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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
6R01AI044856-15
Application #
8484336
Study Section
Special Emphasis Panel (ZRG1-GGG-F (02))
Program Officer
Lacourciere, Karen A
Project Start
1999-03-01
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
15
Fiscal Year
2013
Total Cost
$535,987
Indirect Cost
$198,888
Name
Rutgers University
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
078795851
City
Newark
State
NJ
Country
United States
Zip Code
07103
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Kurthkoti, Krishna; Tare, Priyanka; Paitchowdhury, Rakhi et al. (2015) The mycobacterial iron-dependent regulator IdeR induces ferritin (bfrB) by alleviating Lsr2 repression. Mol Microbiol 98:864-77
Subbian, Selvakumar; Pandey, Ruchi; Soteropoulos, Patricia et al. (2015) Vaccination with an Attenuated Ferritin Mutant Protects Mice against Virulent Mycobacterium tuberculosis. J Immunol Res 2015:385402
Pandey, Ruchi; Russo, Riccardo; Ghanny, Saleena et al. (2015) MntR(Rv2788): a transcriptional regulator that controls manganese homeostasis in Mycobacterium tuberculosis. Mol Microbiol 98:1168-83
Pandey, Ruchi; Rodriguez, G Marcela (2014) IdeR is required for iron homeostasis and virulence in Mycobacterium tuberculosis. Mol Microbiol 91:98-109
Rodriguez, G Marcela; Neyrolles, Olivier (2014) Metallobiology of Tuberculosis. Microbiol Spectr 2:
Prados-Rosales, Rafael; Weinrick, Brian C; Piqué, Daniel G et al. (2014) Role for Mycobacterium tuberculosis membrane vesicles in iron acquisition. J Bacteriol 196:1250-6
Serafini, Agnese; Pisu, Davide; Palù, Giorgio et al. (2013) The ESX-3 secretion system is necessary for iron and zinc homeostasis in Mycobacterium tuberculosis. PLoS One 8:e78351
Madigan, Cressida A; Cheng, Tan-Yun; Layre, Emilie et al. (2012) Lipidomic discovery of deoxysiderophores reveals a revised mycobactin biosynthesis pathway in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 109:1257-62
Santhanagopalan, Sujatha M; Rodriguez, G Marcela (2012) Examining the role of Rv2895c (ViuB) in iron acquisition in Mycobacterium tuberculosis. Tuberculosis (Edinb) 92:60-2

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