lactoferrin and Hemochromatosis

Iron is essential to all microorganisms. To obtain iron from the very low concentrations present in their environment, microorganisms have developed sophisticated mechanisms such as the siderophore system. As a primitive defense mechanism, humans have developed mechanisms to withhold iron from microorganisms. Iron-binding proteins such as transferrin, ferritin, and lactoferrin have a central role in human ferrokinetics. These iron-binding proteins also participate in the process of decreasing iron availability for the microorganisms. They do so by decreasing iron reutilization. Anemia of inflammation (previously called anemia of chronic disease) is seen in the setting of infectious, inflammatory, and neoplastic diseases. It results, in part, from changes in the intracellular metabolism of iron. Alterations of iron physiology seen in many clinical circumstances make excess iron available to microorganisms, thus enhancing their pathogenicity. Understanding the molecular basis of iron withholding by the human host, both in the absence of and during infection, and that of iron acquisition by microorganisms may provide us with new and innovative antimicrobial agents and vaccines.

Topics: Anemia; Bacteria; Bacterial Infections; Blood Transfusion; Carrier Proteins; Conalbumin; Deferoxamine; Diabetic Ketoacidosis; Ferritins; Hemochromatosis; Hemolysis; Humans; Inflammation; Iron; Iron-Binding Proteins; Lactoferrin; Transferrin; Transferrin-Binding Proteins

Topics: Anemia, Hypochromic; Animals; Bacteria; Blood Proteins; Bone Marrow; Diet; Female; Fungi; Hemochromatosis; Hemosiderosis; Humans; Intestinal Absorption; Intestinal Mucosa; Iron; Lactoferrin; Liver; Male; Metabolism, Inborn Errors; Mice; Rabbits; Rats; Reticulocytes; Spleen; Transferrin

Iron (Fe) acquisition is essential for the growth of intracellular Mycobacterium tuberculosis (M.tb). How this occurs is poorly understood. Hereditary hemochromatosis is an inherited disease in which most cells become overloaded with Fe. However, hereditary hemochromatosis macrophages have lower than normal levels of intracellular Fe. This suggests M.tb growth should be slower in those cells if macrophage intracellular Fe is used by M.tb. Therefore, we compared trafficking and acquisition of transferrin (Tf)- and lactoferrin (Lf)-chelated Fe by M.tb within the phagosome of monocyte-derived macrophages (MDM) from healthy controls and subjects with hereditary hemochromatosis. M.tb in both sets of macrophages acquired more Fe from Lf than Tf. Fe acquisition by M.tb within hereditary hemochromatosis macrophages was decreased by 84% from Tf and 92% from Lf relative to that in healthy control macrophages. There was no difference in Fe acquired from Tf and Lf by the two macrophage phenotypes. Both acquired 3 times more Fe from Lf than Tf. M.tb infection and incubation with interferon gamma (IFN-gamma) reduced macrophage Fe acquisition by 20% and 50%, respectively. Both Tf and Lf colocalized with M.tb phagosomes to a similar extent, independent of macrophage phenotype. M.tb growth was 50% less in hereditary hemochromatosis macrophages. M.tb growing within macrophages from subjects with hereditary hemochromatosis acquire less Fe compared with healthy controls. This is associated with reduced growth of M.tb. These data support a role for macrophage intracellular Fe as a source for M.tb growth.

Topics: Case-Control Studies; Hemochromatosis; Humans; Interferon-gamma; Iron Chelating Agents; Lactoferrin; Macrophages; Microscopy, Confocal; Mycobacterium tuberculosis; Phagosomes; Protein Transport; Transferrin

Various properties of lactoferrin from neutrophils of normal individuals and patients with familial haemochromatosis were compared. No difference was found with respect to (1) the lactoferrin content of neutrophils, the molecular weight and isoelectric point of the protein, the dissociation of its complex with iron at acidic pH, its binding to isolated monocytes, and its uptake by the mouse reticulo-endothelial system. Macrophages from patients and controls were also found to be similar in their ability to bind and ingest lactoferrin and to process the iron provided by the protein. Therefore a defect in the interaction of lactoferrin with the reticulo-endothelial system, related either to the protein itself or to the cells, seems unlikely. A comparison of the lactoferrin- and the transferrin-mediated iron processing by monocytes is finally presented.

Topics: Adult; Aged; Animals; Cells, Cultured; Hemochromatosis; Humans; Iron; Lactoferrin; Lactoglobulins; Macrophages; Male; Mice; Mice, Inbred BALB C; Middle Aged; Monocytes

Topics: Animals; Female; Hemochromatosis; Humans; Intestinal Absorption; Intestinal Mucosa; Iron; Lactoferrin; Macrophages; Male; Transferrin