Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is one of the oldest known human maladies. Yet this disease is still one of the major causes of mortality, as almost 2 million people die each year from this disease. Despite the widespread use of an attenuated live vaccine and several antibiotics, there is more TB than ever before, requiring new vaccines, drugs and more specific and rapid diagnostics. Mtb is a facultative intracellular pathogen that replicates in macrophages and extracellularly in lung cavities. During infection, Mtb is exposed to diferent environments and stres 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 as cofactor for enzymes that are involved in essential functions, including respiration, DNA replication and defense against toxic oxidative stress. Thus, if ways can be found to interfere with Mtb's ability to acquire iron, this information could be useful in designing new anti-tubercular therapies.
The specific aims of the proposal are first, to understand how the major pathway of Mtb iron acquisition, using siderophores, functions. This includes learning how iron complexed to siderophores is imported into Mtb and how iron is then released in a form that can be used by the cell for its essential functions. Because iron acquisition is essential, pathogens do not usually rely in a single method to get this nutrient. We found that Mtb can use heme and hemoglobin as iron source independently of siderophores. We will explore the mechanisms for iron acquisition from heme and the possible role of heme utilization in Mtb's virulence. The 2nd aim seeks to understand why IdeR, the major regulator of iron uptake and storage is essential, using a combination of in vitro and in vivo approaches. The 3rd aim wil use the information obtained in the first two aims and earlier work to develop new live attenuated, safe vaccine strains that could be used to prevent TB in the general population, as well as immunocompromised individuals.
Iron is an essential element for M. tuberculosis (Mtb) that is not freely available in the infected host. Mtb uses specialized molecular machinery to obtain iron from the host, which is actively sequestering this element. Mtb mutants that can not acquire iron are attenuated for virulence, indicating that these processes could be good targets for new anti-tubercular therapies. This project studies how Mtb acquires iron so that ways to interfere with this process can be designed.
|Pandey, Ruchi; Rodriguez, G Marcela (2014) IdeR is required for iron homeostasis and virulence in Mycobacterium tuberculosis. Mol Microbiol 91:98-109|
|Fontan, P A; Voskuil, M I; Gomez, M et al. (2009) The Mycobacterium tuberculosis sigma factor sigmaB is required for full response to cell envelope stress and hypoxia in vitro, but it is dispensable for in vivo growth. J Bacteriol 191:5628-33|
|Rao, Prahlad K; Rodriguez, G Marcela; Smith, Issar et al. (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 80:6860-9|
|Fontan, Patricia A; Aris, Virginie; Alvarez, Maria E et al. (2008) Mycobacterium tuberculosis sigma factor E regulon modulates the host inflammatory response. J Infect Dis 198:877-85|
|Fontan, Patricia; Aris, Virginie; Ghanny, Saleena et al. (2008) Global transcriptional profile of Mycobacterium tuberculosis during THP-1 human macrophage infection. Infect Immun 76:717-25|
|Williams, Diana L; Pittman, Tana L; Deshotel, Mike et al. (2007) Molecular basis of the defective heat stress response in Mycobacterium leprae. J Bacteriol 189:8818-27|
|Maciag, Anna; Dainese, Elisa; Rodriguez, G Marcela et al. (2007) Global analysis of the Mycobacterium tuberculosis Zur (FurB) regulon. J Bacteriol 189:730-40|
|Giacomini, Elena; Sotolongo, Ambar; Iona, Elisabetta et al. (2006) Infection of human dendritic cells with a Mycobacterium tuberculosis sigE mutant stimulates production of high levels of interleukin-10 but low levels of CXCL10: impact on the T-cell response. Infect Immun 74:3296-304|
|Dainese, Elisa; Rodrigue, Sebastien; Delogu, Giovanni et al. (2006) Posttranslational regulation of Mycobacterium tuberculosis extracytoplasmic-function sigma factor sigma L and roles in virulence and in global regulation of gene expression. Infect Immun 74:2457-61|
|Rodriguez, G Marcela; Smith, Issar (2006) Identification of an ABC transporter required for iron acquisition and virulence in Mycobacterium tuberculosis. J Bacteriol 188:424-30|
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