Host Iron Status Research Articles

Intravenous ferric carboxymaltose and ferric derisomaltose alter the intestinal microbiome in female iron-deficient anemic mice.

Iron deficiency anemia (IDA) is a leading global health concern affecting approximately 30% of the population. Treatment for IDA consists of replenishment of iron stores, either by oral or intravenous (IV) supplementation. There is a complex bidirectional interplay between the gut microbiota, the host's iron status, and dietary iron availability. Dietary iron deficiency and supplementation can influence the gut microbiome; however, the effect of IV iron on the gut microbiome is unknown. We studied how commonly used IV iron preparations, ferric carboxymaltose (FCM) and ferric derisomaltose (FDI), affected the gut microbiome in female iron-deficient anemic mice. At the phylum level, vehicle-treated mice showed an expansion in Verrucomicrobia, mostly because of the increased abundance of Akkermansia muciniphila, along with contraction in Firmicutes, resulting in a lower Firmicutes/Bacteroidetes ratio (indicator of dysbiosis). Treatment with either FCM or FDI restored the microbiome such that Firmicutes and Bacteroidetes were the dominant phyla. Interestingly, the phyla Proteobacteria and several members of Bacteroidetes (e.g., Alistipes) were expanded in mice treated with FCM compared with those treated with FDI. In contrast, several Clostridia class members were expanded in mice treated with FDI compared with FCM (e.g., Dorea spp., Eubacterium). Our data demonstrate that IV iron increases gut microbiome diversity independently of the iron preparation used; however, differences exist between FCM and FDI treatments. In conclusion, replenishing iron stores with IV iron preparations in clinical conditions, such as inflammatory bowel disease or chronic kidney disease, could affect gut microbiome composition and consequently contribute to an altered disease outcome.

Iron Supplementation May Selectively Reprofile the Gut Microbiome in Iron-Deficient Bangladeshi Infants

Children in low- and middle-income countries (LMICs) have a high burden of anemia, much of which is attributable to iron deficiency. The World Health Organization (WHO) recommends universal iron interventions in preschool-aged children in countries where there is a high anemia prevalence. However, oral iron supplementation is associated with increased risks of infection, including diarrhea. In small studies in Africa, iron has been shown to reprofile the intestinal microbiota leading to a reduction in commensal bacteria and an increase in pathogenic taxa. Gut dysbiosis has been implicated in the pathogenesis of gastrointestinal, autoimmune and inflammatory disease. The BRISC (Benefits and Risks of Iron Interventions in Children) trial was a double-blind, placebo-controlled randomized controlled trial of oral iron supplementation in 3,300 infants in Bangladesh. Children were randomized to receive one of iron syrup, iron-containing multiple micronutrient powder (MNP) or placebo daily for three months. The primary outcome of the trial was child cognitive development. Key findings from the trial were an improvement in hematological indices with iron but no effect on the functional outcomes assessed (Pasricha et al New Engl J Med 2021). We aimed to study the effect of iron on microbiome composition, diversity and function in the BRISC participants. To achieve this aim we undertook a substudy in which we collected stool samples from 925 children at the three time points of the main BRISC trial: at recruitment, end of intervention and at nine-month follow up. DNA was extracted and analyzed by 16S ribosomal RNA gene (rRNA) amplicon sequencing (2,339 samples across three timepoints) and shotgun metagenomics (965 samples across three timepoints). Episodes of infection were documented as per the main BRISC trial and included diarrhea, respiratory symptoms, antibiotic use, and clinic/hospital visits. The V4 hypervariable region of the 16S rRNA gene was amplified and sequenced on the Illumina MiSeq instrument together with negative and positive controls. Demultiplexed forward and reverse FASTQ files for each sample were trimmed and processed using the DADA2 package in RStudio, and taxonomy was assigned using the SILVA 138 SSU Ref NR 99 reference database. Control samples and samples with fewer than 500 reads were removed (2,284 samples met this minimum read threshold). Taxonomic, alpha diversity and beta diversity measures were conducted using phyloseq and microbiomeSeq packages in RStudio. Differential abundance was calculated by two separate methods: i. limma voom (using trimmed mean of M values [TMM] normalization and log transformation) and ii. ANCOM-BC (using additive log-ratio transformation). Prior to implementing differential abundance methods a filter was applied such that operational taxonomic units (OTUs) found in under 10% of samples were pruned from the samples. As previously reported, there was no overall significant increase in diarrhea incidence among participants receiving iron compared to those given placebo among BRISC trial participants. Baseline iron deficiency, anemia and iron deficiency anemia prevalence among substudy participants was 33%, 42% and 26% respectively. 16S rRNA analysis demonstrated that recent antibiotic (12% of children at end of intervention) was associated with a significant reduction in alpha diversity. Accordingly, analysis was conducted to exclude recent antibiotic use from analysis by intervention arm. Using this analysis, there were no significant differences in alpha or beta diversity between trial intervention groups at the end of intervention (alpha diversity by Shannon index shown in Figure 1). Members of Ruminococcus torques group (limma voom and ANCOM-BC) and Leuconostoc (limma voom only) were more abundant in the intestinal microbiota of children randomized to iron, but no genus was found to be differentially abundant when controlling for multiple comparisons. However, several bacterial genera were differentially abundant in children who were iron deficient at baseline who received iron. Two forms of analyses (Limma voom and ANCOM-BC) showed agreement in finding a reduction in Sutterella and Lactococcus species in iron deficient children receiving iron. These results are shown in Table 1. These data indicate that reprofiling of the intestinal microbiota in response to iron supplementation is dependent on baseline host iron status. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Irradiation Causes Alterations of Polyamine, Purine, and Sulfur Metabolism in Red Blood Cells and Multiple Organs.

Investigating the metabolic effects of radiation is critical to understand the impact of radiotherapy, space travel, and exposure to environmental radiation. In patients undergoing hemopoietic stem cell transplantation, iron overload is a common risk factor for poor outcomes. However, no studies have interrogated the multiorgan effects of these treatments concurrently. Herein, we use a model that recapitulates transfusional iron overload, a condition often observed in chronically transfused patients. We applied an omics approach to investigate the impact of both the iron load and irradiation on the host metabolome. The results revealed dose-dependent effects of irradiation in the red blood cells, plasma, spleen, and liver energy and redox metabolism. Increases in polyamines and purine salvage metabolites were observed in organs with high oxygen consumption including the heart, kidneys, and brain. Irradiation also impacted the metabolism of the duodenum, colon, and stool, suggesting a potential effect on the microbiome. Iron infusion affected the response to radiation in the organs and blood, especially in erythrocyte polyamines and spleen antioxidant metabolism, and affected glucose, methionine, and glutathione systems and tryptophan metabolism in the liver, stool, and the brain. Together, the results suggest that radiation impacts metabolism on a multiorgan level with a significant interaction of the host iron status.

636. The Hepcidin-25 and Iron Kinetics During the Acute Phase of Systemic Infection

BackgroundHepcidin-25, a central regulator of iron metabolism, can decrease serum iron levels by inhibiting the iron transporter ferroportin. Production of hepcidin-25 in hepatocytes is tightly regulated by various stimulations and is promoted by inflammation via the IL-6 pathway. The role of hepcidin-25 in acute infections has not been fully understood; therefore, we investigated the hepcidin and iron kinetics during the acute phase of systemic infection.MethodsWe collected clinical samples of bloodstream infections at various stages and measured plasma hepcidin-25 levels using surface enhanced laser desorption/ionization time-of-flight mass spectrometry. In addition, plasma levels of IL-6, C-reactive protein, procalcitonin, presepsin, lipocalin-2 were measured.ResultsIn this study, 50 patients (median age: 72 years; 52% males) were included. In the acute phase of infection (first 3 days after onset of symptom), plasma hepcidin-25 levels were rapidly elevated, accompanied with a reduction in serum iron concentration. As the inflammation subsequently resolved and the patients’ general condition improved (≥10 days after symptom onset), serum hepcidin-25 levels were decreased and serum iron levels were restored. Therefore, hepcidin-25 and iron levels dynamically vary during the acute phase of infection, and the enhanced production of hepcidin-25 due to severe inflammation can precipitate a rapid decrease of serum iron levels. This series of reactions may be regarded as a host defense involving the inhibition of the nutrient acquirement of bacteria. In this setting, the iron requirement of bacteria is expected to be increased and the iron uptake of bacteria via iron transporter systems may be activated.ConclusionDuring the acute phase of infectious disease with severe inflammation, iron levels were immediately decreased due to enhanced production of hepcidin-25. Understanding of host iron status may be essential for effective use of siderophore cephalosporin, with a unique mechanism of action involving the use of bacterial iron uptake systems.Disclosures All authors: No reported disclosures.

Iron Status and Associated Malaria Risk Among African Children.

BackgroundIt remains unclear whether improving iron status increases malaria risk, and few studies have looked at the effect of host iron status on subsequent malaria infection. We therefore aimed to determine whether a child’s iron status influences their subsequent risk of malaria infection in sub-Saharan Africa.MethodsWe assayed iron and inflammatory biomarkers from community-based cohorts of 1309 Kenyan and 1374 Ugandan children aged 0–7 years and conducted prospective surveillance for episodes of malaria. Poisson regression models were fitted to determine the effect of iron status on the incidence rate ratio (IRR) of malaria using longitudinal data covering a period of 6 months. Models were adjusted for age, sex, parasitemia, inflammation, and study site.ResultsAt baseline, the prevalence of iron deficiency (ID) was 36.9% and 34.6% in Kenyan and Ugandan children, respectively. ID anemia (IDA) affected 23.6% of Kenyan and 17.6% of Ugandan children. Malaria risk was lower in children with ID (IRR, 0.7; 95% confidence interval [CI], 0.6, 0.8; P < .001) and IDA (IRR, 0.7; 95% CI, 0.6, 0.9; P = .006). Low transferrin saturation (<10%) was similarly associated with lower malaria risk (IRR, 0.8; 95% CI, 0.6, 0.9; P = .016). However, variation in hepcidin, soluble transferrin receptors (sTfR), and hemoglobin/anemia was not associated with altered malaria risk.ConclusionsID appears to protect against malaria infection in African children when defined using ferritin and transferrin saturation, but not when defined by hepcidin, sTfR, or hemoglobin. Additional research is required to determine causality.Clinical Trials RegistrationISRCTN32849447

Hepcidin deficiency and iron deficiency do not alter tuberculosis susceptibility in a murine M.tb infection model.

Tuberculosis (TB), caused by the macrophage-tropic pathogen Mycobacterium tuberculosis (M.tb) is a highly prevalent infectious disease. Since an immune correlate of protection or effective vaccine have yet to be found, continued research into host-pathogen interactions is important. Previous literature reports links between host iron status and disease outcome for many infections, including TB. For some extracellular bacteria, the iron regulatory hormone hepcidin is essential for protection against infection. Here, we investigated hepcidin (encoded by Hamp1) in the context of murine M.tb infection. Female C57BL/6 mice were infected with M.tb Erdman via aerosol. Hepatic expression of iron-responsive genes was measured by qRT-PCR and bacterial burden determined in organ homogenates. We found that hepatic Hamp1 mRNA levels decreased post-infection, and correlated with a marker of BMP/SMAD signalling pathways. Next, we tested the effect of Hamp1 deletion, and low iron diets, on M.tb infection. Hamp1 knockout mice did not have a significantly altered M.tb mycobacterial load in either the lungs or spleen. Up to 10 weeks of dietary iron restriction did not robustly affect disease outcome despite causing iron deficiency anaemia. Taken together, our data indicate that unlike with many other infections, hepcidin is decreased following M.tb infection, and show that hepcidin ablation does not influence M.tb growth in vivo. Furthermore, because even severe iron deficiency did not affect M.tb mycobacterial load, we suggest that the mechanisms M.tb uses to scavenge iron from the host must be extremely efficient, and may therefore represent potential targets for drugs and vaccines.

Host iron status and erythropoietic response to iron supplementation determines susceptibility to the RBC stage of falciparum malaria during pregnancy

Anaemia and malaria are both common in pregnant women in Sub-Saharan Africa. Previous evidence has shown that iron supplementation may increase malaria risk. In this observational cohort study, we evaluated P. falciparum pathogenesis in vitro in RBCs from pregnant women during their 2nd and 3rd trimesters. RBCs were collected and assayed before (n = 327), 14 days (n = 82), 49 days (n = 112) and 84 days (n = 115) after iron supplementation (60 mg iron as ferrous fumarate daily). P. falciparum erythrocytic stage growth in vitro is reduced in anaemic pregnant women at baseline, but increased during supplementation. The elevated growth rates parallel increases in circulating CD71-positive reticulocytes and other markers of young RBCs. We conclude that Plasmodium growth in vitro is associated with elevated erythropoiesis, an obligate step towards erythroid recovery in response to supplementation. Our findings support current World Health Organization recommendations that iron supplementation be given in combination with malaria prevention and treatment services in malaria endemic areas.

Host iron status and erythropoietic response to iron supplementation determines susceptibility to the RBC stage of falciparum malaria during pregnancy

Host iron status and erythropoietic response to iron supplementation determines susceptibility to the RBC stage of falciparum malaria during pregnancy

Low dietary iron intake restrains the intestinal inflammatory response and pathology of enteric infection by food-borne bacterial pathogens.

Orally administrated iron is suspected to increase susceptibility to enteric infections among children in infection endemic regions. Here we investigated the effect of dietary iron on the pathology and local immune responses in intestinal infection models. Mice were held on iron-deficient, normal iron, or high iron diets and after 2 weeks they were orally challenged with the pathogen Citrobacter rodentium. Microbiome analysis by pyrosequencing revealed profound iron- and infection-induced shifts in microbiota composition. Fecal levels of the innate defensive molecules and markers of inflammation lipocalin-2 and calprotectin were not influenced by dietary iron intervention alone, but were markedly lower in mice on the iron-deficient diet after infection. Next, mice on the iron-deficient diet tended to gain more weight and to have a lower grade of colon pathology. Furthermore, survival of the nematode Caenorhabditis elegans infected with Salmonella enterica serovar Typhimurium was prolonged after iron deprivation. Together, these data show that iron limitation restricts disease pathology upon bacterial infection. However, our data also showed decreased intestinal inflammatory responses of mice fed on high iron diets. Thus additionally, our study indicates that the effects of iron on processes at the intestinal host-pathogen interface may highly depend on host iron status, immune status, and gut microbiota composition.

Hepatic Hepcidin Protects against Polymicrobial Sepsis in Mice by Regulating Host Iron Status

Hepcidin is a master regulator of iron metabolism primarily produced by the liver. Markedly increased hepcidin levels have been observed in septic individuals, while decreased hepatic hepcidin expression has been demonstrated in liver diseases that tend to develop into sepsis. However, the role of liver hepcidin in sepsis remains unknown. Mouse hepatic hepcidin expression was silenced using adenovirus-mediated hepcidin-specific short hairpin RNA injected via the tail vein. Sepsis was induced by cecal ligation and puncture, and the outcome (n = 23 for hepcidin knockdown mice, n = 15 for controls) and pathogenic changes (n = 5) related to sepsis were evaluated. The impact of alteration of iron status on the survival rate of hepatic hepcidin knockdown mice (n = 18 to 19) was also investigated. Disruption of liver hepcidin expression increased serum iron level (537.8 ± 28.1 μg/dl [mean ± SD] vs. 235.9 ± 62.2 μg/dl; P < 0.05) and reduced iron content in the spleen macrophages at the steady state. Hepatic hepcidin knockdown mice not only showed increased 7-day mortality (73.9% vs. 46.7%; P < 0.05), but also had exacerbated organ damage and oxidative stress, as well as compromised host inflammatory responses and bacterial clearance at 24 h after polymicrobial sepsis. Treating the hepatic hepcidin knockdown mice with low-iron diet plus iron chelation decreased systemic iron content (serum level: 324.0 ± 67.4 μg/dl vs. 517.4 ± 13.4 μg/dl; P < 0.05) and rescued the mice from lethal sepsis (7-day survival: 36.8% vs. 83.3%; P < 0.01). Hepatic hepcidin plays an important role in sepsis through regulation of iron metabolism. The findings may have potential therapeutic implications for liver diseases in which hepcidin expression is decreased.

Influence of host iron status on Plasmodium falciparum infection.

Iron deficiency affects one quarter of the world's population and causes significant morbidity, including detrimental effects on immune function and cognitive development. Accordingly, the World Health Organization (WHO) recommends routine iron supplementation in children and adults in areas with a high prevalence of iron deficiency. However, a large body of clinical and epidemiological evidence has accumulated which clearly demonstrates that host iron deficiency is protective against falciparum malaria and that host iron supplementation may increase the risk of malaria. Although many effective antimalarial treatments and preventive measures are available, malaria remains a significant public health problem, in part because the mechanisms of malaria pathogenesis remain obscured by the complexity of the relationships that exist between parasite virulence factors, host susceptibility traits, and the immune responses that modulate disease. Here we review (i) the clinical and epidemiological data that describes the relationship between host iron status and malaria infection and (ii) the current understanding of the biological basis for these clinical and epidemiological observations.

Host iron status and iron supplementation mediate susceptibility to erythrocytic stage Plasmodium falciparum

Host iron status and iron supplementation mediate susceptibility to erythrocytic stage Plasmodium falciparum

Influence of iron status on risk of maternal or neonatal infection and on neonatal mortality with an emphasis on developing countries

Infection is a major cause of neonatal death in developing countries. This review investigates whether host iron status affects the risk of maternal and/or neonatal infection, potentially contributing to neonatal death, and summarizes the iron acquisition mechanisms described for pathogens causing stillbirth, preterm birth, and congenital infection. In vitro evidence shows that iron availability influences the severity and chronicity of infections that cause these negative outcomes of pregnancy. In vivo evidence is lacking, as relevant studies of maternal iron supplementation have not assessed the effect of iron status on the risk of maternal and/or neonatal infection. Reducing iron-deficiency anemia among women is beneficial and should improve the iron stores of babies; moreover, there is evidence that iron status in young children predicts the risk of malaria and, possibly, the risk of invasive bacterial diseases. Caution with maternal iron supplementation is indicated in iron-replete women who may be at high risk of exposure to infection, although distinguishing between iron-replete and iron-deficient women is currently difficult in developing countries, where a point-of-care test is needed. Further research is indicated to investigate the risk of infection relative to iron status in mothers and babies in order to avoid iron intervention strategies that may result in detrimental birth outcomes in some groups of women.

Host iron redistribution as a risk factor for incident tuberculosis in HIV infection: an 11-year retrospective cohort study.

BackgroundIdentifying people at higher risk of developing tuberculosis with human immunodeficiency virus (HIV) infection may improve clinical management of co-infections. Iron influences tuberculosis (TB) pathogenesis, but understanding the exact mechanisms of how and timing of when iron is involved remains challenging since biological samples are rarely available from the disease susceptibility period due to the difficulty in predicting in who and when, if ever, TB will develop. The objective of this research was to determine how host iron status measured at HIV diagnosis and genotypes related to host iron metabolism were associated with incident TB.MethodsArchived clinical data, plasma and DNA were analyzed from 1139 adult participants in a large HIV-1, HIV-2 and dual seroprevalent cohort based at the Medical Research Council Laboratories in The Gambia. Incident pulmonary and/or extrapulmonary TB diagnoses a minimum of 28 days after HIV diagnosis were independently re-confirmed using available evidence (n=152). Multiple host iron status biomarkers, Haptoglobin and solute carrier family 11, member 1 (SLC11A1) genotypes were modeled to characterize how indicators of host iron metabolism were associated with TB susceptibility.ResultsHemoglobin (incidence rate ratio, IRR=0.88, 95% CI=0.79-0.98), plasma transferrin (IRR=0.53, 0.33-0.84) and ferritin (IRR=1.26, 1.05-1.51) were significantly associated with TB after adjusting for TB susceptibility factors. While genotype associations were not statistically significant, SLC11A1 associations replicated similar directions as reported in HIV-seronegative meta-analyses.ConclusionsEvidence of host iron redistribution at HIV diagnosis was associated with incident TB, and genetic influences on iron homeostasis may be involved. Low hemoglobin was associated with subsequent diagnosis of TB, but when considered in combination with additional iron status biomarkers, the collective findings point to a mechanism whereby anemia and iron redistribution are likely due to viral and/or bacteria-driven processes and the host immune response to infection. As a result, iron supplementation may not be efficacious or safe under these circumstances. Clinical and nutritional management of HIV and Mycobacterium tuberculosis co-infected individuals, especially in regions where food insecurity and malnutrition co-exist, may be further improved when the iron-related TB risk factors identified here are better understood and managed to favor host rather than pathogen outcomes.

Zinc erythrocyte protoporphyrin as marker of malaria risk in pregnancy - a retrospective cross-sectional and longitudinal study.

BackgroundThe effects of iron interventions and host iron status on infection risk have been a recurrent clinical concern, although there has been little research on this interaction in pregnant women.MethodsCross-sectional and longitudinal analyses were undertaken to determine the association of whole blood zinc erythrocyte protoporphyrin (ZPP) with malaria parasitaemia in pregnant women attending antenatal and delivery care at Montfort and Chikwawa Hospitals, Shire Valley, Malawi. Prevalence of antenatal, delivery and placental malaria was assessed in relation to maternal ZPP levels. The main outcome measures were prevalence of peripheral and placental Plasmodium falciparum parasitaemia and odds ratios of malaria risk.ResultsA total of 4,103 women were evaluated at first antenatal visit, of whom at delivery 1327 were screened for peripheral and 1285 for placental parasitaemia. Risk of malaria at delivery (peripheral or placental) was higher in primigravidae (p < 0.001), and lower (peripheral) with use of intermittent preventive anti-malarials during pregnancy (p < 0.001). HIV infection was associated with increased malaria parasitaemia (p < 0.02, peripheral or placental). Parasitaemia prevalence was lower in women with normal ZPP levels compared to those with raised concentrations at both first antenatal visit (all gravidae, p = 0.048, and at delivery (all gravidae, p < 0.001; primigravidae, p = 0.056). Between first antenatal visit and delivery women who transitioned from raised (at first antenatal visit) to normal ZPP values (at delivery) had lower peripheral parasitaemia prevalence at delivery compared to those who maintained normal ZPP values at both these visits (all gravidae: 0.70, 95%CI 0.4-1.1; primigravidae: 0.3, 0.1-0.8). In regression analysis this difference was lost with inclusion of HIV infection in the model.ConclusionsRaised ZPP concentrations in pregnancy were positively associated with P. falciparum parasitaemia and were probably secondary to malaria inflammation, rather than indicating an increased malaria risk with iron deficiency. It was not possible from ZPP measurements alone to determine whether iron deficiency or repletion alters malaria susceptibility in pregnancy.

Implications of Malaria On Iron Deficiency Control Strategies

AbstractThe populations in greatest need of iron supplementation are also those at greatest risk of malaria: pregnant women and young children. Iron supplementation has been shown to increase malaria risk in these groups in numerous studies, although this effect is likely diminished by factors such as host immunity, host iron status, and effective malaria surveillance and control. Conversely, the risk of anemia is increased by malaria infections and preventive measures against malaria decrease anemia prevalence in susceptible populations without iron supplementation. Studies have shown that subjects with malaria experience diminished absorption of orally administered iron, so that as a consequence, iron supplementation may have generally reduced efficacy in malarious populations. A possible mechanistic link between malaria, poor absorption of iron, and anemia is provided by recent research on hepcidin, the human iron control hormone. Our improved understanding of iron metabolism may contribute to the control of malaria and the treatment of anemia. Malaria surveillance and control are necessary components of programs to control iron deficiency and may enhance the efficacy of iron supplementation.

Host Iron Withholding Demands Siderophore Utilization for Candida glabrata to Survive Macrophage Killing

The fungal pathogen Candida glabrata has risen from an innocuous commensal to a major human pathogen that causes life-threatening infections with an associated mortality rate of up to 50%. The dramatic rise in the number of immunocompromised individuals from HIV infection, tuberculosis, and as a result of immunosuppressive regimens in cancer treatment and transplant interventions have created a new and hitherto unchartered niche for the proliferation of C. glabrata. Iron acquisition is a known microbial virulence determinant and human diseases of iron overload have been found to correlate with increased bacterial burden. Given that more than 2 billion people worldwide suffer from iron deficiency and that iron overload is one of the most common single-gene inherited diseases, it is important to understand whether host iron status may influence C. glabrata infectious disease progression. Here we identify Sit1 as the sole siderophore-iron transporter in C. glabrata and demonstrate that siderophore-mediated iron acquisition is critical for enhancing C. glabrata survival to the microbicidal activities of macrophages. Within the Sit1 transporter, we identify a conserved extracellular SIderophore Transporter Domain (SITD) that is critical for siderophore-mediated ability of C. glabrata to resist macrophage killing. Using macrophage models of human iron overload disease, we demonstrate that C. glabrata senses altered iron levels within the phagosomal compartment. Moreover, Sit1 functions as a determinant for C. glabrata to survive macrophage killing in a manner that is dependent on macrophage iron status. These studies suggest that host iron status is a modifier of infectious disease that modulates the dependence on distinct mechanisms of microbial Fe acquisition.

Increased Iron Stores Correlate with Worse Disease Outcomes in a Mouse Model of Schistosomiasis Infection

Schistosomiasis is a significant parasitic infection creating disease burden throughout many of the world's developing nations. Iron deficiency anemia is also a significant health burden resulting from both nutritional deficit as well as parasitic infection in these countries. In this study we investigated the relationships between the disease outcomes of Schistosoma japonicum infection and iron homeostasis. We aimed to determine if host iron status has an effect on schistosome maturation or egg production, and to investigate the response of iron regulatory genes to chronic schistosomiasis infection. Wild-type C57BL/6 and Transferrin Receptor 2 null mice were infected with S. japonicum, and sacrificed at the onset of chronic disease. Transferrin Receptor 2 null mice are a model of type 3 hereditary hemochromatosis and develop significant iron overload providing increased iron stores at the onset of infection. The infectivity of schistosomes and egg production was assessed along with the subsequent development of granulomas and fibrosis. The response of the iron regulatory gene Hepcidin to infection and the changes in iron status were assessed by real-time PCR and Western blotting. Our results show that Hepcidin levels responded to the changing iron status of the animals, but were not significantly influenced by the inflammatory response. We also show that with increased iron availability at the time of infection there was greater development of fibrosis around granulomas. In conclusion, our studies indicate that chronic inflammation may not be the primary cause of the anemia seen in schistosomiasis, and suggest that increased availability of iron, such as through iron supplementation, may actually lead to increased disease severity.

Mortality in HIV infection is independently predicted by host iron status and SLC11A1 and HP genotypes, with new evidence of a gene-nutrient interaction

Background:Iron-related genes and iron status may independently contribute to variable HIV outcomes. The nature of the biologically plausible gene-nutrient interaction remains unknown. Objectives:The objectives were to investigate whether iron-related genotypes and clinically abnormal iron status independently predict mortality in HIV and whether a gene-nutrient interaction exists. Design:Baseline plasma, DNA, and clinical data were obtained from 1362 HIV-seropositive Gambian adults followed for 11.5 y to ascertain all-cause mortality. Iron status was estimated on the basis of plasma iron, soluble transferrin receptor (sTfR), ferritin, transferrin, transferrin index, and log(sTfR/ferritin). One haptoglobin (HP) and 5SLC11A1 (NRAMP1) polymorphisms were genotyped. Results:SLC11A1-SLC3andCAAA polymorphisms were the best independent genetic predictors of mortality [adjusted mortality rate ratio (95% CI)]:SLC3:G/C = 0.59 (95% CI: 0.45, 0.85),CAAA:del/ins = 1.51 (95% CI: 1.10, 2.07). In an adjusted model that included all polymorphisms,SLC1:199/199,SLC1:other/other,SLC6a:A/A, andCAAA:del/ins were associated with significantly greater mortality, whereas Hp 2–1 andSLC3:G/C were protective. In unadjusted analyses, all biomarker concentrations were significantly associated with mortality. In an extension of previous findings, both low and elevated iron states were associated with mortality, but the nature of the risk was variable, with linear, inversely linear, and U-shaped associations depending on the biomarker. Mortality was significantly lower in HIV-2 than in HIV-1 infection in the presence of abnormal (low or elevated) iron status. A gene-iron interaction was detected (likelihood-ratio testP = 0.018); however, subject numbers restricted category-specific interpretation. Conclusions:Iron-related genes, iron status, and their interaction predict mortality in HIV. These findings illustrate the complexity and uncertainty surrounding best practice for managing abnormal iron status and anemia during HIV infection and in regions with a high risk of infection.

Alterations in Helicobacter pylori outer membrane and outer membrane vesicle-associated lipopolysaccharides under iron-limiting growth conditions*

Outer membrane vesicles (OMVs) shed from the gastroduodenal pathogen Helicobacter pylori have measurable effects on epithelial cell responses. The aim of this study was to determine the effect of iron availability, and its basis, on the extent and nature of lipopolysaccharide (LPS) produced on H. pylori OMVs and their parental bacterial cells. Electrophoretic, immunoblotting and structural analyses revealed that LPSs of bacterial cells grown under iron-limited conditions were notably shorter than those of bacteria and OMVs obtained from iron-replete conditions. Structural analysis and serological probing showed that LPSs of iron-replete cells and OMVs expressed O-chains of Lewis(x) with a terminal Lewis(y) unit, whereas Lewis(y) expression was notably reduced on bacteria and OMVs from iron-limiting conditions. Unlike the O-chain, the core oligosaccharide and lipid A moieties of iron-replete and iron-limited bacteria and their OMVs were similar. Quantitatively, shed OMVs from iron-replete bacteria were found to be LPSenriched, whereas shed OMVs from iron-limited bacteria had a significantly reduced content of LPS. These differences were linked to bacterial ATP levels. Since iron availability affects the extent and nature of LPS expressed by H. pylori, host iron status may contribute to H. pylori pathogenesis.