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Phagosomal escape and sabotage: The role of ESX-1 and PDIMs in Mycobacterium tuberculosis pathogenesis
Mohd Shariq1, Farhan Ahmed1, Onaiza Ansari2
1GITAM School of Life Sciences, Gandhi Institute of Technology and Management (GITAM) University, Hyderabad, India.
Abstract:
Mycobacterium tuberculosis (M. tb) employs diverse virulence factors to evade immune defenses and persist intracellularly. The ESAT-6 secretion system-1 (ESX-1) type VII secretion system (T7SS) releases EsxA, EspA, and EspB, inducing phagosomal rupture and cytosolic access while triggering host defenses, including galectin recruitment and stress granule formation. To counteract host responses, M. tb utilizes phthiocerol dimycocerosates (PDIMs) to inhibit autophagy and LC3-associated phagocytosis (LAP) by suppressing NADPH oxidase (NOX2) recruitment and reactive oxygen species (ROS) production. Additionally, CspA blocks LC3 lipidation, impairing LAP activation and phagosome maturation. EsxG and EsxH interfere with ESCRT-mediated phagosomal repair, further enhancing intracellular survival. Cytosolic M. tb is ubiquitinated by host E3 ligases, marking it for selective autophagy (xenophagy), yet M. tb evades degradation by manipulating autophagic flux. Simultaneously, M. tb-derived DNA activates the cyclic GMP-AMP synthase-stimulator of interferon response cGAMP interactor 1 (CGAS-STING1) axis, leading to type I interferon (IFN) signaling and inflammasome activation, which drive IL-1B and IL-18 secretion, necrosis, and pyroptosis, facilitating bacterial dissemination. Additionally, exosomes released during infection disseminate bacterial components, modulating immune responses systemically. This review uniquely integrates current findings on the coordinated actions of ESX-1 T7SS and PDIMs in mediating phagosomal rupture and immune evasion, offering a unified framework for understanding M. tb's intracellular survival strategies. By bridging lipid- and protein-mediated virulence mechanisms and their impact on host autophagy, inflammasome activation, and phagosomal repair pathways, this work provides novel insights into therapeutic targets aimed at restoring host immune function.
Insights
Mycobacterium tuberculosis uses virulence factors like ESX-1 T7SS and PDIMs to rupture phagosomes and evade immune cells. These mechanisms, along with others, help the bacteria survive and spread within the host.
Area of Science:
- Microbiology
- Immunology
- Cell Biology
Background:
- Mycobacterium tuberculosis (M. tb) employs sophisticated virulence factors to evade host immune defenses and establish intracellular infections.
- Key virulence factors include the ESAT-6 secretion system-1 (ESX-1) type VII secretion system (T7SS) and phthiocerol dimycocerosates (PDIMs).
- M. tb's intracellular survival relies on disrupting host cellular processes like phagocytosis, autophagy, and inflammasome activation.
Purpose of the Study:
- To review and integrate the coordinated roles of ESX-1 T7SS and PDIMs in M. tb's immune evasion strategies.
- To elucidate how M. tb manipulates host autophagy, phagosomal integrity, and inflammasome signaling for intracellular persistence.
- To identify potential therapeutic targets by understanding the interplay between bacterial virulence factors and host immune responses.
Main Methods:
- Literature review integrating findings on M. tb virulence factors and host immune responses.
- Analysis of protein- and lipid-mediated mechanisms of immune evasion.
- Examination of M. tb's impact on phagosomal dynamics, autophagy, and inflammasome activation pathways.
Main Results:
- ESX-1 T7SS facilitates phagosomal rupture and cytosolic access, while PDIMs inhibit autophagy and LC3-associated phagocytosis (LAP) by suppressing NADPH oxidase (NOX2) and reactive oxygen species (ROS).
- M. tb utilizes CspA to block LC3 lipidation and EsxG/EsxH to interfere with ESCRT-mediated phagosomal repair, enhancing survival.
- Bacterial DNA triggers the CGAS-STING1 pathway, activating type I interferon signaling and inflammasomes, leading to cytokine release and cell death, promoting dissemination.
Conclusions:
- The coordinated action of ESX-1 T7SS and PDIMs is crucial for M. tb's phagosomal escape and immune evasion.
- M. tb effectively manipulates host cellular pathways, including autophagy and inflammasome activation, to ensure intracellular survival and dissemination.
- Understanding these intricate virulence strategies offers novel therapeutic avenues for restoring host immunity against tuberculosis.
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