Tuberculosis (TB) and acquired immunodeficiency syndrome (AIDS) are diseases of exceptional public health significance. Their importance is further heightened by the global TB-AIDS co-pandemic. A co-infection with the respective etiologic agents, Mycobacterium tuberculosis (Mtb) and human immunodeficiency virus (HIV) alters the course of diseases caused by each infectious agent alone. Typically, only 10% of Mtb infections progress to clinically active TB in the absence of HIV. Instead, a controlled, long lasting asymptomatic infection, referred to as latent TB infection (LTBI), is established. Establishment of LTBI and the drivers of progression to active disease are not fully understood. Previously untried approaches are needed to move the field forward. In this application, we will take a new approach by demonstrating the key role of autophagy in maintaining the balance between LTBI and progression to active TB, and as a process targeted by the virus during HIV-Mtb co-infection. Autophagy is a newly recognized but nevertheless evolutionary ancient innate immunity mechanism that acts as a cell-autonomous defense against a variety of intracellular pathogens including Mtb. Our published work and studies by others indicate that autophagy, when appropriately induced, is a significant anti-Mtb cell- autonomous innate immunity defense. We propose that autophagy prevents progression to active disease and favors LTBI. The host-protective action is based on two effector functions of autophagy: first, it eliminates intracellulr Mtb, and, second, it suppresses pathogenic cytokine responses. In this project, we will test the hypothesis that autophagy maintains a host-protective state and prevents progression to active TB, whereas intrinsic host factors or HIV co-infection interfere with autophagy and promote clinically overt TB. If this hypothesis is correct, pharmacological targeting of autophagy and specific processes identified in this project will provide new prophylactic and treatment opportunities.
The specific aims of this application are:
Specific Aim 1. Determine whether and how HIV interferes with autophagic elimination of Mtb in co- infected macrophages. Mechanistically, we will define the role of the HIV protein Nef and its alleles from clinical HIV isolates and test their capacity to inhibit Beclin 1-dependent autophagy and suppress Mtb elimination in macrophages.
Specific Aim 2. Determine whether and how autophagy inhibits type I interferon (IFN) responses associated with progression to active disease. We will test whether autophagy prevents induction of type I IFN associated with active TB, and how this affects TB pathogenesis.
Specific Aim 3. Define whether and how cellular neutral lipid loads affect autophagic control of Mtb. To determine how intrinsic host factors (in the absence of HIV) influence autophagy's ability to maintain a host- protective state-i.e. the LTBI status-we will tes whether host cell lipid stores and imbalances in cellular lipid loads affect autophagic control of Mtb.

Public Health Relevance

Mycobacterium tuberculosis (Mtb) and human immunodeficiency virus (HIV) are pathogens of a paramount global significance. Mtb infects over 2 billion individuals, causes 2 million deaths every year, and multi-drug resistance makes it increasingly difficult to control. The incidence of active tuberculosis (TB), clinical presentation of TB, and TB treatment and prognosis are aggravated by HIV co-infection. We have described a new process, termed autophagy, which can kill both HIV and Mtb and is inherently present in every cell of our bodies. To unleash this newly-fund power, we need to understand how it works. The purpose of this project is to identify the key elements of how autophagy controls Mtb, and how host cell physiological status and HIV co-infection affect the ability of autophagy to eliminate Mtb. If we are successful, new therapies will be developed to pharmacologically induce autophagy and control TB. This is realistic because there are existing drugs that can be repurposed to activate autophagy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI111935-05
Application #
9422667
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Frank, Daniel J
Project Start
2014-03-01
Project End
2019-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
5
Fiscal Year
2018
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:
Claude-Taupin, Aurore; Jia, Jingyue; Mudd, Michal et al. (2017) Autophagy's secret life: secretion instead of degradation. Essays Biochem 61:637-647
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
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
Gupta, Anuradha; Misra, Amit; Deretic, Vojo (2016) Targeted pulmonary delivery of inducers of host macrophage autophagy as a potential host-directed chemotherapy of tuberculosis. Adv Drug Deliv Rev 102:10-20
Deretic, Vojo (2016) Autophagy in leukocytes and other cells: mechanisms, subsystem organization, selectivity, and links to innate immunity. J Leukoc Biol 100:969-978

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