A major challenge facing global tuberculosis (TB) eradication efforts is the fact that two billion people are latently infected with Mycobacterium tuberculosis (Mtb), many of whom, especially in the setting of HIV co-infection, will develop reactivation disease. Efforts to gain insight into the molecular mechanisms by which Mtb persists in the host have been impeded by the lack of adequate research models and molecular tools. Current research has focused on identifying individual Mtb genes or host factors required for TB latency and reactivation in specific models and inferring their relevance for TB latency and reactivation in humans. The central hypothesis of this proposal is that no single host or microbial pathway is responsible for Mtb entry into or emergence from latency, but rather, that these complex phenomena are attributable to multiple interdependent host and mycobacterial molecular networks, which cannot be deduced from any one particular model. Using a systems biology approach, including several novel animal models of latent TB infection in combination with transcriptional, proteomic, genetic, imaging, and computational techniques, followed by experimental verification of the data using human samples, we will identify host cytokine networks responsible for immunological control of Mtb growth, as well as Mtb regulatory and metabolic pathways required for bacillary growth restriction and reactivation. Our data are expected to yield: 1) Novel potential drug targets for nonreplicating bacilli, with the goal of shortening the duration of TB chemotherapy;2) Novel diagnostic markers specific to the latent stage of infection and to reactivation disease;and 3) Novel attenuated vaccine candidates with an inability to reactivate, which would be particularly important in the setting of HIV/AIDS.

Public Health Relevance

Antibiotic treatment for TB requires at least 6 months of therapy because the germs that cause TB can go "dormant" in the infected host, becoming very difficult to kill with currently available drugs, which kill dividing bacteria. In this proposal, we plan to use a multidisciplinary approach to uncover some of the important mechanisms that lead TB germs to stop dividing and to start growing again when the immune system weakens. Our results are expected to yield new drug targets to shorten the time it takes to cure TB, as well as new vaccine candidates and diagnostic tests for different stages of the infection.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL106786-04
Application #
8525429
Study Section
Special Emphasis Panel (ZHL1-CSR-Z (S1))
Program Officer
Peavy, Hannah H
Project Start
2010-09-17
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2013
Total Cost
$716,068
Indirect Cost
$230,136
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Dutta, Noton K; Karakousis, Petros C (2014) PA-824 is as effective as isoniazid against latent tuberculosis infection in C3HeB/FeJ mice. Int J Antimicrob Agents 44:564-6
Rifat, Dalin; Karakousis, Petros C (2014) Differential regulation of the two-component regulatory system senX3-regX3 in Mycobacterium tuberculosis. Microbiology 160:1125-33
Dutta, Noton K; Illei, Peter B; Jain, Sanjay K et al. (2014) Characterization of a novel necrotic granuloma model of latent tuberculosis infection and reactivation in mice. Am J Pathol 184:2045-55
Dutta, Noton K; Bandyopadhyay, Nirmalya; Veeramani, Balaji et al. (2014) Systems biology-based identification of Mycobacterium tuberculosis persistence genes in mouse lungs. MBio 5:
Dutta, Noton K; Pinn, Michael L; Karakousis, Petros C (2014) Reduced emergence of isoniazid resistance with concurrent use of thioridazine against acute murine tuberculosis. Antimicrob Agents Chemother 58:4048-53
Dutta, Noton K; Karakousis, Petros C (2014) Latent tuberculosis infection: myths, models, and molecular mechanisms. Microbiol Mol Biol Rev 78:343-71
Skerry, Ciaran; Pinn, Michael L; Bruiners, Natalie et al. (2014) Simvastatin increases the in vivo activity of the first-line tuberculosis regimen. J Antimicrob Chemother 69:2453-7
Chuang, Yu-Min; Belchis, Deborah A; Karakousis, Petros C (2013) The polyphosphate kinase gene ppk2 is required for mycobacterium tuberculosis inorganic polyphosphate regulation and virulence. MBio 4:e00039-13
Klinkenberg, Lee G; Karakousis, Petros C (2013) Rv1894c is a novel hypoxia-induced nitronate monooxygenase required for Mycobacterium tuberculosis virulence. J Infect Dis 207:1525-34
Zhou, Aiping; Ni, Jinjing; Xu, Zhihong et al. (2013) Application of (1)h NMR spectroscopy-based metabolomics to sera of tuberculosis patients. J Proteome Res 12:4642-9

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