The long-term goals of the research are to biochemically and genetically characterize the potential virulence factors used by intracellular mycobacteria to acquire iron from host cells. Mammals have an anti-infective system that attempts to withhold the biologically essential metal iron from invading microbes, but the """"""""iron- withholding"""""""" defenses may be most effective against extracellular pathogens. Another possible defense system (called """"""""iron-depletion"""""""" because it includes efflux of non-heme iron from infected host cells) may operate against pathogens living inside host cells. Successful pathogens must overcome these barriers by including effective iron acquisition among their virulence properties. Siderophore production is a common iron gathering tactic of microbes and in mycobacteria cultured extra- cellularly, a siderophore (mycobactin)-mediated iron uptake system is known. However, there is scant information on iron acquisition mechanisms used by mycobacteria present in macrophage phagosomes. Mycobactin may not be essential for intracellular iron uptake because pathogenic myco- bacterial strains lacking mycobactin production are known. The hypothesis is that the unidentified intracellular iron uptake mechanism(s) may be crucial for virulence of mycobacteria.
The specific aims are: 1. to establish a mycobacteria/macrophage culture system that will accurately monitor the flow of iron to mycobacteria present within phagosomes, 2. to identify and characterize the mycobacterial factors and processes, as well as the genes encoding synthesis of these, that are essential for intracellular iron uptake.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI035235-05
Application #
2442585
Study Section
Special Emphasis Panel (SRC (36))
Project Start
1993-09-30
Project End
1999-06-30
Budget Start
1997-07-01
Budget End
1999-06-30
Support Year
5
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Mississippi Medical Center
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
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Zhu, W; Arceneaux, J E; Beggs, M L et al. (1998) Exochelin genes in Mycobacterium smegmatis: identification of an ABC transporter and two non-ribosomal peptide synthetase genes. Mol Microbiol 29:629-39
Lundrigan, M D; Arceneaux, J E; Zhu, W et al. (1997) Enhanced hydrogen peroxide sensitivity and altered stress protein expression in iron-starved Mycobacterium smegmatis. Biometals 10:215-25