Mycobacterium tuberculosis is responsible for millions of deaths annually, including a large proportion of HIV co-infected patients. The host defenses controlling M. tuberculosis remain to be fully delineated. Recently, several groups, including ours, have demonstrated that autophagic degradation is a major, previously unrecognized mechanism for elimination of intracellular microbes. Our work has shown that autophagy is a process that can inhibit intracellular survival of M. tuberculosis, and that in addition to pharmacological and physiological agonists, autophagy can be controlled by immunological means. Autophagy is a fundamental biological process defined as a cytoplasmic homeostasis pathway whereby cytoplasm portions become sequestered by membrane for delivery to lysosomes. This leads to removal of damaged or surplus organelles and turnover of stable, long-lived macromolecules. Autophagy has been previously implicated in both health-promoting and disease-associated states in cancer, neurodegeneration, development, and aging. Its recently demonstrated protective role in infectious diseases represents a previously unrecognized innate and adaptive immunity mechanism. Our long-term goals are to dissect the molecular mechanisms of autophagy in the context of elimination of M. tuberculosis during macrophage infection. Our main hypothesis is that induction of autophagy by pharmacological, physiological, and immunological means eliminates intracellular M. tuberculosis.
The specific aims of our proposal are: 1) Delineate autophagy pathways eliminating intracellular M. tuberculosis. This will be accomplished using macrophages derived from transgenic mice defective in a key autophagy gene, ATG5, and other recently developed molecular tools for autophagy investigations. 2) Define autophagy as an immunological effector of M. tuberculosis control. The focus will be on IFN-y and its downstream effectors modulating autopjiagy. 3) Determine how other known agonists and antagonists of mycobacterial intracellular survival affect autophagy and examine their mode of action in mechanistic studies. This project will delineate autophagic mechanisms that control intracellular M. tuberculosis, and show that autophagy can be induced and modulated by immunological and pharmacological means. Our studies will provide novel pharmacological and immunological approaches in treatment and prophylaxis of tuberculosis, with strong implications for immunity and infectious diseases in general.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI069345-05
Application #
7992442
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Parker, Tina M
Project Start
2006-12-15
Project End
2012-11-30
Budget Start
2010-12-01
Budget End
2012-11-30
Support Year
5
Fiscal Year
2011
Total Cost
$358,151
Indirect Cost
Name
University of New Mexico
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
868853094
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
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Korolchuk, Viktor I; Saiki, Shinji; Lichtenberg, Maike et al. (2011) Lysosomal positioning coordinates cellular nutrient responses. Nat Cell Biol 13:453-60

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