Tuberculosis, one of the great scourges of humankind, continues to be a serious and significant health problem in the world today. The World Health Organization estimates that one-third of the world's population is infected with Mycobacterium tuberculosis, the causative agent of TB. Approximately 8 million new cases of TB are diagnosed annually worldwide. Of those individuals with active disease, nearly 2 million die each year. Small wonder, then that in 1993, WHO declared tuberculosis to be a global health emergency, as it remains today. During the past 12-14 years, significant progress has been made in the development of genetic tools to facilitate analysis of the genes and gene products of M. tuberculosis. The nucleotide sequences of the entire genomes of two strains of M. tuberculosis have been determined. The techniques of DNA microarray analysis and two-dimensional gel electrophoresis analysis have provided valuable information about global gene expression and protein production by M. tuberculosis grown in defined environments. We developed a method to identify M. tuberculosis genes that are expressed when the mycobacteria are growing in their favored ecological niche, the human macrophage. Although much has been learned, fundamental aspects of M. tuberculosis pathogenesis remain unknown. Employing a number of currently available genetic, genomic, proteomic, and molecular biological tools, we propose to (1) characterize the regulons of the TrcRS, Rv1626, and PrrAB regulatory systems, (2) determine the contribution of specific gene products to M. tuberculosis pathogenesis by comparisons between wild-type M. tuberculosis H37Rv and strains of H37Rv with mutations in specific genes expressed during growth in human macrophages and (3) compare gene expression by M. tuberculosis growing in human peripheral blood monocyte-derived macrophages and in infected mouse lungs by cDNA microarray and quantitative RT-PCR (QRT-PCR) analyses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046428-09
Application #
7322807
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Lacourciere, Karen A
Project Start
2000-02-01
Project End
2009-11-30
Budget Start
2007-12-01
Budget End
2008-11-30
Support Year
9
Fiscal Year
2008
Total Cost
$312,886
Indirect Cost
Name
Arizona State University-Tempe Campus
Department
Other Health Professions
Type
Organized Research Units
DUNS #
943360412
City
Tempe
State
AZ
Country
United States
Zip Code
85287
Korch, Shaleen B; Malhotra, Vandana; Contreras, Heidi et al. (2015) The Mycobacterium tuberculosis relBE toxin:antitoxin genes are stress-responsive modules that regulate growth through translation inhibition. J Microbiol 53:783-95
Malhotra, Vandana; Agrawal, Ruchi; Duncan, Tammi R et al. (2015) Mycobacterium tuberculosis response regulators, DevR and NarL, interact in vivo and co-regulate gene expression during aerobic nitrate metabolism. J Biol Chem 290:8294-309
Malhotra, Vandana; Okon, Blessing P; Clark-Curtiss, Josephine E (2012) Mycobacterium tuberculosis protein kinase K enables growth adaptation through translation control. J Bacteriol 194:4184-96
Haydel, Shelley E; Malhotra, Vandana; Cornelison, Garrett L et al. (2012) The prrAB two-component system is essential for Mycobacterium tuberculosis viability and is induced under nitrogen-limiting conditions. J Bacteriol 194:354-61
Malhotra, Vandana; Arteaga-Cortés, Lourdes T; Clay, Gwendolyn et al. (2010) Mycobacterium tuberculosis protein kinase K confers survival advantage during early infection in mice and regulates growth in culture and during persistent infection: implications for immune modulation. Microbiology 156:2829-41
Malhotra, Vandana; Tyagi, Jaya Sivaswami; Clark-Curtiss, Josephine E (2009) DevR-mediated adaptive response in Mycobacterium tuberculosis H37Ra: links to asparagine metabolism. Tuberculosis (Edinb) 89:169-74
Korch, Shaleen B; Contreras, Heidi; Clark-Curtiss, Josephine E (2009) Three Mycobacterium tuberculosis Rel toxin-antitoxin modules inhibit mycobacterial growth and are expressed in infected human macrophages. J Bacteriol 191:1618-30
Haydel, Shelley E; Clark-Curtiss, Josephine E (2006) The Mycobacterium tuberculosis TrcR response regulator represses transcription of the intracellularly expressed Rv1057 gene, encoding a seven-bladed beta-propeller. J Bacteriol 188:150-9
Haydel, Shelley E; Clark-Curtiss, Josephine E (2004) Global expression analysis of two-component system regulator genes during Mycobacterium tuberculosis growth in human macrophages. FEMS Microbiol Lett 236:341-7
Clark-Curtiss, Josephine E; Haydel, Shelley E (2003) Molecular genetics of Mycobacterium tuberculosis pathogenesis. Annu Rev Microbiol 57:517-49

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