly lower in the same group. Correlational analyses demonstrated a significant and inverse relationship between left ventricular function and inflammatory parameters in patients with reduced ejection fraction, as well as a direct correlation between ferritin and inflammatory parameters. Conclusions: Our data demonstrate a different immune-mediated inflammatory burden in heart failure patients with reduced or preserved ejection fraction, as well as significant differences in iron status. These data contribute to further elucidate pathophysiologic mechanisms leading to cardiac dysfunction.
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Exercise-Induced Illness and Inflammation: Can Immunonutrition and Iron Help?
Castell, LM, Nieman, DC, Bermon, S, Peeling, P
International journal of sport nutrition and exercise metabolism. 2019;(2):181-188
Abstract
The main focus of this review is illness among elite athletes, how and why it occurs, and whether any measures can be taken to combat it or to prevent its onset. In particular, there is particular interest in exercise-induced immunodepression, which is a result of the immune system regarding exercise (e.g., prolonged, exhaustive exercise) as a challenge to its function. This promotes the inflammatory response. There is often a high incidence of illness in athletes after undertaking strenuous exercise, particularly among those competing in endurance events, not only mainly in terms of upper respiratory tract illness, but also involving gastrointestinal problems. It may well be that this high incidence is largely due to insufficient recovery time being allowed after, for example, a marathon, a triathlon, or other endurance events. Two examples of the incidence of upper respiratory tract illness in moderate versus endurance exercise are provided. In recent years, increasing numbers of research studies have investigated the origins, symptoms, and incidence of these bouts of illness and have attempted to alleviate the symptoms with supplements, sports foods, or immunonutrition. One aspect of the present review discusses iron deficiency, which has been primarily suggested to have an impact upon cell-mediated immunity. Immunonutrition is also discussed, as are new techniques for investigating links between metabolism and immune function.
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The Iron Tug-of-War between Bacterial Siderophores and Innate Immunity.
Golonka, R, Yeoh, BS, Vijay-Kumar, M
Journal of innate immunity. 2019;(3):249-262
Abstract
Iron is necessary for the survival of almost all aerobic organisms. In the mammalian host, iron is a required cofactor for the assembly of functional iron-sulfur (Fe-S) cluster proteins, heme-binding proteins and ribonucleotide reductases that regulate various functions, including heme synthesis, oxygen transport and DNA synthesis. However, the bioavailability of iron is low due to its insolubility under aerobic conditions. Moreover, the host coordinates a nutritional immune response to restrict the accessibility of iron against potential pathogens. To counter nutritional immunity, most commensal and pathogenic bacteria synthesize and secrete small iron chelators termed siderophores. Siderophores have potent affinity for iron, which allows them to seize the essential metal from the host iron-binding proteins. To safeguard against iron thievery, the host relies upon the innate immune protein, lipocalin 2 (Lcn2), which could sequester catecholate-type siderophores and thus impede bacterial growth. However, certain bacteria are capable of outmaneuvering the host by either producing "stealth" siderophores or by expressing competitive antagonists that bind Lcn2 in lieu of siderophores. In this review, we summarize the mechanisms underlying the complex iron tug-of-war between host and bacteria with an emphasis on how host innate immunity responds to siderophores.