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Infection and Immunity, October 2000, p. 5619-5627, Vol. 68, No. 10
Division of Infectious Diseases, Department of
Medicine,1 Departments of
Microbiology3 and Veterans
Affairs,2 and The Interdisciplinary
Immunology Program,4 The University of Iowa
College of Medicine, Iowa City, Iowa 52242
Received 6 January 2000/Returned for modification 18 February
2000/Accepted 29 June 2000
Mycobacterium tuberculosis and M. avium
complex (MAC) enter and multiply within monocytes and macrophages in
phagosomes. In vitro growth studies using standard culture media
indicate that siderophore-mediated iron (Fe) acquisition plays a
critical role in the growth and metabolism of both M. tuberculosis and MAC. However, the applicability of such studies
to conditions within the macrophage phagosome is unclear, due in part
to the absence of experimental means to inhibit such a process. Based
on the ability of gallium (Ga3+) to concentrate within
mononuclear phagocytes and on evidence that Ga disrupts cellular
Fe-dependent metabolic pathways by substituting for Fe3+
and failing to undergo redox cycling, we hypothesized that Ga could
disrupt Fe acquisition and Fe-dependent metabolic pathways of
mycobacteria. We find that Ga(NO3)3 and
Ga-transferrin produce an Fe-reversible concentration-dependent growth
inhibition of M. tuberculosis strains and MAC grown
extracellularly and within human macrophages. Ga is bactericidal for
M. tuberculosis growing extracellularly and within
macrophages. Finally, we provide evidence that exogenously added Fe is
acquired by intraphagosomal M. tuberculosis and that Ga
inhibits this Fe acquisition. Thus, Ga(NO3)3
disruption of mycobacterial Fe metabolism may serve as an experimental
means to study the mechanism of Fe acquisition by intracellular
mycobacteria and the role of Fe in intracellular survival. Furthermore,
given the inability of biological systems to discriminate between Ga and Fe, this approach could have broad applicability to the study of Fe
metabolism of other intracellular pathogens.
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Gallium Disrupts Iron Metabolism of Mycobacteria
Residing within Human Macrophages
*
Corresponding author. Mailing address: The University
of Iowa, Department of Internal Medicine, 200 Hawkins Dr., SW54 GH, Iowa City, IA 52242. Phone: (319) 356-1387. Fax: (319) 356-4600. E-mail: larry-schlesinger{at}uiowa.edu.
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