Tuberculosis (TB) is an ancient infectious disease that has maintained its ability to claim human lives within the modern world population. This disease has especially flourished within human immunodeficiency virus- (HIV-) infected individuals, with the devastating consequence of becoming a leading cause of death within this vulnerable population. Effective control of TB is critically hindered by the lack of quality diagnostics, a protective vaccine, and chemotherapy regimens with potency for drug-resistant TB patients. One aspect of TB biology that has not been investigated for translational breakthroughs is the role of bacterial small molecules. There is growing evidence that secretion of small molecules, such as cyclic-di-nucleotides, by pathogenic bacteria may influence host signal transduction to mediate bacterial survival and virulence. The genome of Mycobacterium tuberculosis (M.tb.), the causative agent of TB, encodes tens of nucleotide and di-nucleotide cyclases, indicating an important role for such small molecules in the context of human TB. Furthermore, research in our laboratory has demonstrated for the first time secretion of cyclic-di-nucleotides by M.tb. These M.tb.-secreted small molecules therefore represent an untapped opportunity to both enrich our general knowledge of the biological interplay between M.tb. and its host, as well as to identify biological indicators of disease. We hypothesize that M.tb. secretes small molecules that modulate host cell signaling events, generating both small molecule and host response signatures that could be exploited as biomarkers of TB. In this proposal, we have carefully defined three specific aims designed to provide direct and relevant data for the evaluation of our hypothesis.
Aim 1 : Characterization of the role of M.tb.-secreted small molecules 3',5'-cyclic-di-guanylate (c-di- GMP), 3',5'-cyclic-di-adenylate (c-di-AMP), and mycobactin T in the context of a mammalian infection.
Aim 2 : Analysis of c-di-GMP, c-di-AMP and mycobactin T levels and the host response specific to each of these small molecules in both the granulomatous mouse and rabbit cavitary TB models.
Aim 3 : Definition of human TB biomarker signatures. Identification and characterization of such molecular signatures would serve as a significant and novel contribution to the TB research field, with the potential to greatly accelerate the development of new diagnostics and tools for the clinical analysis of new TB drugs and drug regimens.
It is currently estimated that one-third of the world's population is infected with the bacteria that cause tuberculosis (TB). These bacteria are known to produce unique, small, non-protein signaling molecules, and there is growing evidence that these small molecules affect how the bacteria survive and how the immune system responds to infection during TB. We will investigate the role of these small molecules during TB and also examine the possibility of using TB small molecule signatures to develop better TB diagnostic tools.
|Dey, Ruchi Jain; Dey, Bappaditya; Zheng, Yue et al. (2017) Inhibition of innate immune cytosolic surveillance by an M. tuberculosis phosphodiesterase. Nat Chem Biol 13:210-217|
|Maiga, Mamoudou; Cohen, Keira; Baya, Bocar et al. (2016) Stool microbiome reveals diverse bacterial ureases as confounders of oral urea breath testing for Helicobacter pylori and Mycobacterium tuberculosis in Bamako, Mali. J Breath Res 10:036012|
|Winglee, Kathryn; Manson McGuire, Abigail; Maiga, Mamoudou et al. (2016) Whole Genome Sequencing of Mycobacterium africanum Strains from Mali Provides Insights into the Mechanisms of Geographic Restriction. PLoS Negl Trop Dis 10:e0004332|
|Gupta, Shashank; Tyagi, Sandeep; Bishai, William R (2015) Verapamil increases the bactericidal activity of bedaquiline against Mycobacterium tuberculosis in a mouse model. Antimicrob Agents Chemother 59:673-6|
|Maiga, Mamoudou; Ahidjo, Bintou Ahmadou; Maiga, Mariama C et al. (2015) Efficacy of Adjunctive Tofacitinib Therapy in Mouse Models of Tuberculosis. EBioMedicine 2:868-73|
|Sullivan, Zuri A; Wong, Emily B; Ndung'u, Thumbi et al. (2015) Latent and Active Tuberculosis Infection Increase Immune Activation in Individuals Co-Infected with HIV. EBioMedicine 2:334-340|
|Dey, Bappaditya; Dey, Ruchi Jain; Cheung, Laurene S et al. (2015) A bacterial cyclic dinucleotide activates the cytosolic surveillance pathway and mediates innate resistance to tuberculosis. Nat Med 21:401-6|
|Pan, Shih-Jung; Tapley, Asa; Adamson, John et al. (2015) Biomarkers for Tuberculosis Based on Secreted, Species-Specific, Bacterial Small Molecules. J Infect Dis 212:1827-34|
|Winglee, Kathryn; Lun, Shichun; Pieroni, Marco et al. (2015) Mutation of Rv2887, a marR-like gene, confers Mycobacterium tuberculosis resistance to an imidazopyridine-based agent. Antimicrob Agents Chemother 59:6873-81|
|Hiruy, Hiwot; Rogers, Zoe; Mbowane, Chris et al. (2015) Subtherapeutic concentrations of first-line anti-TB drugs in South African children treated according to current guidelines: the PHATISA study. J Antimicrob Chemother 70:1115-23|
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