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

Abstract

As a resident of early endosomal phagosomes, Mycobacterium tuberculosis is connected to the iron uptake system of the host macrophage. β-2-microglobulin (β2m) 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, β2m 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, β2m-deficient mice suffer from tissue iron overload. Here, we show that modulating the extracellular iron pool in β2m–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 β2m–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 β2m-KO mice over MHC-I–KO mice, and (b) iron overload represents an exacerbating cofactor for tuberculosis.

Alternative activation deprives macrophages of a coordinated defense program to Mycobacterium tuberculosis

“…3A). Reduced TfR expression by IFN-c activation is in accordance with previous studies, and increased transcription has been reported as a consequence of IL-4 and IL-13 activation [46,47]. When alternatively activated macrophages were infected with M. tuberculosis, TfR surface expression was significantly elevated as compared to classically activated or resting macrophages, as assessed by fluorescence microscopy.…”

“…TfR mediates uptake of extracellular transferrin in its iron-loaded form, and the transferrin-TfR complex is subsequently directed to the early endosome, where iron is released upon acidification. Because competition for iron between host and pathogen is crucial for the outcome of tuberculosis [46], we determined the effects of IL-4 activation on TfR expression in macrophages subsequently infected with M. tuberculosis. Mean surface expression of TfR on alternatively activated macrophages was quantified by flow cytometry.…”

Nippostrongylus brasiliensis: Identification of intelectin-1 and -2 as Stat6-dependent genes expressed in lung and intestine during infection

“…Lactoferrin is involved in antibacterial responses by either agglutinating bacteria or binding of iron, which lowers the available iron critically required for bacterial growth (Otto, 1992;Teraguchi, 1996). Indeed, the growth advantage of M. tuberculosis in β2m-deficient mice is at least partially due to iron overload in these mice, as this can be relieved by lactoferrin treatment (Schaible, 2002). Given the two potential antimicrobial activities of intelectins against M. tuberculosis, including recognition of galactofuranose present in the cell wall of these organisms (Pan, 2001) and the ability to sequester iron-loaded lactoferrin (thereby lowering the local iron availability), we further investigated whether intelectin-transgenic mice were more resistant to M. tuberculosis infection and whether intelectins could have therapeutic potential against TB infection.…”

IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin

“…It is characterized by low serum iron levels (hypoferremia), low serum iron-binding capacity, and normal to elevated ferritin concentrations (17). This decreased availability of iron may be a host defense mechanism against invading microorganisms (15,18). The pathogenesis of AI has been attributed to hypoferremia due to impaired mobilization of iron stores from macrophages and decreased iron absorption (15,19), but iron-independent effects such as shortened red cell survival and direct suppression of erythropoiesis could also contribute.…”