title: Hereditary hemochromatosis results in decreased iron acquisition and growth by Mycobacterium tuberculosis within human macrophages.
abstract: 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.
authors.affiliation: Department of Internal Medicine and Research Service, VA Medical Center-Cincinnati, and University of Cincinnati, OH 45267-0557, USA.
authors.forename: Oyebode
authors.initials: O
authors.lastname: Olakanmi
authors.forename: Larry S
authors.initials: LS
authors.lastname: Schlesinger
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Britigan
mesh_terms: D016022:Case-Control Studies; D006432:Hemochromatosis / Q000235:genetics* / Q000382:microbiology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000494:pharmacology*; D007781:Lactoferrin / Q000737:chemistry / Q000493:pharmacokinetics; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology*; D018613:Microscopy, Confocal; D009169:Mycobacterium tuberculosis / Q000254:growth & development*; D010588:Phagosomes / Q000378:metabolism / Q000382:microbiology; D021381:Protein Transport; D014168:Transferrin / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D007502:Iron Chelating Agents; D014168:Transferrin; D007371:Interferon-gamma; D007781:Lactoferrin