Tuberculosis, one of the great scourges of humankind, is the leading cause of death worldwide from a single infectious disease. Although the incidence of TB has again begun to decline in the U.S., TB remains a significant health problem in this country, most frequently affecting the elderly, the homeless, individuals with AIDS and immigrants from nations where TB is endemic. Although the causative agent of TB, Mycobacterium tuberculosis, was identified a century ago, knowledge about fundamental physiological capabilities, the genetics and the mechanisms of pathogenicity of M. tuberculosis is only now beginning to emerge. We have identified several genes which are expressed by M. tuberculosis H37Rv when the bacilli are growing in human macrophages in culture, but which are not expressed by the bacilli when they are growing in laboratory broth culture. We hypothesize that these genes and their products may be important in the survival and growth of M. tuberculosis in macrophages and may contribute to the pathogenicity of the tubercle bacilli. We propose to (1) determine the contribution of specific macrophage-expressed gene products to survival and growth of M. tuberculosis in macrophages by molecular and genetic characterization of genes on a cosmid that appear to be coordinately expressed, a putative response regulator gene, and mceD, a gene that has been shown to enhance survival of E. coli in cultured macrophages; and (2) to identify and characterize genes and gene products of M. tuberculosis that are expressed at early times after phagocytosis, at late times, and throughout growth in human macrophages in culture.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046428-02
Application #
6349919
Study Section
Special Emphasis Panel (ZRG1-BM-2 (07))
Program Officer
Sizemore, Christine F
Project Start
2000-02-01
Project End
2004-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
2
Fiscal Year
2001
Total Cost
$252,783
Indirect Cost
Name
Washington University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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

Showing the most recent 10 out of 13 publications