The exploitation of host autophagy and ubiquitin machinery by Mycobacterium tuberculosis in shaping immune responses and host defense during infection

Autophagy, Journal Year: 2022, Volume and Issue: 19(1), P. 3 - 23

Published: Jan. 9, 2022

Intracellular pathogens have evolved various efficient molecular armaments to subvert innate defenses. Cellular ubiquitination, a normal physiological process maintain homeostasis, is emerging one such exploited mechanism. Ubiquitin (Ub), small protein modifier, conjugated diverse substrates regulate many functions. Structurally linkages of poly-Ub target proteins allow enormous functional diversity with specificity being governed by evolutionarily conserved enzymes (E3-Ub ligases). The Ub-binding domain (UBD) and LC3-interacting region (LIR) are critical features macroautophagy/autophagy receptors that recognize Ub-conjugated on substrates. Emerging evidence suggests E3-Ub ligases unexpectedly protect against intracellular tagging their surfaces targeting them phagophores. Two ligases, PRKN SMURF1, provide immunity Mycobacterium tuberculosis (M. tb). Both conjugate K63 K48-linked M. tb for successful delivery Intriguingly, exploits virulence factors effectively dampen host-directed autophagy utilizing mechanisms. Autophagy contain LIR-motifs interact Atg8-family modulate phagophore biogenesis fusion the lysosome. vast repertoire effectors subdue host-immunity via hijacking host ubiquitination process. This review highlights xenophagy-mediated clearance involving counter-strategy inhibition using factors. role mode regulation also explained. We discuss co-opting utilization Ub system its survival virulence.

Language: Английский

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M. tuberculosis PknG manipulates host autophagy flux to promote pathogen intracellular survival

Autophagy, Journal Year: 2021, Volume and Issue: 18(3), P. 576 - 594

Published: June 7, 2021

The eukaryotic-type protein kinase G (PknG), one of the eleven eukaryotic type serine-threonine (STPK) in Mycobacterium tuberculosis (Mtb), is involved mycobacterial survival within macrophages, presumably by suppressing phagosome and autophagosome maturation, which makes PknG an attractive drug target. However, exact mechanism inhibits pathogen clearance during infection remains largely unknown. Here, we show that promotes macroautophagy/autophagy induction but causing overall effect blocked autophagy flux enhanced intracellular survival. prevents activation AKT (AKT serine/threonine kinase) via competitively binding to its pleckstrin homology (PH) domain, leading induction. Remarkably, could also inhibit maturation block targeting host small GTPase RAB14. Specifically, directly interacts with RAB14 RAB14-GTP hydrolysis. Furthermore, phosphorylates TBC1D4/AS160 (TBC1 domain family member 4) suppress GTPase-activating (GAP) activity toward In macrophages vivo, Mtb through blocking flux, dependent on Taken together, our data unveil a dual-functional bacterial effector tightly regulates benefit survival.Abbreviations: AKT: kinase; ATG5: related 5; BMDMs: bone marrow-derived macrophages; DTT: dithiothreitol; FBS: fetal calf serum; GAP: protein; MOI: multiplicity infection; Mtb: tuberculosis; MTOR: mechanistic target rapamycin OADC: oleic acid-albumin-dextrose-catalase; PC, phosphatidylcholine; PH: homology; PI3K: phosphoinositide 3-kinase; PknG: G; PtdIns(3,4,5)P3: phosphatidylinositol(3,4,5)-trisphosphate; SQSTM1: sequestosome 1; STPK: TB: TBC1D4: TBC1 4; TPR: tetratricopeptide repeat; ULK1: unc-51 like activating WT: wild-type.

Language: Английский

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Positive Aspects of Oxidative Stress at Different Levels of the Human Body: A Review

Antioxidants, Journal Year: 2022, Volume and Issue: 11(3), P. 572 - 572

Published: March 17, 2022

Oxidative stress is the subject of numerous studies, most them focusing on negative effects exerted at both molecular and cellular levels, ignoring possible benefits free radicals. More more people admit to having heard term "oxidative stress", but few understand meaning it. We summarized analyzed published literature data in order emphasize importance adaptation mechanisms basal oxidative stress. This review aims provide an overview underlying positive stress, highlighting these effects, as well risks for population consuming higher doses than recommended daily intake antioxidants. The biological dose-response curve unpredictable reactive species are clearly responsible degradation, whereas antioxidant therapies can alleviate senescence by maintaining redox balance; nevertheless, excessive latter modify balance cell, leading a outcome. It be stated that presence status or physiological condition with well-defined roles, yet have been insufficiently researched explored. involvement oxygen pathophysiology some associated diseases well-known processes senescence, apoptosis, autophagy, maintenance homeostasis cannot denied. All this support idea undesirable phenomenon high long-term concentrations, regular exposure consistent hormetic theory.

Language: Английский

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From immunology to artificial intelligence: revolutionizing latent tuberculosis infection diagnosis with machine learning

Military Medical Research, Journal Year: 2023, Volume and Issue: 10(1)

Published: Nov. 28, 2023

Latent tuberculosis infection (LTBI) has become a major source of active (ATB). Although the tuberculin skin test and interferon-gamma release assay can be used to diagnose LTBI, these methods only differentiate infected individuals from healthy ones but cannot discriminate between LTBI ATB. Thus, diagnosis faces many challenges, such as lack effective biomarkers Mycobacterium (MTB) for distinguishing low diagnostic efficacy derived human host, absence gold standard Sputum culture, diagnosing tuberculosis, is time-consuming distinguish ATB LTBI. In this article, we review pathogenesis MTB immune mechanisms host in including innate adaptive responses, multiple evasion MTB, epigenetic regulation. Based on knowledge, summarize current status challenges present application machine learning (ML) diagnosis, well advantages limitations ML context. Finally, discuss future development directions applied diagnosis.

Language: Английский

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In silico design of a promiscuous chimeric multi-epitope vaccine against Mycobacterium tuberculosis

Computational and Structural Biotechnology Journal, Journal Year: 2023, Volume and Issue: 21, P. 991 - 1004

Published: Jan. 1, 2023

Tuberculosis (TB) is a global health threat, killing approximately 1.5 million people each year. The eradication of Mycobacterium tuberculosis, the main causative agent TB, increasingly challenging due to emergence extensive drug-resistant strains. Vaccination considered an effective way protect host from pathogens, but only clinically approved TB vaccine, Bacillus Calmette-Guérin (BCG), has limited protection in adults. Multi-epitope vaccines have been found enhance immunity diseases by selectively combining epitopes several candidate proteins. This study aimed design multi-epitope vaccine against using immuno-informatics approach. Through functional enrichment, we identified eight proteins secreted M. tuberculosis that are either required for pathogenesis, into extracellular space, or both. We then analyzed these and selected 16 helper T lymphocyte with interferon-γ inducing activity, 15 cytotoxic epitopes, 10 linear B-cell conjugated them adjuvant Pan HLA DR-binding epitope (PADRE) appropriate linkers. Moreover, predicted tertiary structure this its potential interaction Toll-Like Receptor-4 (TLR4), immune response it might elicit. results showed had strong affinity TLR4, which could significantly stimulate CD4+ CD8+ cells secrete factors B lymphocytes immunoglobulins, so as obtain good humoral cellular immunity. Overall, protein was be stable, safe, highly antigenic, immunogenic, serve TB.

Language: Английский

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