Induction of autophagy through CLEC4E in combination with TLR4: an innovative strategy to restrict the survival of <i>Mycobacterium tuberculosis</i>

Pahari, Susanta; Negi, Shikha; Aqdas, Mohammad; Arnett, Eusondia; Schlesinger, Larry S.; Agrewala, Javed N.

doi:10.1080/15548627.2019.1658436

Cited by 71 publications

(56 citation statements)

References 93 publications

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“…Single cell suspension obtained from lungs, spleen and lymph nodes of vaccinated animals (2 × 10 5 /well) were added to 96 well U-bottom culture plates and cultured with Mtb-specific purified protein derivative (PPD; 20 µg/ml) or L91 (1 nmol) for 48 h at 37 • C/5% CO 2 (14,15). Later, these cells were harvested and used for immunological phenotype assessment using flow cytometer and cytokine estimation by ELISA in culture supernatants.…”

Section: In Vitro Stimulation With Antigenmentioning

confidence: 99%

Gut Dysbiosis Thwarts the Efficacy of Vaccine Against Mycobacterium tuberculosis

et al. 2020

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The generation of enduring protective immunity by vaccines is of utmost importance. Intriguingly, there is considerable variation in the efficacy of vaccines amongst individuals. Various studies have shown that normal flora of gastrointestinal tract plays a vital role in maintaining host homeostasis and immunity. Since gut microbiome is also extremely variable between individuals, we speculate that it might impact individual's response to vaccines. Consequently, we administered broad spectrum antibiotics cocktail to induce gut dysbiosis and monitored its impact on the generation of longlasting memory T cells and thereby BCG vaccine efficacy. Interestingly, gut dysbiosis significantly decreased the activation of CD4 + T cells and CD8 + T cells. Further, there was decline in the frequency of memory CD4 + T cells and CD8 + T cells in lungs and secondary lymphoid organs of the vaccinated animals. Moreover, it dampened the IFN-γ and TNF-α secretion and proliferation of Mtb-specific T cells. Most importantly, dysbiosis hampered Mtb clearance in vaccinated animals, as evidenced by increase in the colony forming units (CFUs) in lungs and spleen. Our findings indicate that gut dysbiosis can be one of the major factors responsible for variable efficacy of TB vaccines across the world.

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Section: In Vitro Stimulation With Antigenmentioning

confidence: 99%

Gut Dysbiosis Thwarts the Efficacy of Vaccine Against Mycobacterium tuberculosis

et al. 2020

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“…List of abbreviations AMBT -antimycobacterial treatment CD -Cluster of Differentiation /CD antigens DNA -deoxyribonucleic acid EDTA -ethylene diamine tetraacetic acid IP -intensive phase MTB -Mycobacterium tuberculosis PS -phosphatidylserine TB -tuberculosis 7AAD -7-aminoactinomycin understanding of cell death in TB patients, as a chance to improve safety and efficacy of antimycobacterial treatment (AMBT) [12][13][14] . The creation of host-directed treatment regimen is gaining considerable interest, because of the emergence of drug-resistant strains of MTB as response to the standard therapy.…”

Section: Introductionmentioning

confidence: 99%

Study of cell death and stages of leukocytes apoptosis in pulmonary tuberculosis patients with different antimycobacterial treatments

Шевченко¹,

Наконечна²,

Тодоріко³

et al. 2019

Arch Balk Med Union

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L'étude des types de la mort cellulaire et les stades de l'apoptose des leucocytes chez les patients atteints de la tuberculose pulmonaire aux différents programmes de traitement antimycobactérien L'objectif. D'évaluer l'état des membranes cytoplasmiques des leucocytes et étudier leur viabilité, déterminer les variétés et les stades de la mort cellulaire des leucocytes chez des patients avec tuberculose pulmonaire traités par différents schémas de traitement antimycobactérien. Matériaux et méthodes. L'étude a été réalisée sur 30 patients atteints de tuberculose pulmonaire: 1er groupe-12 patients traités par un schéma thérapeutique standard avec des médicaments en ligne; 2-ème groupe-patients traités individuellement avec les médicaments de la gamme I et II. Le groupe témoin comprenait 12 donneurs en bonne santé. L'étude a été réalisée par la cytométrie en flux sur un cytomètre en

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“…Immune pathways specific to autophagy inhibition include: Fc receptor (FcR) signaling, Toll-like receptor (TLR) signaling, T cell receptor (TCR) signaling, c-type lectin receptor (CLR) signaling and chemokine signaling pathways ( Supplementary Table S6). It has been reported that stimulation of TLRs, FcRs, TCRs, and CLRs can induce autophagy [82,83]. We thus hypothesize that the mechanism of action of selected autophagy inhibitors is through blockage of these pathways.…”

Section: Functional Analysis Of the Targets Reveals Enriched Pathwaysmentioning

confidence: 84%

Mechanisms of Action of Autophagy Modulators Dissected by Quantitative Systems Pharmacology Analysis

Shi

Pei

Perlmutter

et al. 2020

Preprint

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Autophagy plays an essential role in cell survival/death and functioning. Modulation of autophagy has been recognized as a promising therapeutic strategy against diseases/disorders associated with uncontrolled growth or accumulation of biomolecular aggregates, organelles or cells including those caused by cancer, aging, neurodegeneration, and liver diseases such as α1antitrypsin deficiency. Numerous pharmacological agents that enhance or suppress autophagy have been discovered. However, their molecular mechanisms of action are far from clear. Here we collected a set of 225 autophagy modulators and carried out a comprehensive quantitative systems pharmacology (QSP) analysis of their targets using both existing databases and predictions made by our machine learning algorithm. Autophagy modulators include several highly promiscuous drugs (e.g. artenimol and olanzapine acting as activator, fostamatinib as inhibitor, or melatonin as dual-modulator), as well as selected drugs uniquely targeting specific proteins (~30% of modulators). They are mediated by three layers of regulation: (i) pathways involving core autophagy-related (ATG) proteins such as mTOR, AKT, and AMPK; (ii) upstream signaling events that regulates the activity of ATG pathways such as calcium-, cAMP-, and MAPK-signaling pathways; and (iii) transcription factors regulating the expression ATG proteins such as TFEB, TFE3, HIF-1, FoxO, and NF-κB. Our results suggest that PKA serves as a linker bridging between various signal transduction events and autophagy. These new insights contribute to a better assessment of the mechanism of action of autophagy modulators as well as their side effects, development of novel polypharmacological strategies, and identification of drug repurposing opportunities.

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Induction of autophagy through CLEC4E in combination with TLR4: an innovative strategy to restrict the survival of Mycobacterium tuberculosis

Cited by 71 publications

References 93 publications

Gut Dysbiosis Thwarts the Efficacy of Vaccine Against Mycobacterium tuberculosis

Gut Dysbiosis Thwarts the Efficacy of Vaccine Against Mycobacterium tuberculosis

Study of cell death and stages of leukocytes apoptosis in pulmonary tuberculosis patients with different antimycobacterial treatments

Mechanisms of Action of Autophagy Modulators Dissected by Quantitative Systems Pharmacology Analysis

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