Mycobacterium tuberculosis has re-emerged over the last decade as an increasing health risk in inner cities and in immunocompromised individuals. The success of the pathogen is due in large part to its ability to infect and persist within the phagocytes of its host. Classical tuberculosis is the reactivation of a latent infection where the balance between the host and pathogen has apparently shifted in favor of the bacteria. This delicate interplay between Mycobacterium tuberculosis and its host is poorly understood yet it holds the key to the control of tuberculosis. The biology of the bacterium and its intracellular environment lie at the center of the transition from a dormant state to a fulminating infection. Although Mycobacterium does not show clear morphological differentiation during its life cycle we have found that its environment can markedly alter its pattern of protein synthesis, revealing distinctive sets of intracellular """"""""stasis"""""""" and """"""""growth"""""""" polypeptides. In this proposal we describe an integrated approach that will enable us to define the properties of the intramacrophage vacuole inhabited by M. tuberculosis and characterize the protein synthesis profiles of the intracellular """"""""stasis"""""""" and """"""""replicative"""""""" life cycle stages of the bacterium. This information will then be applied to understanding the biology of reactivation tuberculosis in a murine lung model. The development of the infection foci will be experimentally manipulated through the use of """"""""knockout"""""""" mice and modulation of the cellular immune response.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL055936-05
Application #
6056338
Study Section
Special Emphasis Panel (ZHL1-CSR-N (S1))
Project Start
1995-09-30
Project End
2000-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Washington University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Lee, Wonsik; VanderVen, Brian C; Walker, Suzanne et al. (2017) Novel protein acetyltransferase, Rv2170, modulates carbon and energy metabolism in Mycobacterium tuberculosis. Sci Rep 7:72
Tan, Shumin; Yates, Robin M; Russell, David G (2017) Mycobacterium tuberculosis: Readouts of Bacterial Fitness and the Environment Within the Phagosome. Methods Mol Biol 1519:333-347
VanderVen, Brian C; Huang, Lu; Rohde, Kyle H et al. (2016) The Minimal Unit of Infection: Mycobacterium tuberculosis in the Macrophage. Microbiol Spectr 4:
Liu, Yancheng; Tan, Shumin; Huang, Lu et al. (2016) Immune activation of the host cell induces drug tolerance in Mycobacterium tuberculosis both in vitro and in vivo. J Exp Med 213:809-25
Russell, David G (2016) The ins and outs of the Mycobacterium tuberculosis-containing vacuole. Cell Microbiol 18:1065-9
Tan, Shumin; Russell, David G (2015) Trans-species communication in the Mycobacterium tuberculosis-infected macrophage. Immunol Rev 264:233-48
Subbian, Selvakumar; Tsenova, Liana; Kim, Mi-Jeong et al. (2015) Lesion-Specific Immune Response in Granulomas of Patients with Pulmonary Tuberculosis: A Pilot Study. PLoS One 10:e0132249
Podinovskaia, Maria; Russell, David G (2015) Detection and quantification of microbial manipulation of phagosomal function. Methods Cell Biol 126:305-29
Sukumar, Neelima; Tan, Shumin; Aldridge, Bree B et al. (2014) Exploitation of Mycobacterium tuberculosis reporter strains to probe the impact of vaccination at sites of infection. PLoS Pathog 10:e1004394
Lee, Wonsik; VanderVen, Brian C; Fahey, Ruth J et al. (2013) Intracellular Mycobacterium tuberculosis exploits host-derived fatty acids to limit metabolic stress. J Biol Chem 288:6788-800

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