Hepcidin and the Iron-Infection Axis Drakesmith, Hal; Prentice, Andrew M.
Science (American Association for the Advancement of Science),
11/2012, Letnik:
338, Številka:
6108
Journal Article
Recenzirano
Iron lies at the center of a battle for nutritional resource between higher organisms and their microbial pathogens. The iron status of the human host affects the pathogenicity of numerous infections ...including malaria, HIV-1, and tuberculosis. Hepcidin, an antimicrobial-like peptide hormone, has emerged as the master regulator of iron metabolism. Hepcidin controls the absorption of dietary iron and the distribution of iron among cell types in the body, and its synthesis is regulated by both iron and innate immunity. We describe how hepcidin integrates signals from diverse physiological inputs, forming a key molecular bridge between iron trafficking and response to infection.
Despite worldwide economic and scientific development, more than a quarter of the world's population remains anemic, and about half of this burden is a result of iron deficiency anemia (IDA). IDA is ...most prevalent among preschool children and women. Among women, iron supplementation improves physical and cognitive performance, work productivity, and well-being, and iron during pregnancy improves maternal, neonatal, infant, and even long-term child outcomes. Among children, iron may improve cognitive, psychomotor, and physical development, but the evidence for this is more limited. Strategies to control IDA include daily and intermittent iron supplementation, home fortification with micronutrient powders, fortification of staple foods and condiments, and activities to improve food security and dietary diversity. The safety of routine iron supplementation in settings where infectious diseases, particularly malaria, are endemic remains uncertain. The World Health Organization is revising global guidelines for controlling IDA. Implementation of anemia control programs in developing countries requires careful baseline epidemiologic evaluation, selection of appropriate interventions that suit the population, and ongoing monitoring to ensure safety and effectiveness. This review provides an overview and an approach for the implementation of public health interventions for controlling IDA in low- and middle-income countries, with an emphasis on current evidence-based recommendations.
The area under the curve for receiver operating characteristic curves for serum iron to identify severe hypoxemia was 0.95; the optimal Youden Index for distinguishing between severe and non-severe ...hypoxemia was a serum iron concentration of 2.9 μmol/L (sensitivity 0.9, specificity 1.0) (Fig. 1b). The association of serum iron with lymphocyte counts could reflect the requirement of the adaptive immune response for iron 5 and may contribute to possible T cell dysfunction reported in COVID-19 6. Low serum iron levels are associated with elevated plasma levels of coagulation factor VIII and pulmonary emboli/deep venous thromboses in replicate cohorts of patients with hereditary haemorrhagic telangiectasia.
Decreased hepcidin mobilizes iron, which facilitates erythropoiesis, but excess iron is pathogenic in β-thalassemia. Erythropoietin (EPO) enhances erythroferrone (ERFE) synthesis by erythroblasts, ...and ERFE suppresses hepatic hepcidin production through an unknown mechanism. The BMP/SMAD pathway in the liver is critical for hepcidin control, and we show that EPO suppressed hepcidin and other BMP target genes in vivo in a partially ERFE-dependent manner. Furthermore, recombinant ERFE suppressed the hepatic BMP/SMAD pathway independently of changes in serum and liver iron. In vitro, ERFE decreased SMAD1, SMAD5, and SMAD8 phosphorylation and inhibited expression of BMP target genes. ERFE specifically abrogated the induction of hepcidin by BMP5, BMP6, and BMP7 but had little or no effect on hepcidin induction by BMP2, BMP4, BMP9, or activin B. A neutralizing anti-ERFE antibody prevented ERFE from inhibiting hepcidin induction by BMP5, BMP6, and BMP7. Cell-free homogeneous time-resolved fluorescence assays showed that BMP5, BMP6, and BMP7 competed with anti-ERFE for binding to ERFE. We conclude that ERFE suppresses hepcidin by inhibiting hepatic BMP/SMAD signaling via preferentially impairing an evolutionarily closely related BMP subgroup of BMP5, BMP6, and BMP7. ERFE can act as a natural ligand trap generated by stimulated erythropoiesis to regulate the availability of iron.
•ERFE suppresses BMP/SMAD signaling in vitro and in vivo.•ERFE inhibits hepcidin induction by BMP5, BMP6, and BMP7.
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Natural killer (NK) cells are important early responders against viral infections. Changes in metabolism are crucial to fuel NK cell responses, and altered metabolism is linked to NK cell dysfunction ...in obesity and cancer. However, very little is known about the metabolic requirements of NK cells during acute retroviral infection and their importance for antiviral immunity. Here, using the Friend retrovirus mouse model, we show that following infection NK cells increase nutrient uptake, including amino acids and iron, and reprogram their metabolic machinery by increasing glycolysis and mitochondrial metabolism. Specific deletion of the amino acid transporter Slc7a5 has only discrete effects on NK cells, but iron deficiency profoundly impaires NK cell antiviral functions, leading to increased viral loads. Our study thus shows the requirement of nutrients and metabolism for the antiviral activity of NK cells, and has important implications for viral infections associated with altered iron levels such as HIV and SARS-CoV-2.
Iron plays a key role in human immune responses; however, the influence of iron deficiency on the coronavirus disease 2019 (COVID-19) vaccine effectiveness is unclear.
To assess the effectiveness of ...the BNT162b2 messenger RNA COVID-19 vaccine in preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19-related hospitalization and death in individuals with or without iron deficiency.
This large retrospective, longitudinal cohort study analyzed real-world data from the Maccabi Healthcare Services database (covering 25% of Israeli residents). Eligible adults (aged ≥16 years) received a first BNT162b2 vaccine dose between December 19, 2020, and February 28, 2021, followed by a second dose as per approved vaccine label. Individuals were excluded if they had SARS-CoV-2 infection before vaccination, had hemoglobinopathy, received a cancer diagnosis since January 2020, had been treated with immunosuppressants, or were pregnant at the time of vaccination. Vaccine effectiveness was assessed in terms of incidence rates of SARS-CoV-2 infection confirmed by real-time polymerase chain reaction assay, relative risks of COVID-19-related hospitalization, and mortality in individuals with iron deficiency (ferritin <30 ng/mL or transferrin saturation <20%). The two-dose protection period was Days 7 to 28 after the second vaccination.
Data from 184,171 individuals with (mean standard deviation; SD age 46.2 19.6 years; 81.2% female) versus 1,072,019 without (mean SD age 46.9 18.0 years; 46.2% female) known iron deficiency were analyzed. Vaccine effectiveness in the two-dose protection period was 91.9% (95% confidence interval CI 83.7-96.0%) and 92.1% (95% CI 84.2-96.1%) for those with versus without iron deficiency (P = 0.96). Of patients with versus without iron deficiency, hospitalizations occurred in 28 and 19 per 100,000 during the reference period (Days 1-7 after the first dose), and in 19 and 7 per 100,000 during the two-dose protection period, respectively. Mortality rates were comparable between study groups: 2.2 per 100,000 (4/181,012) in the population with iron deficiency and 1.8 per 100,000 (19/1,055,298) in those without known iron deficiency.
Results suggest that the BNT162b2 COVID-19 vaccine is >90% effective in preventing SARS-CoV-2 infection in the 3 weeks after the second vaccination, irrespective of iron-deficiency status. These findings support the use of the vaccine in populations with iron deficiency.
Many nutrients have powerful immunomodulatory actions with the potential to alter susceptibility to coronavirus disease 2019 (COVID-19) infection, progression to symptoms, likelihood of severe ...disease, and survival.
The aim was to review the latest evidence on how malnutrition across all its forms (under- and overnutrition and micronutrient status) may influence both susceptibility to, and progression of, COVID-19.
We synthesized information on 13 nutrition-related components and their potential interactions with COVID-19: overweight, obesity, and diabetes; protein-energy malnutrition; anemia; vitamins A, C, D, and E; PUFAs; iron; selenium; zinc; antioxidants; and nutritional support. For each section we provide: 1) a landscape review of pertinent material; 2) a systematic search of the literature in PubMed and EMBASE databases, including a wide range of preprint servers; and 3) a screen of 6 clinical trial registries. All original research was considered, without restriction to study design, and included if it covered: 1) severe acute respiratory syndrome coronavirus (CoV) 2 (SARS-CoV-2), Middle East respiratory syndrome CoV (MERS-CoV), or SARS-CoV viruses and 2) disease susceptibility or 3) disease progression, and 4) the nutritional component of interest. Searches took place between 16 May and 11 August 2020.
Across the 13 searches, 2732 articles from PubMed and EMBASE, 4164 articles from the preprint servers, and 433 trials were returned. In the final narrative synthesis, we include 22 published articles, 38 preprint articles, and 79 trials.
Currently there is limited evidence that high-dose supplements of micronutrients will either prevent severe disease or speed up recovery. However, results of clinical trials are eagerly awaited. Given the known impacts of all forms of malnutrition on the immune system, public health strategies to reduce micronutrient deficiencies and undernutrition remain of critical importance. Furthermore, there is strong evidence that prevention of obesity and type 2 diabetes will reduce the risk of serious COVID-19 outcomes. This review is registered at PROSPERO as CRD42020186194.
Hemoglobinopathies in the Fetal Position Pasricha, Sant-Rayn; Drakesmith, Hal
The New England journal of medicine,
2018-Oct-25, Letnik:
379, Številka:
17
Journal Article
The battle for iron in enteric infections Sousa Gerós, Ana; Simmons, Alison; Drakesmith, Hal ...
Immunology,
November 2020, Letnik:
161, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Summary
Iron is an essential element for almost all living organisms, but can be extremely toxic in high concentrations. All organisms must therefore employ homeostatic mechanisms to finely regulate ...iron uptake, usage and storage in the face of dynamic environmental conditions. The critical step in mammalian systemic iron homeostasis is the fine regulation of dietary iron absorption. However, as the gastrointestinal system is also home to >1014 bacteria, all of which engage in their own programmes of iron homeostasis, the gut represents an anatomical location where the inter‐kingdom fight for iron is never‐ending. Here, we explore the molecular mechanisms of, and interactions between, host and bacterial iron homeostasis in the gastrointestinal tract. We first detail how mammalian systemic and cellular iron homeostasis influences gastrointestinal iron availability. We then focus on two important human pathogens, Salmonella and Clostridia; despite their differences, they exemplify how a bacterial pathogen must navigate and exploit this web of iron homeostasis interactions to avoid host nutritional immunity and replicate successfully. We then reciprocally explore how iron availability interacts with the gastrointestinal microbiota, and the consequences of this on mammalian physiology and pathogen iron acquisition. Finally, we address how understanding the battle for iron in the gastrointestinal tract might inform clinical practice and inspire new treatments for important diseases.
Intestinal absorption of dietary iron is the key step regulating systemic iron homeostasis, but the human gut is also home to 100 trillion bacteria, which have their own, highly variable, iron requirements. Here, we explore molecular mechanisms underlying competition for this essential nutrient, focussing on salmonella, clostridia, and effects of iron acquisition on physiology during enteric infections. We discuss how understanding the battle for iron in the gut impacts on treatments for common intestinal inflammatory disorders.
Hepcidin controls the levels and distribution of iron, an element whose availability can influence the outcome of infections. We investigated hepcidin regulation by infection-associated cytokines, ...pathogen-derived molecules, and whole pathogens in vitro and in vivo. We found that IL-22, an effector cytokine implicated in responses to extracellular infections, caused IL-6–independent hepcidin up-regulation in human hepatoma cells, suggesting it might represent an additional inflammatory hepcidin agonist. Like IL-6, IL-22 caused phosphorylation of STAT3 and synergized with BMP6 potentiating hepcidin induction. In human leukocytes, IL-6 caused potent, transient hepcidin up-regulation that was augmented by TGF-β1. Pathogen-derived TLR agonists also stimulated hepcidin, most notably the TLR5 agonist flagellin in an IL-6–dependent manner. In contrast, leukocyte hepcidin induction by heat-killed Candida albicans hyphae was IL-6–independent, but partially TGF-β–dependent. In a murine acute systemic candidiasis model, C albicans strongly stimulated hepcidin, accompanied by a major reduction in transferrin saturation. Similarly, hepcidin was up-regulated with concomitant lowering of serum iron during acute murine Influenza A/PR/8/34 virus (H1N1) infection. This intracellular pathogen also stimulated hepcidin expression in leukocytes and hepatoma cells. Together, these results indicate that hepcidin induction represents a component of the innate immune response to acute infection, with the potential to affect disease pathogenesis.
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