Tuberculosis and elevation of iron

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FEMS Immunology and Medical Microbiology
Volume 45, Issue 2 , 1 August 2005, Pages 103-112

doi:10.1016/j.femsim.2005.02.007
Copyright © 2005 Federation of European Microbiological Societies
Published by Elsevier B.V.

Iron and iron chelating agents modulate Mycobacterium tuberculosis
growth and monocyte-macrophage viability and effector functions

Leandra Cronjéa, Nicole Edmondsona, b, Kathleen D. Eisenachb and Liza
Bornmana, ,

aDepartment of Biochemistry, University of Johannesburg, P.O. Box 524,
Auckland Park, Johannesburg 2006, South Africa
bDepartment of Pathology and Microbiology/Immunology, University of
Arkansas for Medical Sciences, Little Rock, Arkansas, USA

Received 20 August 2004; revised 6 January 2005; accepted 18 February
2005. Available online 30 March 2005.

Abstract
Excess of iron promotes Mycobacterium tuberculosis infection, its
replication and progression to clinical disease and death from
tuberculosis. Chelation of iron may reduce M. tuberculosis replication,
restore host defence mechanisms and it could constitute an application
in the prevention and treatment strategies where both iron overload and
tuberculosis are prevalent. We investigated the effect of iron and iron
chelating agents, like desferrioxamine and silybin, individually and in
combination with iron on mycobacterial number, viability in culture and
after recovery from monocyte-macrophages, together with
monocyte-macrophages viability and oxidative defence. Mycobacterial
number and viability in culture were assessed using real-time
quantitative PCR of H37Rv IS6110 DNA, 16S rRNA and 85B mRNA, whereas
the microplate AlamarBlueTM assay was used to detect viability in
culture post-infection. Mitochondrial membrane potential and
phosphatidyl serine exposure of monocyte-macrophages, detected using
Mitotracker Red fluorescence and Annexin V binding, respectively,
served as indicators of host cell viability. Superoxide generation
served as marker of monocyte-macrophage effector functions.
Extracellular H37Rv showed a significant increase in number and
viability in presence of excess iron and, by large, a significant
decrease in number and viability in presence of the iron chelating
agents, silybin and desferrioxamine, compared to cultivation without
supplementation. Intracellularly, excess iron increased H37Rv viability
significantly but reduced monocyte-macrophages mitochondrial membrane
potential and compromised superoxide production. Desferrioxamine had
little influence on intracellular parameters, but consistently
prevented effects of excess iron, while silybin significantly altered
most intracellular parameters and mostly failed to prevent effects of
excess iron. These findings suggest that chelation therapy should be
considered in conditions of iron overload and that effective chelating
agents like desferrioxamine, with limited intracellular access might
need to be used in combination with lypophilic chelating agents.

Keywords: Desferrioxamine; Silybin; H37Rv; Mycobacterium tuberculosis;
Iron chelation

Corresponding author. Tel.: + 27 11 489 2406; fax: + 27 11 489 2605

FEMS Immunology and Medical Microbiology
Volume 45, Issue 2 , 1 August 2005, Pages 103-112

Copyright © 2005 Elsevier B.V. All rights reserved. ScienceDirect® is
a registered trademark of Elsevier B.V.

Dietary Iron Associated With Pulmonary Tuberculosis In Rural Africans
A DGReview of :"Association of Pulmonary Tuberculosis with Increased
Dietary Iron"
Journal of Infectious Diseases

10/17/2001
By James Adams

Increased dietary iron is associated with a 3.5 fold increase in the
estimated odds of developing active tuberculosis in rural Africans.

Researchers from multiple institutions, including the University of
Zimbabwe School of Medicine in Harare, Zimbabwe, and the National
Institute of Child Health and Human Development (NICHD) in Bethesda,
Maryland, United States, investigated the possibility that increased
dietary iron is a risk factor for tuberculosis.

"Exposure to high levels of dietary iron in the form of traditional
beer is associated with increased iron stores in rural Africans,"
according to the investigators.

Ninety-eight pulmonary tuberculosis patients and 98 controls from rural
Zimbabwe were included in the study. Their dietary iron history and
human immunodeficiency virus (HIV) status were evaluated.

Results showed that HIV seropositivity was associated with a 17.3-fold
increase in the estimated odds of developing active tuberculosis. Also,
HIV seropositivity in patients treated for tuberculosis was associated
with a 3.8-fold increase in the estimated hazard ratio of death.

Increased dietary iron was associated with a 3.5-fold increase in the
odds of developing active tuberculosis and a 1.3-fold increase in the
estimated hazard ratio of death.

The study was financially supported by the Office of Minority Health to
the Cell Biology and Metabolism Branch of the NICHD, the Cell Biology
and Metabolism Branch of the NICHD and the J.F. Kapnek Charitable Trust
in Harare, Zimbabwe.
J Infect Dis 2001; 184: 936-939. "Association of Pulmonary Tuberculosis
with Increased Dietary Iron"

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