Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), continues to negatively impact human health on a global scale. The long term goal of this project is to understand the means by which Mtb senses and responds to its host environment during infection, so that improved biomarkers and treatments for TB disease can be developed. Cyclic AMP (cAMP), which is generated from ATP by adenylyl cyclases, is a universal second messenger used by both microbial pathogens and their mammalian hosts to sense and respond to environmental cues. cAMP plays a central role in virulence gene regulation in Mtb and other bacterial pathogens through its allosteric interactions with cAMP receptor protein (CRP)-like transcription factors. Mtb encodes two such transcription factors: CrpMt, which contributes to virulence in a murine model;and Cmr, which regulates Mtb gene expression within macrophages. Previous work has shown that levels of cAMP within Mtb bacteria increase dramatically upon bacterial entry into macrophages, suggesting a role for cAMP in sensing and responding to the intra-macrophage environment. The current project addresses the hypothesis that cAMP signaling contributes to Mtb-host interactions by regulating gene expression within the bacterium in response to environmental conditions. This hypothesis will be addressed in three specific aims.
Aim 1 will redefine the CrpMt regulon and its role in Mtb biology during infection at the global, cellular and molecular levels.
Aim 2 addresses the role of Cmr in Mtb biology with a focus on its role in regulating propionate metabolism during macrophage infection and within granulomas.
Aim 3 addresses the roles of CrpMt and Cmr as co-regulators with other transcription factors, of the espA virulence operon using a combination of molecular, genetic and cellular approaches. Completion of these studies will significantly advance understanding of cAMP's role in Mtb biology, particularly in the context of bacterial sensing and response to host-associated conditions. This information will contribute to the identification of stage-specific biomarkers of infection and new drug targets. The significance of this project is further enhanced by cAMP's established role in regulating virulence in a wide range of important bacterial pathogens, as well as the exceptionally large and unusual network of cAMP-associated signaling proteins in Mtb.

Public Health Relevance

Tuberculosis (TB) is a major global health problem, and new intervention strategies are urgently needed to reduce its deadly impact. Characterization of gene regulatory mechanisms in Mtb, and the means by which TB bacteria respond to their environments during infection, will contribute to our understanding of the factors that control establishment of tuberculosis infection and disease. This work will explore new insights regarding the role of cAMP in Mtb's response to host-associated environmental conditions, with the potential to identify new biomarkers of infection, as well as targets for anti-TB therapeutics, and/or diagnostics.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Jacobs, Gail G
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Wadsworth Center
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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
DeMott, Christopher M; Girardin, Roxie; Cobbert, Jacqueline et al. (2018) Potent Inhibitors of Mycobacterium tuberculosis Growth Identified by Using in-Cell NMR-based Screening. ACS Chem Biol 13:733-741
Ranganathan, Sridevi; Cheung, Jonah; Cassidy, Michael et al. (2018) Novel structural features drive DNA binding properties of Cmr, a CRP family protein in TB complex mycobacteria. Nucleic Acids Res 46:403-420
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