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Query: UMLS:C0004623 (bacterial infection)
 15,226 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Use of erythropoietin (EPO) therapy and iron supplementation has improved the management of anemia in patients with end-stage renal disease (ESRD). As more patients receive supplemental iron, however, concerns are being raised about a potential link between iron and infection. There is biologic plausibility for this link, since iron is a growth factor for bacteria and certain host defense mechanisms are iron-sensitive. Animal models show that injection of iron leads to increased susceptibility to bacterial infection. In some studies, patients with high serum ferritin levels have reduced neutrophil function. However, these studies did not determine whether serum ferritin levels were elevated because of increased iron stores or because of infection. If infection is present, it might cause both the elevated serum ferritin levels and the neutrophil dysfunction. Several clinical studies have found an association between high serum ferritin levels and increased infectious risk. In studies that control for important covariates such as use of catheters and previous infections, the infectious risk associated with iron administration or elevated serum ferritin levels is reduced or eliminated. Collectively, these studies suggest that our current understanding of the relationship between iron and infection is incomplete and further studies are needed. There is no reason to alter current iron treatment strategies based on this literature.
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PMID:Review of issues relating to iron and infection. 1051 76

Nramp genes code for a widely distributed class of proteins involved in a variety of processes, ranging from the control of susceptibility to bacterial infection in mammalian cells and taste behaviour in Drosophila to manganese uptake in yeast. Some of the NRAMP proteins in mammals and in yeast are capable of transporting metal ions, including iron. In plants, iron transport was shown to require a reduction/Fe(II) transport system. In Arabidopsis thaliana this process involves the IRT1 and Fro2 genes. Here we report the sequence of five NRAMP proteins from A. thaliana. Sequence comparison suggests that there are two classes of NRAMP proteins in plants: A. thaliana (At) NRAMP1 and Oriza sativa (Os) NRAMP1 and 3 (two rice isologues) represent one class, and AtNRAMP2-5 and OsNRAMP2 the other. AtNramp1 and OsNramp1 are able to complement the fet3fet4 yeast mutant defective both in low- and high-affinity iron transports, whereas AtNramp2 and OsNramp2 fail to do so. In addition, AtNramp1 transcript, but not AtNramp2 transcript, accumulates in response to iron deficiency in roots but not in leaves. Finally, overexpression of AtNramp1 in transgenic A. thaliana plants leads to an increase in plant resistance to toxic iron concentration. Taken together, these results demonstrate that AtNramp1 participates in the control of iron homoeostasis in plants.
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PMID:Involvement of NRAMP1 from Arabidopsis thaliana in iron transport. 1076 79

Transferrins are iron-binding proteins that are involved in iron storage and resistance to bacterial disease. Previous work has shown that nonsynonymous-to-synonymous-site substitution ratios (d(n)/d(s) ratios) between transferrin genes from some salmonid species were significantly greater than 1.0, providing evidence for positive selection at the transferrin gene. The purpose of the current study was to put these earlier results in a broader evolutionary context by examining variation among 25 previously published transferrin sequences from fish, amphibians, and mammals. The results of the study show that evidence for positive selection at transferrin is limited to salmonids-d(n)/d(s) ratios estimated for nonsalmonid lineages were generally less than 1.0. Within the salmonids, approximately 13% of the transferrin codon sites are estimated to be subject to positive selection, with an estimated d(n)/d(s) ratio of approximately 7. The three- dimensional locations of some of the selected sites were inferred by comparing these sites to homologous sites in the bovine lactoferrin crystallographic structure. The selected sites generally fall on the outside of the molecule, within and near areas that are bound by transferrin-binding proteins from human pathogenic bacteria. The physical locations of sites estimated to be subject to positive selection support previous speculation that competition for iron from pathogenic bacteria could be the source of positive selection.
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PMID:Molecular evolution of transferrin: evidence for positive selection in salmonids. 1126 16

Iron status affects both microbial growth and immune function. Mammalian iron homeostasis is maintained primarily by regulating the absorption of the micronutrient in the proximal small intestine. The iron concentration of the enterocyte can fluctuate widely in response to both dietary and whole body iron status, as well as in response to infections. The possibility that an enterocyte with an elevated iron concentration is more susceptible to invasion by enteric pathogens is not known. Therefore, we examined the impact of enterocyte iron status on the invasion and survival of an enteric pathogen, as well as on the levels of several cytokine and chemokine mRNAs by the host cell. The enterocyte-like Caco-2 human intestinal cell line and Salmonella enteritidis served as the models to examine the effect of iron on the host-parasite interaction. Iron status of Caco-2 cells was altered by incubation in serum-free medium supplemented with varying levels of iron. Elevated iron status of Caco-2 cells increased the efficiency of the invasion and the number of bacteria surviving in the intracellular environment. Caco-2 cells constitutively expressed transforming growth factor-beta1, interleukin-8, monocyte chemotactic protein-1, tumor necrosis factor-alpha and interleukin-1beta, and infection with S. enteritidis increased the relative quantities of all cytokine/chemokine mRNAs except interleukin-1beta. Elevated iron status of Caco-2 cells decreased the levels of cytokine/chemokine mRNAs by 25-45% in uninfected cells. In contrast, bacterial infection was associated with a 21-95% increase in cytokine/chemokine mRNAs levels in Caco-2 cells with higher iron concentration compared with infected cells with lower iron concentration. These data support the hypothesis that elevated enterocyte iron status increases susceptibility to infection and exacerbates the mucosal inflammatory response initiated by microbial invasion by increasing cytokine/chemokine expression.
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PMID:Elevated iron status increases bacterial invasion and survival and alters cytokine/chemokine mRNA expression in Caco-2 human intestinal cells. 1134 99

Unmethylated CpG dinucleotide motifs in bacterial DNA, as well as oligodeoxynucleotides (ODN) containing these motifs, are potent stimuli for many host immunological responses. These CpG motifs may enhance host responses to bacterial infection and are being examined as immune activators for therapeutic applications in cancer, allergy/asthma, and infectious diseases. However, little attention has been given to processes that down-modulate this response. The iron-binding protein lactoferrin is present at mucosal surfaces and at sites of infection. Since lactoferrin is known to bind DNA, we tested the hypothesis that lactoferrin will bind CpG-containing ODN and modulate their biological activity. Physiological concentrations of lactoferrin (regardless of iron content) rapidly bound CpG ODN. The related iron-binding protein transferrin lacked this capacity. ODN binding by lactoferrin did not require the presence of CpG motifs and was calcium independent. The process was inhibited by high salt, and the highly cationic N-terminal sequence of lactoferrin (lactoferricin B) was equivalent to lactoferrin in its ODN-binding ability, suggesting that ODN binding by lactoferrin occurs via charge-charge interaction. Heparin and bacterial LPS, known to bind to the lactoferricin component of lactoferrin, also inhibited ODN binding. Lactoferrin and lactoferricin B, but not transferrin, inhibited CpG ODN stimulation of CD86 expression in the human Ramos B cell line and decreased cellular uptake of ODN, a process required for CpG bioactivity. Lactoferrin binding of CpG-containing ODN may serve to modulate and terminate host response to these potent immunostimulatory molecules at mucosal surfaces and sites of bacterial infection.
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PMID:Lactoferrin binds CpG-containing oligonucleotides and inhibits their immunostimulatory effects on human B cells. 1150 40

Some studies have suggested that intravenous iron therapy may be associated with an increased risk of infection. We analyzed the incidence of bacterial infection in 111 hemodialysis patients. Group 1 (n = 39, transferrin saturation <20%) received 10 doses of 100 mg of intravenous iron saccharate, 3 doses per week (28 treatment days); Group 2 (n = 13, transferrin saturation <20%) received 20 doses, 3 doses per week (70 treatment days); and Group 3 (n = 59, transferrin saturation 20-50%) received 10 doses, 1 dose per week (70 treatment days). The follow-up was 150 days for all groups, and all infectious episodes were recorded. Pulmonary infection was the most frequent event observed in all of the groups. In an incidence-density analysis, Group 2, which received a total of 20 doses, presented a significantly higher incidence of infection than Group 3, which received only 10 doses over the same period (0.13 versus 0.06 infections per patient per month, p = 0.04). No difference was observed between Groups 1 and 2 suggesting that the risk of infection during iron therapy is dose dependent rather than time length dependent.
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PMID:Risk of bacterial infection in patients under intravenous iron therapy: dose versus length of treatment. 1190 38

Lactoferrin (Lf) is an iron-binding protein of external secretions and neutrophil secondary granules with antimicrobial and immunomodulatory activities. To further define these properties of Lf, we have investigated the response to Staphylococcus aureus infection in transgenic mice carrying a functional human Lf gene. The transgenic mice cleared bacteria significantly better than congenic littermates, associated with a trend to reduced incidence of arthritis, septicemia, and mortality. We identified two pathways by which S. aureus clearance was enhanced. First, human Lf directly inhibited the growth of S. aureus LS-1 in vitro. Second, S. aureus-infected transgenic mice exhibited enhanced Th1 immune polarization. Thus, spleen cells from infected transgenic mice produced higher levels of TNF-alpha and IFN-gamma and less IL-5 and IL-10 upon stimulation ex vivo with the exotoxin toxic shock syndrome toxin-1 compared with congenic controls. To confirm that these effects of Lf transgene expression could occur in the absence of live bacterial infection, we also showed that Lf-transgenic DBA/1 mice exhibited enhanced severity of collagen-induced arthritis, an established model of Th1-induced articular inflammation. Higher levels of stainable iron in the spleens of transgenic mice correlated with human Lf distribution, but all other parameters of iron metabolism did not differ between transgenic mice and wild-type littermates. These results demonstrate that human Lf can mediate both antimicrobial and immunomodulatory activities with downstream effects on the outcome of immune pathology in infectious and inflammatory disease.
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PMID:Enhanced Th1 response to Staphylococcus aureus infection in human lactoferrin-transgenic mice. 1193 51

Antimicrobial factors form one arm of the innate immune system, which protects mucosal surfaces from bacterial infection. These factors can rapidly kill bacteria deposited on mucosal surfaces and prevent acute invasive infections. In many chronic infections, however, bacteria live in biofilms, which are distinct, matrix-encased communities specialized for surface persistence. The transition from a free-living, independent existence to a biofilm lifestyle can be devastating, because biofilms notoriously resist killing by host defence mechanisms and antibiotics. We hypothesized that the innate immune system possesses specific activity to protect against biofilm infections. Here we show that lactoferrin, a ubiquitous and abundant constituent of human external secretions, blocks biofilm development by the opportunistic pathogen Pseudomonas aeruginosa. This occurs at lactoferrin concentrations below those that kill or prevent growth. By chelating iron, lactoferrin stimulates twitching, a specialized form of surface motility, causing the bacteria to wander across the surface instead of forming cell clusters and biofilms. These findings reveal a specific anti-biofilm defence mechanism acting at a critical juncture in biofilm development, the time bacteria stop roaming as individuals and aggregate into durable communities.
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PMID:A component of innate immunity prevents bacterial biofilm development. 1203 68

Hemoglobin is an endotoxin (lipopolysaccharide; LPS)-binding protein that synergistically increases the release of proinflammatory cytokines from the innate immune system in response to LPS. It has been suggested that this activity of hemoglobin facilitates the recognition of Gram-negative bacteria in a wound, thereby maximizing immune efficiency. This synergy may be important to the pathogenesis of a broad spectrum of clinical conditions because elevated hemoglobin levels frequently are observed in patients after the transfusion of red cells, trauma, cardiopulmonary bypass surgery, hemolysis, in addition to other disorders. To determine the molecular basis of the specific hemoglobin-LPS synergy, in this article we tested the effects of globin itself on macrophage responses to LPS. Paradoxically, these studies revealed that globin suppressed tumor necrosis factor (TNF) synthesis in LPS-stimulated murine and human macrophage cultures. LPS comigrated with globin on non-denaturing electrophoretic gels, giving direct evidence for binding. Globin specifically inhibited LPS activity in the standard Limulus assay but did not inhibit interleukin-1beta-mediated TNF synthesis. Iron supplementation of macrophage cultures significantly increased interleukin-1beta-induced TNF release. Intraperitoneal administration of globin protected mice against both LPS-induced lethality and experimentally induced bacterial infection. Thus, the heme-iron moiety of hemoglobin, and not the binding of LPS to globin, enhanced macrophage responses to LPS.
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PMID:Globin attenuates the innate immune response to endotoxin. 1206 85

Bacterial diseases are serious complications of beta-thalassemia syndromes but the mechanisms underlying the increased susceptibility to these infections are not fully understood. Factors which are likely to be involved are anemia, splenectomy, iron-overload and alterations in innate/adaptive immune responses. There is substantial evidence that a defect in innate effector functions of phagocytes (neutrophils, monocytes/macrophages) plays an important role in the weakened resistance to pathogenic bacteria and is at least in part due to iron overload. There is substantial evidence of an iron-related defect in bacterial phagocytosis by neutrophils. Moreover, reduced chemotaxis by these phagocytes has been repeatedly demonstrated. Similarly, an impairment of monocyte bacterial phagocytosis and generation of anti-bacterial compounds have recently been delineated but any relation to iron overload needs to be established. Additional mechanisms of defective innate immune responses such as altered expression of pathogen recognising receptors and function seem possible and have to be explored. Further insight into innate phagocyte effector functions in beta-thalassemia is essential for understanding the increased susceptibility to bacterial infections and their management.
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PMID:Impaired phagocyte antibacterial effector functions in beta-thalassemia: a likely factor in the increased susceptibility to bacterial infections. 1262 25


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