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Nisheeth Agarwal, PhD
There are more than one hundred regulatory proteins in mycobacteria. Out of these, 7 belong to a family named as the Wbl (WhiB-like) family. Wbl proteins are very novel in mycobacteria and each of these proteins contains 4 invariant cysteine residues, is relatively short in length (76-139 residues) and possesses a characteristic helix-turn-helix motif. In an earlier study, it has been observed that one of the Wbl proteins, WhmD is essential in M. smegmatis and is required for proper septation and cell division.
Currently I am working on one member of the wbl family of genes of M. tuberculosis, whiB1, which has been shown to be induced under different environmental conditions including hypoxia. Based on sequence homology, we are proposing that WhiB1 could have the ability to bind with iron-sulfur clusters and thus may be involved in maintaining the redox status of the cell. The purified WhiB1 will be subjected to electron paramagnetic resonance spectroscopy after chemically reducing the protein to observe its oxidation state. Any change in its oxidation state would be indicative of the direct role of this protein in maintaining the redox status of mycobacterial cells. In order to find out the WhiB1 regulon, a WhiB1-overexpressing strain of M. tuberculosis will be subjected to microarray analysis. Another aspect of the current research work is to study the role of cyclic-AMP on the expression of WhiB1, since the promoter sequence of whiB1 exhibits the presence of cAMP receptor protein-binding site and the expression of whiB1 has been shown to be reduced by >3-fold in a mutant strain of M. tuberculosis, lacking the gene Rv3676, encoding cAMP-receptor binding protein. Any effect of cAMP on whiB1 expression will thus indicate the possible role of whiB1 to sense carbon source starvation or when bacilli face high cAMP concentration during host infection.
The Mycobacterium tuberculosis CDC1551 genome reveals 17 genes containing class III adenylate cyclase (AC) domains, a feature shared by pathogenic mycobacteria such as M. avium (12 ACs) and M. marinum (31 ACs). In contrast, Escherichia coli, Pseudomonas aeruginosa, Corynebacterium glutamicum, and Streptomyces coelicolor have only one AC. While a member of the M. tuberculosis complex, M. microti, has been reported to block phagosome maturation by cAMP production within macrophages, the source and effects of cAMP during macrophage infection by mycobacteria remain unclear. Currently we are studying the role of cAMP in mycobacterial growth and virulence as well as its effects on host signal transduction during infection. Our study will help better understand the underlying mechanisms of mycobacterial pathogenesis and several key pathways involved in TB pathology.
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1. Nisheeth Agarwal, Gyanu Lamichhane, Radhika Gupta, Scott Nolan, and William R. Bishai. (2009) cAMP intoxication of macrophages by a Mycobacterium tuberculosis adenylate cyclase. Nature (doi:10.1038/nature08123)
2. Nisheeth Agarwal and William R. Bishai (2009) cAMP signaling in Mycobacterium tuberculosis. Indian J Exp Biol. 47: 393-400.
3. Nisheeth Agarwal, Samuel C. Woolwine, Sandeep Tyagi and William R. Bishai. (2007) Characterization of the Mycobacterium tuberculosis sigma factor SigM by assessment of virulence and identification of SigM-dependent genes. Infect Immun. 75: 452-61.
4. Nisheeth Agarwal and Anil K. Tyagi. (2006) Mycobacterial transcriptional signals: Requirements for recognition by RNA polymerase and optimal transcriptional activity. Nucleic Acids Res. 34(15): 4245-4257.
5. Nisheeth Agarwal, Tirumalai R. Raghunand and William R. Bishai. (2006) Regulation of the expression of whiB1 in Mycobacterium tuberculosis: role of cAMP receptor protein. Microbiology 152: 2749-2756.
6. Deborah E. Geiman, Tirumalai R. Raghunand, Nisheeth Agarwal, and William R. Bishai. (2006) Differential gene expression in response to exposure to antimycobacterial agents and other stress conditions among seven Mycobacterium tuberculosis whiB-like genes. Antimicrob. Agents Chemother. 50: 2836-2841.
7. Nisheeth Agarwal and Anil K. Tyagi. (2003) Role of 5’-TGN-3’ motif in the interaction of mycobacterial RNA polymerase with a promoter of ‘extended –10 class’. FEMS Microbiol. Lett. 225: 75-83.
8. Anjali Tikoo, A.K. Tripathi, S.C. Verma, N. Agrawal and Gopal Nath. (2001) Application of PCR fingerprinting techniques for identification and discrimination of Salmonella isolates. Curr. Science 80: 1049-1052.
9. C.K.M. Tripathi, Amrita Gupta, N. Agarwal, S.C. Tripathi, S.C. Agarwal and Vinod Bihari. (1999) Production of antibacterial metabolites by actinomycetes screened from natural environment. In Fermentation Biotechnology-Industrial Perspectives. (eds. S. Chand and S.C. Jain) pp. 295-299.