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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 - J. Exp. Med. (2002)

Bottom Line: This protein regulates transferrin receptor mediated iron uptake and mutations in its gene cause hereditary iron overload (hemochromatosis).Conversely, iron overload in the immunocompetent host exacerbated disease.Consistent with this, iron deprivation in infected resting macrophages was detrimental for intracellular mycobacteria.

View Article: PubMed Central - PubMed

Affiliation: Max-Planck-Institute for Infection Biology, Schumannstrasse 21-22, D-10117 Berlin, Germany. schaible@mpiib-berlin.mpg.de

ABSTRACT
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.

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Lactoferrin decreased growth of M. tuberculosis in β2m KO but not in MHC class I KO mice. (A) Lactoferrin treatment reduced the growth of M. tuberculosis in β2m–KO but not B6 mice. Mice were infected with 159 bacteria/lung by aerosol and bacterial load was measured at 22 d after infection (untreated, closed symbols; lactoferrin treatment, open symbols). (B) Lactoferrin treatment decreased growth of M. tuberculosis in β2m–KO but less so in B6 or MHC class I KO mice. Mice were infected with 155 bacteria/lung by aerosol and bacterial load was measured at 27 d after infection (untreated, closed symbols; lactoferrin treatment, open symbols). Statistics: *P < 0.01, **P < 0.005 as determined by the non paired Mann-Whitney test (data from one representative experiment out of three). (C) Serum levels of NO measured as NO2 in mice at 27 d after infection by aerosol with five M. tuberculosis/lung (untreated, closed symbols; lactoferrin treated, open symbols).
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fig3: Lactoferrin decreased growth of M. tuberculosis in β2m KO but not in MHC class I KO mice. (A) Lactoferrin treatment reduced the growth of M. tuberculosis in β2m–KO but not B6 mice. Mice were infected with 159 bacteria/lung by aerosol and bacterial load was measured at 22 d after infection (untreated, closed symbols; lactoferrin treatment, open symbols). (B) Lactoferrin treatment decreased growth of M. tuberculosis in β2m–KO but less so in B6 or MHC class I KO mice. Mice were infected with 155 bacteria/lung by aerosol and bacterial load was measured at 27 d after infection (untreated, closed symbols; lactoferrin treatment, open symbols). Statistics: *P < 0.01, **P < 0.005 as determined by the non paired Mann-Whitney test (data from one representative experiment out of three). (C) Serum levels of NO measured as NO2 in mice at 27 d after infection by aerosol with five M. tuberculosis/lung (untreated, closed symbols; lactoferrin treated, open symbols).

Mentions: We reasoned that restriction of iron supply could prevent growth of M. tuberculosis in vivo, therefore extracellular Fe was depleted by the intranasal administration of lactoferrin to B6 and β2m–KO mice prior, and subsequent, to low dose aerosol infection with M. tuberculosis. Lactoferrin treatment did not significantly alter mycobacterial burdens in B6 mice. In marked contrast, bacterial loads were 100-fold lower in lactoferrin treated β2m–KO animals as compared with untreated β2m–KO mice (Fig. 3, A and B) . The numbers of M. tuberculosis in the organs of lactoferrin-treated β2m–KO mice were comparable to those seen in organs of nontreated MHC-I–KO mice. At this early time point, untreated β2m–KO mice had at least fivefold higher bacterial numbers in the respective organs than B6 and MHC-I–KO mice (Fig. 3 B). Thus, treatment with lactoferrin ameliorated M. tuberculosis infection in β2m–KO mice reducing bacterial loads to those seen in B6 and MHC-I–KO mice. Similarly, depletion of Fe by deferroxamine decreased mycobacterial numbers in β2m–KO and B6 mice (unpublished data). This is in contrast to a recent study on murine salmonellosis, which revealed strong exacerbation of infection by deferroxamine treatment through inhibition of the respiratory burst in host cells (14).


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 - J. Exp. Med. (2002)

Lactoferrin decreased growth of M. tuberculosis in β2m KO but not in MHC class I KO mice. (A) Lactoferrin treatment reduced the growth of M. tuberculosis in β2m–KO but not B6 mice. Mice were infected with 159 bacteria/lung by aerosol and bacterial load was measured at 22 d after infection (untreated, closed symbols; lactoferrin treatment, open symbols). (B) Lactoferrin treatment decreased growth of M. tuberculosis in β2m–KO but less so in B6 or MHC class I KO mice. Mice were infected with 155 bacteria/lung by aerosol and bacterial load was measured at 27 d after infection (untreated, closed symbols; lactoferrin treatment, open symbols). Statistics: *P < 0.01, **P < 0.005 as determined by the non paired Mann-Whitney test (data from one representative experiment out of three). (C) Serum levels of NO measured as NO2 in mice at 27 d after infection by aerosol with five M. tuberculosis/lung (untreated, closed symbols; lactoferrin treated, open symbols).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2194267&req=5

fig3: Lactoferrin decreased growth of M. tuberculosis in β2m KO but not in MHC class I KO mice. (A) Lactoferrin treatment reduced the growth of M. tuberculosis in β2m–KO but not B6 mice. Mice were infected with 159 bacteria/lung by aerosol and bacterial load was measured at 22 d after infection (untreated, closed symbols; lactoferrin treatment, open symbols). (B) Lactoferrin treatment decreased growth of M. tuberculosis in β2m–KO but less so in B6 or MHC class I KO mice. Mice were infected with 155 bacteria/lung by aerosol and bacterial load was measured at 27 d after infection (untreated, closed symbols; lactoferrin treatment, open symbols). Statistics: *P < 0.01, **P < 0.005 as determined by the non paired Mann-Whitney test (data from one representative experiment out of three). (C) Serum levels of NO measured as NO2 in mice at 27 d after infection by aerosol with five M. tuberculosis/lung (untreated, closed symbols; lactoferrin treated, open symbols).
Mentions: We reasoned that restriction of iron supply could prevent growth of M. tuberculosis in vivo, therefore extracellular Fe was depleted by the intranasal administration of lactoferrin to B6 and β2m–KO mice prior, and subsequent, to low dose aerosol infection with M. tuberculosis. Lactoferrin treatment did not significantly alter mycobacterial burdens in B6 mice. In marked contrast, bacterial loads were 100-fold lower in lactoferrin treated β2m–KO animals as compared with untreated β2m–KO mice (Fig. 3, A and B) . The numbers of M. tuberculosis in the organs of lactoferrin-treated β2m–KO mice were comparable to those seen in organs of nontreated MHC-I–KO mice. At this early time point, untreated β2m–KO mice had at least fivefold higher bacterial numbers in the respective organs than B6 and MHC-I–KO mice (Fig. 3 B). Thus, treatment with lactoferrin ameliorated M. tuberculosis infection in β2m–KO mice reducing bacterial loads to those seen in B6 and MHC-I–KO mice. Similarly, depletion of Fe by deferroxamine decreased mycobacterial numbers in β2m–KO and B6 mice (unpublished data). This is in contrast to a recent study on murine salmonellosis, which revealed strong exacerbation of infection by deferroxamine treatment through inhibition of the respiratory burst in host cells (14).

Bottom Line: This protein regulates transferrin receptor mediated iron uptake and mutations in its gene cause hereditary iron overload (hemochromatosis).Conversely, iron overload in the immunocompetent host exacerbated disease.Consistent with this, iron deprivation in infected resting macrophages was detrimental for intracellular mycobacteria.

View Article: PubMed Central - PubMed

Affiliation: Max-Planck-Institute for Infection Biology, Schumannstrasse 21-22, D-10117 Berlin, Germany. schaible@mpiib-berlin.mpg.de

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus