Correction of the iron overload defect in beta-2-microglobulin knockout mice by lactoferrin abolishes their increased susceptibility to tuberculosis.
As a resident of early endosomal phagosomes, Mycobacterium tuberculosis is connected to the iron uptake system of the host macrophage. beta-2-microglobulin (beta2m) knockout (KO) mice are more susceptible to tuberculosis than wild-type mice, which is generally taken as a proof for the role of major histocompatibility complex class I (MHC-I)-restricted CD8 T cells in protection against M. tuberculosis. However, beta2m associates with a number of MHC-I-like proteins, including HFE. This protein regulates transferrin receptor mediated iron uptake and mutations in its gene cause hereditary iron overload (hemochromatosis). Accordingly, beta2m-deficient mice suffer from tissue iron overload. Here, we show that modulating the extracellular iron pool in beta2m-KO mice by lactoferrin treatment significantly reduces the burden of M. tuberculosis to numbers comparable to those observed in MHC class I-KO mice. In parallel, the generation of nitric oxide impaired in beta2m-KO mice was rescued. Conversely, iron overload in the immunocompetent host exacerbated disease. Consistent with this, iron deprivation in infected resting macrophages was detrimental for intracellular mycobacteria. Our data establish: (a) defective iron metabolism explains the increased susceptibility of beta2m-KO mice over MHC-I-KO mice, and (b) iron overload represents an exacerbating cofactor for tuberculosis.
Schaible
Ulrich E
UE
Max-Planck-Institute for Infection Biology, Schumannstrasse 21-22, D-10117 Berlin, Germany. schaible@mpiib-berlin.mpg.de
Collins
Helen L
HL
Priem
Friedrich
F
Kaufmann
Stefan H E
SH
D000818:Animals; D004198:Disease Susceptibility; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000502:physiology; D007371:Interferon-gamma / Q000494:pharmacology; D019190:Iron Overload / Q000188:drug therapy* / Q000276:immunology; D007781:Lactoferrin / Q000627:therapeutic use*; D008264:Macrophages / Q000382:microbiology / Q000502:physiology; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000254:growth & development; D009569:Nitric Oxide / Q000096:biosynthesis; D011990:Receptors, Transferrin / Q000032:analysis; D014376:Tuberculosis / Q000276:immunology*; D001613:beta 2-Microglobulin / Q000502:physiology*
D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D011990:Receptors, Transferrin; D001613:beta 2-Microglobulin; D009569:Nitric Oxide; D007371:Interferon-gamma; D007781:Lactoferrin