Tuberculosis (TB) is a major global health problem, and new intervention strategies are urgently needed to reduce its deadly impact. The long term objective of this project is to better understand how Mycobacterium tuberculosis (Mtb) responds to its host environment at the gene regulatory level so that effective strategies can be developed to prevent TB disease. Gene regulation is a critical aspect of Mtb's ability to cause infection, but little is known about gene regulatory mechanisms in Mtb during either active or latent infection. Previous studies have established that a set of acr-coregulated genes (ACGs) is coordinately expressed in response to hypoxia, shallow standing growth conditions, and within macrophages. ACG expression has been associated with Mtb virulence and establishment of latent TB infection, suggesting an important role for these genes during TB pathogenesis. However, neither the regulation nor function of these genes is understood. A multidisciplinary approach will be used to address the mechanisms of ACG regulation and function in Mtb at the molecular, genetic and cellular levels, with a particular focus on the effects of latency-associated environmental conditions.
Specific aims i nclude:
Aim 1 : Characterization of specific mechanisms of DosR-dependent ACG regulation at the molecular and biochemical levels, using promoter:reporter fusions, mutagenesis and DNA-protein binding assays. Studies will focus on the roles of DosR and ACG motif binding sites in regulation of devR, Rv3130c and Rv2623;
Aim 2 : Characterization, using genetic and biochemical approaches, of a new level of DosR-independent negative regulation associated with ACG 5'UTRs, including Rv2623. The cis and trans factors associated with this 5'UTR repression will be identified, and the biological roles of the 5'UTR repressor and Rv2623 regulation will be assessed using in vitro and in vivo models;
Aim 3 : Evaluation of a slow growth Mtb culture model compared with existing latency models in the context of new information on the importance of carbon dioxide to Mtb metabolism and its ability to abrogate hypoxia-associated growth arrest. Culture models will be compared to intramacrophage and in vivo conditions with regards to gene expression and lipid accumulation. Characterization of gene regulatory mechanisms in Mtb, and the environmental cues to which tubercle bacilli respond, will contribute to our understanding of the factors needed for the establishment of TB infection, and may identify new targets for TB vaccines, therapeutics, and/or diagnostic purposes.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-IDM-H (02))
Program Officer
Lacourciere, Karen A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Wadsworth Center
United States
Zip Code
Girardin, Roxie C; Bai, Guangchun; He, Jie et al. (2018) AbmR (Rv1265) is a novel transcription factor of Mycobacterium tuberculosis that regulates host cell association and expression of the non-coding small RNA Mcr11. Mol Microbiol 110:811-830
Ranganathan, Sridevi; Bai, Guangchun; Lyubetskaya, Anna et al. (2016) Characterization of a cAMP responsive transcription factor, Cmr (Rv1675c), in TB complex mycobacteria reveals overlap with the DosR (DevR) dormancy regulon. Nucleic Acids Res 44:134-51
Bai, Guangchun; Knapp, Gwendowlyn S; McDonough, Kathleen A (2011) Cyclic AMP signalling in mycobacteria: redirecting the conversation with a common currency. Cell Microbiol 13:349-58
Bai, Guangchun; Schaak, Damen D; McDonough, Kathleen A (2009) cAMP levels within Mycobacterium tuberculosis and Mycobacterium bovis BCG increase upon infection of macrophages. FEMS Immunol Med Microbiol 55:68-73
Vasudeva-Rao, Hema M; McDonough, Kathleen A (2008) Expression of the Mycobacterium tuberculosis acr-coregulated genes from the DevR (DosR) regulon is controlled by multiple levels of regulation. Infect Immun 76:2478-89
Bai, Guangchun; Gazdik, Michaela A; Schaak, Damen D et al. (2007) The Mycobacterium bovis BCG cyclic AMP receptor-like protein is a functional DNA binding protein in vitro and in vivo, but its activity differs from that of its M. tuberculosis ortholog, Rv3676. Infect Immun 75:5509-17
Bai, Guangchun; McCue, Lee Ann; McDonough, Kathleen A (2005) Characterization of Mycobacterium tuberculosis Rv3676 (CRPMt), a cyclic AMP receptor protein-like DNA binding protein. J Bacteriol 187:7795-804
Florczyk, Matthew A; McCue, Lee Ann; Purkayastha, Anjan et al. (2003) A family of acr-coregulated Mycobacterium tuberculosis genes shares a common DNA motif and requires Rv3133c (dosR or devR) for expression. Infect Immun 71:5332-43
Purkayastha, Anjan; McCue, Lee Ann; McDonough, Kathleen A (2002) Identification of a Mycobacterium tuberculosis putative classical nitroreductase gene whose expression is coregulated with that of the acr aene within macrophages, in standing versus shaking cultures, and under low oxygen conditions. Infect Immun 70:1518-29
Florczyk, M A; McCue, L A; Stack, R F et al. (2001) Identification and characterization of mycobacterial proteins differentially expressed under standing and shaking culture conditions, including Rv2623 from a novel class of putative ATP-binding proteins. Infect Immun 69:5777-85