Public Health Research Institute Center and
UMDNJ - New Jersey Medical School
225 Warren Street
Newark, New Jersey 07103
Phone: (973) 854-3262
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), continues to claim the lives of millions of people worldwide. New drugs and a more efficient vaccine are urgently needed. Mtb is a facultative intracellular pathogen that replicates in macrophages and extracellularly, in lung cavities. During infection, Mtb is exposed to different environments and stress conditions to which it must adapt in order to survive and multiply. Iron deficiency is one of those conditions. As is the case for most living organisms, Mtb requires iron for vital cellular functions. Due to the poor aqueous solubility of ferric ion in the presence of oxygen and at neutral pH, free iron is not found in the mammalian host, but is sequestered in complexes with iron binding glycoproteins or bound to protoporphyrins in heme and hemoproteins. Furthermore, as a defensive response to infection, the host withholds iron from blood and tissues, thus further limiting iron availability to the pathogen.
Like all successful pathogens, Mtb is able to compete for iron in the host through the expression of specialized iron sequestration and transport systems. It has been recognized that iron availability influences the severity of tuberculosis and that abnormally high levels of iron in Mtb infected humans and animal models are associated with exacerbation of the disease. Based on these observations we believe that iron acquisition and the proteins involved in this process are good targets for therapeutic intervention or prevention of TB. In this context the goals of the projects going on in the laboratory are:
1. Understanding the complex process by which Mtb acquires iron. Mtb synthesizes and secretes siderophore molecules that can chelate ferric iron from the environment. Fe+3-siderophore complexes are transported inside the cell by a process that is not completely understood. We have identified an ABC-transporter (IrtAB) essential for iron uptake in Mtb (figure1), but other molecules involved in iron uptake and the functional interactions between them remain to be discovered.
2. Characterizing the regulatory mechanisms involved in the adaptive response of Mtb to iron deficient conditions encountered in the host. We wish to understand the adaptive response of Mtb to iron availability in the host. This response is controlled by the essential iron dependent transcriptional regulator IdeR (figure1) and includes the induction of iron acquisition systems, the global adjustment of basic metabolism and the expression of virulence determinants. We believe that understanding this response and how is regulated will reveal potential targets to interfere with survival of Mtb in an infected host.
3. Applying the knowledge derived from our basic studies to the development of new therapeutic or preventive tools against M. tuberculosis.
Figure 1. Siderophore mediated iron acquisition in M. tuberculosis. M. tuberculosis facing iron deficiency secretes siderophores called carboxymycobactins (CM) which chelate Fe+3. Fe+3-CM complexes are transported into the cell by the iron regulated ABC-transporter IrtAB. In the cytoplasm the amino terminal domain of IrtA binds FAD and may reduce Fe+3 in the Fe+3-CM complex to release Fe+2 for utilization and storage. Iron metabolism is controlled by the iron dependent regulator IdeR which under conditions of iron sufficiency binds Fe+2 and represses transcription of siderophore synthesis and transport genes repressing iron uptake while induces transcription of the iron storage genes bfrA and bfrB.
Pandey R, Rodriguez GM (2012) A ferritin mutant of Mycobacterium tuberculosis is more susceptible to killing by antibiotics and is unable to establish a chronic infection in mice. Infect Immun. PMI: 22802345
Santhanagopalan SM, Rodriguez GM (2012) Examining the role of Rv2895c (ViuB) in iron acquisition in Mycobacterium tuberculosis. Tuberculosis (Edinb) 92: 60-62. PMI: 22015175
Madigan CA, Cheng TY, Layre E, Young DC, McConnell MJ, Debono CA, Murry JP, Wei JR, Barry CE, 3rd, Rodriguez GM, Matsunaga I, Rubin EJ, Moody DB (2012) Lipidomic discovery of deoxysiderophores reveals a revised mycobactin biosynthesis pathway in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 109: 1257-1262. PMI: 22232695
Ryndak MB, Wang S, Smith I, Rodriguez GM (2010) The Mycobacterium tuberculosis high-affinity iron importer, IrtA, contains an FAD-binding domain. J Bacteriol 192: 861-869. PMI: 19948799
Janagama HK, Senthilkumar TM, Bannantine JP, Rodriguez GM, Smith I, Paustian ML, McGarvey JA, Sreevatsan S (2009) Identification and functional characterization of the iron-dependent regulator (IdeR) of Mycobacterium avium subsp. paratuberculosis. Microbiology 155: 3683-3690. PMI: 19684064
Rodriguez GM, Gardner R, Kaur N, Phanstiel Ot (2008) Utilization of Fe3+-acinetoferrin analogs as an iron source by Mycobacterium tuberculosis. Biometals 21: 93-103. PMI: 17401548
Rao PK, Rodriguez GM, Smith I, Li Q (2008) Protein dynamics in iron-starved Mycobacterium tuberculosis revealed by turnover and abundance measurement using hybrid-linear ion trap-Fourier transform mass spectrometry. Anal Chem 80: 6860-6869. PMI: 18690695
Maciag A, Dainese E, Rodriguez GM, Milano A, Provvedi R, Pasca MR, Smith I, Palu G, Riccardi G, Manganelli R (2007) Global analysis of the Mycobacterium tuberculosis Zur (FurB) regulon. J Bacteriol 189: 730-740. PMI: 17098899
Rodriguez GM, Smith I (2006) Identification of an ABC transporter required for iron acquisition and virulence in Mycobacterium tuberculosis. J Bacteriol 188: 424-430. PMI: 16385031
Rodriguez GM (2006) Control of iron metabolism in Mycobacterium tuberculosis. Trends Microbiol 14: 320-327. PMI: 16759864
Rodriguez GM, Smith I (2004) In Crosa J and Payne S (eds.), Iron transport in Bacteria: Molecular Genetics, Biochemistry, Microbial Pathogenesis and Ecology. ASM Press.
Rodriguez GM, Smith I (2003) Mechanisms of iron regulation in mycobacteria: role in physiology and virulence. Mol Microbiol 47: 1485-1494. PMI: 12622807
Rodriguez GM, Voskuil MI, Gold B, Schoolnik GK, Smith I (2002) ideR, An essential gene in mycobacterium tuberculosis: role of IdeR in iron-dependent gene expression, iron metabolism, and oxidative stress response. Infect Immun 70: 3371-3381. PMI: 12065475
Gold B, Rodriguez GM, Marras SA, Pentecost M, Smith I (2001) The Mycobacterium tuberculosis IdeR is a dual functional regulator that controls transcription of genes involved in iron acquisition, iron storage and survival in macrophages. Mol Microbiol 42: 851-865. PMI: 11722747
Rodriguez GM, Gold B, Gomez M, Dussurget O, Smith I (1999) Identification and characterization of two divergently transcribed iron regulated genes in Mycobacterium tuberculosis. Tuber Lung Dis 79: 287-298. PMI: 10707257