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Rapid One-step Enzymatic Synthesis and All-aqueous Purification of Trehalose Analogues
Published on: February 17, 2017
Trehalose limits opportunistic mycobacterial survival during HIV co-infection by reversing HIV-mediated autophagy
Vartika Sharma1, Muzamil Makhdoomi2, Lakshyaveer Singh1
1Cellular Immunology Group, International Center for Genetic Engineering and Biotechnology, New Delhi, India.
Abstract:
Opportunistic bacterial infections amongst HIV-infected individuals contribute significantly to HIV-associated mortality. The role of HIV-mediated modulation of innate mechanisms like autophagy in promoting opportunistic infections, however, remains obscure. Here we show, HIV reactivation in or infection of macrophages inhibits autophagy and helps the survival of pathogenic Mycobacterium tuberculosis (Mtb) and nonpathogenic non-tuberculous mycobacterial strains (NTMs). The HIV-mediated impairment of xenophagy flux facilitated bacterial survival. Activation of autophagy by trehalose could induce xenophagy flux and kill intracellular Mtb or NTMs either during single or co-infections. Trehalose, we delineate, activates PIKFYVE leading to TFEB nuclear translocation in MCOLN1-dependent manner to induce autophagy. Remarkably, trehalose significantly reduced HIV-p24 levels in ex-vivo-infected PBMCs or PBMCs from treatment-naive HIV patients and also controlled mycobacterial survival within Mtb-infected animals. To conclude, we report leveraging of HIV-mediated perturbed host innate-immunity by opportunistic bacterial pathogens and show an attractive therapeutic strategy for HIV and associated co-morbidities.Abbreviations: AIDS: acquired immune deficiency syndrome; AMPK: AMP-activated protein kinase; ATG5: autophagy related 5; BafA1: bafilomycin A1; CFU: colony forming unit; CTSD: cathepsin D; CD63: CD63 molecule; EGFP: enhanced green fluorescent protein; FRET: Förster resonance energy transfer; GABARAP: gamma-aminobutyric acid receptor-associated protein; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; GLUT: glucose transporter; HIV: human immunodeficiency virus; hMDMs: human monocyte derived macrophages; IL2: interleukin 2; LAMP1: lysosomal-associated membrane protein 1; LC3B-II: lipidated microtubule-associated proteins 1A/1B light chain 3B; Mtb: Mycobacterium tuberculosis; MTOR: mechanistic target of rapamycin; mRFP: monomeric red fluorescent protein; M6PR: mannose-6-phosphate receptor; NAC: N- acetyl- L -cysteine; NTM's: non-tuberculous mycobacteria; PBMC: Peripheral Blood Mononuclear cells; PIKFYVE: phosphoinositide kinase; FYVE-Type Zinc Finger; PHA: phytohemagglutinin; PMA: phorbol 12-myristate 13-acetate; PtdIns(3,5)P2: Phosphatidylinositol 3,5-bisphosphate; ptfLC3: pEGFP-mRFP-LC3; ROS: reactive oxygen species; SQSTM1: sequestosome1; TFEB: transcription factor EB; MCOLN1/TRPML1: mucolipin 1; PIP4P1/TMEM55B: Human trans-membrane Protein 55B; UVRAG: UV Radiation Resistance Associate; VPS35: vacuolar protein sorting associated protein 35; WDR45: WD repeat domain 45; YCAM: Yellow Chameleon.
Insights
Human immunodeficiency virus (HIV) infection impairs autophagy, aiding opportunistic mycobacterial infections. Trehalose activates autophagy, killing bacteria and reducing HIV levels, offering a new therapy for HIV-associated comorbidities.
Area of Science:
- Immunology
- Microbiology
- Cell Biology
Background:
- Opportunistic bacterial infections significantly increase mortality in individuals with human immunodeficiency virus (HIV).
- The precise mechanisms by which HIV affects innate immunity, particularly autophagy, in promoting these infections are not fully understood.
Purpose of the Study:
- To investigate how HIV modulates autophagy and its impact on the survival of mycobacterial pathogens.
- To explore trehalose as a therapeutic agent to restore autophagy and combat HIV and co-infections.
Main Methods:
- Examined the effect of HIV infection/reactivation on macrophage autophagy and mycobacterial survival.
- Assessed the efficacy of trehalose in activating autophagy, enhancing xenophagy flux, and controlling intracellular mycobacteria.
- Investigated the molecular pathway of trehalose-induced autophagy activation (PIKFYVE, TFEB, MCOLN1).
- Evaluated trehalose's impact on HIV-p24 levels in patient-derived cells and mycobacterial control in animal models.
Main Results:
- HIV infection/reactivation in macrophages inhibits autophagy, promoting the survival of Mycobacterium tuberculosis (Mtb) and non-tuberculous mycobacteria (NTMs).
- Trehalose activates autophagy via PIKFYVE and TFEB, restoring xenophagy flux and killing intracellular Mtb/NTMs.
- Trehalose significantly reduced HIV-p24 levels in ex-vivo infected PBMCs and PBMCs from HIV patients, and controlled Mtb in vivo.
Conclusions:
- Opportunistic bacterial pathogens exploit HIV-induced defects in host innate immunity.
- Trehalose represents a promising therapeutic strategy to simultaneously address HIV and associated mycobacterial co-infections by restoring autophagy.
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