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.
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.
|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|
|Kumar, Suresh; Chauhan, Santosh; Jain, Ashish et al. (2017) Galectins and TRIMs directly interact and orchestrate autophagic response to endomembrane damage. Autophagy 13:1086-1087|
|Kimura, Tomonori; Jia, Jingyue; Claude-Taupin, Aurore et al. (2017) Cellular and molecular mechanism for secretory autophagy. Autophagy 13:1084-1085|
|Galluzzi, Lorenzo; Baehrecke, Eric H; Ballabio, Andrea et al. (2017) Molecular definitions of autophagy and related processes. EMBO J 36:1811-1836|
|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|
|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|
Showing the most recent 10 out of 94 publications