Tuberculosis (TB) is an infectious disease of paramount public health importance. TB is increasingly difficult to control due to the HIV syndemic and escalating resistance to antibiotics. The key aspects of TB pathogenesis include intracellular parasitism of the causative agent Mycobacterium tuberculosis (Mtb) and a pernicious balance between insidious, asymptomatic infection and progression to active disease. We have discovered that the process called autophagy can kill intracellular Mtb. At the time we reported this newly-found power of cells to rid themselves of intracellular microbes, autophagy was not viewed as an immunological process, but rather as a cytoplasmic quality control and nutritional pathway. Today, based on our work and work by others, autophagy is perceived as a general antibacterial and antiviral mechanism, with control of Mtb being one of the leading examples. Our latest findings show that autophagy also acts as a suppressor of excessive immune responses that can cause inflammatory pathology and uncontrolled tissue damage. We need to answer two principal questions before we can effectively harness the power of autophagy for treatment and prevention of TB. We need to define the molecular machinery that captures intracellular Mtb and delivers it for degradation in autophagic organelles. Furthermore, we need to know if and how autophagy prevents immune responses that may cause pathology and progression to active disease. This proposal will close these gaps in our knowledge. The following are the specific aims of this proposal:
Specific Aim 1. Define the cell-autonomous mechanism of autophagic elimination of Mtb. We will identify the autophagic pattern recognition receptors that recognize Mtb and deliver it to autophagosomes. We will test the hypothesis that IRGM, a genetic risk factor for TB and an enigmatic autophagy regulator, functions as a receptor recognizing the bacteria and orchestrates autophagy of Mtb. Furthermore, we will test a hypothesis that HIV co-infection influences the anti-Mtb action of IRGM.
Specific Aim 2. Delineate the role of autophagy in preventing endogenous inflammation and pathogenic cytokine responses during Mtb infection. We will test the hypothesis that autophagy inhibits progression to active disease by preventing excessive inflammation and tissue damage.

Public Health Relevance

Tuberculosis remains an utmost public health concern globally and-based on recent and past outbreaks- domestically as well. Escalating public health threats include a relentless global increase in multi-drug- resistance, emergence of extremely-drug-resistant, and even totally-drug-resistant Mycobacterium tuberculosis, the causative agent of tuberculosis. The co-epidemic of tuberculosis and HIV/AIDS further adds complexity to public health control. In this proposal, we seek to harness the powerful process called autophagy, present in every cell in the body. We have recently discovered that, not only does autophagy clear the intracellular bacteria, but it also protects against M. tuberculosis activities that cause the highly transmissibe clinical disease. To unleash this internal power that our cells possess, we will identify specific proteins and processes carrying out autophagic elimination of M. tuberculosis and suppressing active disease. This will enable us to develop new autophagy-based therapies and drugs to treat tuberculosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI042999-17
Application #
8724799
Study Section
Special Emphasis Panel ()
Program Officer
Lacourciere, Karen A
Project Start
1998-04-10
Project End
2018-03-31
Budget Start
2014-04-10
Budget End
2015-03-31
Support Year
17
Fiscal Year
2014
Total Cost
$399,998
Indirect Cost
$133,623
Name
University of New Mexico Health Sciences Center
Department
Genetics
Type
Schools of Medicine
DUNS #
829868723
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Mandell, Michael A; Jain, Ashish; Kumar, Suresh et al. (2016) TRIM17 contributes to autophagy of midbodies while actively sparing other targets from degradation. J Cell Sci 129:3562-3573
Chauhan, Santosh; Kumar, Suresh; Jain, Ashish et al. (2016) TRIMs and Galectins Globally Cooperate and TRIM16 and Galectin-3 Co-direct Autophagy in Endomembrane Damage Homeostasis. Dev Cell 39:13-27
Kimura, Tomonori; Mandell, Michael; Deretic, Vojo (2016) Precision autophagy directed by receptor regulators - emerging examples within the TRIM family. J Cell Sci 129:881-91
Deretic, Vojo (2016) Autophagy in leukocytes and other cells: mechanisms, subsystem organization, selectivity, and links to innate immunity. J Leukoc Biol 100:969-978
Chauhan, Santosh; Ahmed, Zahra; Bradfute, Steven B et al. (2015) Pharmaceutical screen identifies novel target processes for activation of autophagy with a broad translational potential. Nat Commun 6:8620
Deretic, Vojo; Kimura, Tomonori; Timmins, Graham et al. (2015) Immunologic manifestations of autophagy. J Clin Invest 125:75-84
Ponpuak, Marisa; Mandell, Michael A; Kimura, Tomonori et al. (2015) Secretory autophagy. Curr Opin Cell Biol 35:106-16
Chauhan, Santosh; Mandell, Michael A; Deretic, Vojo (2015) IRGM governs the core autophagy machinery to conduct antimicrobial defense. Mol Cell 58:507-21
Kimura, Tomonori; Jain, Ashish; Choi, Seong Won et al. (2015) TRIM-mediated precision autophagy targets cytoplasmic regulators of innate immunity. J Cell Biol 210:973-89
Rubinsztein, David C; Bento, Carla F; Deretic, Vojo (2015) Therapeutic targeting of autophagy in neurodegenerative and infectious diseases. J Exp Med 212:979-90

Showing the most recent 10 out of 79 publications