The outcome of Mycobacterium tuberculosis (Mtb) infection depends on host?s immune, metabolic and tissue- protective responses. Autophagy is a process that contributes to all three aspects of protection against tuberculosis (TB). The effectiveness or failure of autophagy and related processes is of direct relevance for central issues in TB. These include collusion between tuberculosis and HIV, immunometabolism and metabolic dysregulation in diabetes, tissue damage in the lung or other organs such as the central nervous system, and chronic pulmonary impairment or acute conditions following completion of chemotherapy. This project intends to define the role of autophagy and associated processes in active TB, TB latency, HIV- TB interactions, cellular metabolism, and as a cell/tissue-protective mechanism. Specifically, in this renewal application we will delineate how autophagy and related processes marshal metabolic and cytoprotective responses against Mtb in active and latent infection. While defining these relationships in the context of TB, we will uncover fundamental mechanisms of significance for diverse health and pathological states of both basic and translational value in TB. Based on our latest findings, we propose to focus on the endomembrane damage inflicted by Mtb in infected macrophages, as a trigger of cascading immunopathological and immunometabolic changes in the host. We refer to this set of cellular responses as membrane repair, removal and replacement (MERET). Autophagy is a key aspect of MERET, but MERET also includes immunometabolic switching, of relevance for tissue protection vs. pathogenesis, and for active TB disease vs. latency.
The specific aims are:
Aim 1 Define the in vivo role of key autophagy factors in protection against Mtb.
This aim will focus on the role of the sole integral membrane autophagy (ATG) factor, ATG9, as the ultimate test of the role of autophagic membranes in protection against active or latent TB. We will use murine models of acute and chronic Mtb infection to test whether autophagy prevents or favors transitions to latent infection.
Aim 2. Determine the roles of TBK1 and ATG9 during critical stages of autophagy. We will focus on ATG9 and TBK1 and how these factors contribute to cytoplasmic homeostasis and protection against Mtb. Points of HIV interference will be tested.
Aim 3, Define host cell responses to endomembrane damage associated with Mtb infection. We will focus on endomembrane damage, an intriguing but poorly understood phenomenon occurring during Mtb infection of macrophages. We will test the hypothesis that host cell membrane damage caused by Mtb is a critical determinant of autophagic and immunometabolic control of TB.

Public Health Relevance

Tuberculosis remains of paramount public health concern globally and?based on recurring outbreaks? domestically. 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 is a continuing threat. However, a new risk factor has emerged globally ? diabetes, tripling the risk of tuberculosis and worsening the clinical course of TB. This reflects enduring connections between metabolism, tuberculosis and disnutrition, with malnutrition and obesity as it ?bookends?. Here, we seek to harness the powerful metabolic and quality control process called autophagy, present in every cell in our bodies. We discovered a new dimension of autophagic responses linked to metabolic switching of key relevance for TB. To capitalize on this new knowledge and opportunity for eventual intervention, we need to identify specific targets and processes, which is the goal of our project. This will enable us to develop new therapies and nutritional approaches to treat and control tuberculosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI111935-06
Application #
9769998
Study Section
HIV Coinfections and HIV Associated Cancers Study Section (HCAC)
Program Officer
Frank, Daniel J
Project Start
2014-03-01
Project End
2024-02-29
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
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
Kumar, Suresh; Jain, Ashish; Farzam, Farzin et al. (2018) Mechanism of Stx17 recruitment to autophagosomes via IRGM and mammalian Atg8 proteins. J Cell Biol 217:997-1013
Claude-Taupin, Aurore; Bissa, Bhawana; Jia, Jingyue et al. (2018) Role of autophagy in IL-1? export and release from cells. Semin Cell Dev Biol 83:36-41
Jia, Jingyue; Abudu, Yakubu Princely; Claude-Taupin, Aurore et al. (2018) Galectins Control mTOR in Response to Endomembrane Damage. Mol Cell 70:120-135.e8
Choi, Seong Won; Gu, Yuexi; Peters, Ryan Scott et al. (2018) Ambroxol Induces Autophagy and Potentiates Rifampin Antimycobacterial Activity. Antimicrob Agents Chemother 62:
Kimura, Tomonori; Jain, Ashish; Choi, Seong Won et al. (2017) TRIM-directed selective autophagy regulates immune activation. Autophagy 13:989-990
Kimura, Tomonori; Jia, Jingyue; Kumar, Suresh et al. (2017) Dedicated SNAREs and specialized TRIM cargo receptors mediate secretory autophagy. EMBO J 36:42-60
Claude-Taupin, Aurore; Jia, Jingyue; Mudd, Michal et al. (2017) Autophagy's secret life: secretion instead of degradation. Essays Biochem 61:637-647
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
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222

Showing the most recent 10 out of 25 publications