TB & Iron

J Exp Med 2002 Dec 2;196(11):1507-13

Correction of the Iron Overload Defect in beta-2-Microglobulin Knockout Mice by
Lactoferrin Abolishes Their Increased Susceptibility to Tuberculosis.

Schaible UE, Collins HL, Priem F, Kaufmann SH
Max-Planck-Institute for Infection Biology, Schumannstr. 21-22. Institut fur
Laboratoriumsmedizin und Pathochemie, Charite, Humboldt-University,
Schumannstr. 20-21, D-10117 Berlin, Germany.

[Medline record in process]


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.

PMID: 12461085, UI: 22349887