A third of the world's population is infected with Mycobacterium tuberculosis (MTB) and most of these infections are in a latent state. Tubercle bacilli can remain inactive in lung lesions only to emerge decades later as new outbreaks of tuberculosis. Current therapy for tuberculosis often involves the administration of multiple antimicrobial agents over several months, probably because bacilli exist in a drug tolerant, dormant-like state in tubercle lesions. Understanding the physiology of bacilli during the latent infection phase is central to the goal of controlling and ultimately eradicating tuberculosis. We have demonstrated that as aerobic respiration is impeded (by reduced oxygen or by the presence of nitric oxide), bacilli strongly induce a co-regulated 48-gene genetic program called the """"""""dormancy regulon"""""""". This regulon encodes a program required for adaptation to a long-term viable """"""""dormant"""""""" or non-proliferating state. Bacillus survival during an anaerobic non-proliferating state requires conservation of energy, alternative mechanisms to maintain redox balance, and mechanisms to protect DNA and proteins. Our working hypothesis is: The dormancy regulon is a genetic program that confers survival to MTB during latency. To test this hypothesis we will investigate key aspects of dormant MTB that involve the role of dormancy regulon proteins in nucleotide and nucleic acid biology during dormancy. The research proposed herein is pivotal to understanding how the tubercle bacillus survives indefinitely during latent infection, and characterizes numerous candidate targets for drug development. This study compliments a collaboration with the Russian Research Center for Molecular Diagnostics and Therapy. A joint proposal will be submitted to the US Department of Health and Human Services Biotechnology Engagement Program that will address aspects of dormant MTB in human infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI061505-01A1
Application #
6979854
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Jacobs, Gail G
Project Start
2005-06-01
Project End
2010-02-28
Budget Start
2005-06-01
Budget End
2006-02-28
Support Year
1
Fiscal Year
2005
Total Cost
$308,133
Indirect Cost
Name
University of Colorado Denver
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Reichlen, Matthew J; Leistikow, Rachel L; Scobey, Micah S et al. (2017) Anaerobic Mycobacterium tuberculosis Cell Death Stems from Intracellular Acidification Mitigated by the DosR Regulon. J Bacteriol 199:
Ofori-Anyinam, Boatema; Dolganov, Gregory; Van, Tran et al. (2017) Significant under expression of the DosR regulon in M. tuberculosis complex lineage 6 in sputum. Tuberculosis (Edinb) 104:58-64
Bartek, I L; Reichlen, M J; Honaker, R W et al. (2016) Antibiotic Bactericidal Activity Is Countered by Maintaining pH Homeostasis in Mycobacterium smegmatis. mSphere 1:
Garcia, Benjamin J; Loxton, Andre G; Dolganov, Gregory M et al. (2016) Sputum is a surrogate for bronchoalveolar lavage for monitoring Mycobacterium tuberculosis transcriptional profiles in TB patients. Tuberculosis (Edinb) 100:89-94
Walter, Nicholas D; de Jong, Bouke C; Garcia, Benjamin J et al. (2016) Adaptation of Mycobacterium tuberculosis to Impaired Host Immunity in HIV-Infected Patients. J Infect Dis 214:1205-11
Walter, Nicholas D; Dolganov, Gregory M; Garcia, Benjamin J et al. (2015) Transcriptional Adaptation of Drug-tolerant Mycobacterium tuberculosis During Treatment of Human Tuberculosis. J Infect Dis 212:990-8
Voskuil, Martin I; Schlesinger, Larry S (2015) Toward Resolving the Paradox of the Critical Role of the DosR Regulon in Mycobacterium tuberculosis Persistence and Active Disease. Am J Respir Crit Care Med 191:1103-5
Irwin, Scott M; Gruppo, Veronica; Brooks, Elizabeth et al. (2014) Limited activity of clofazimine as a single drug in a mouse model of tuberculosis exhibiting caseous necrotic granulomas. Antimicrob Agents Chemother 58:4026-34
Bartek, I L; Woolhiser, L K; Baughn, A D et al. (2014) Mycobacterium tuberculosis Lsr2 is a global transcriptional regulator required for adaptation to changing oxygen levels and virulence. MBio 5:e01106-14
Tischler, Anna D; Leistikow, Rachel L; Kirksey, Meghan A et al. (2013) Mycobacterium tuberculosis requires phosphate-responsive gene regulation to resist host immunity. Infect Immun 81:317-28

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