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Review
. 2025 Jul 18:1-27.
doi: 10.1080/08830185.2025.2531828. Online ahead of print.

Phagosomal escape and sabotage: The role of ESX-1 and PDIMs in Mycobacterium tuberculosis pathogenesis

Mohd Shariq  1 , Farhan Ahmed  1 , Onaiza Ansari  2 , Anam Mursaleen  2 , Javaid Ahmad Sheikh  2
Affiliations
Review

Phagosomal escape and sabotage: The role of ESX-1 and PDIMs in Mycobacterium tuberculosis pathogenesis

Mohd Shariq et al. Int Rev Immunol. .

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.

Keywords: Autophagy; ESX-1; EsxA; PDIM; cytosol access; inflammasome; lysosome.

Plain language summary

M. tb, the causative agent of TB, is a highly infectious pathogen that has evolved complex mechanisms to evade the immune system and survive inside human cells. This review focuses on two key virulence factors of M. tb: the ESX-1 T7SS and phthiocerol PDIMs. These factors work together to damage the phagosomal membrane inside immune cells, allowing the bacteria to escape into the cytosol and avoid destruction. ESX-1 secretes proteins such as EsxA, which disrupts the phagosomal membrane, while PDIMs help M. tb evade immune recognition and suppress autophagy, a process by which cells degrade harmful pathogens. The review highlights how phagosomal damage triggers immune responses, including inflammasome activation and cytokine production (IL-1B and IL-18), which can paradoxically aid bacterial persistence. Host cells attempt to repair this damage using the ESCRT system, but M. tb counteracts this by interfering with membrane repair mechanisms. Furthermore, the review discusses how M. tb manipulates selective autophagy to evade clearance. Instead of being degraded, the bacteria hijack cellular pathways to block autophagosome maturation and lysosomal fusion. Additionally, PDIMs suppress host immune signaling, allowing M. tb to establish a niche for long-term survival. Understanding these mechanisms provides insights into new therapeutic strategies aimed at enhancing the host’s ability to fight TB. Approaches such as boosting immune responses, targeting bacterial evasion strategies, and developing novel treatments are critical for controlling TB infections. HIGHLIGHTSM. tb employs the ESX-1 T7SS and PDIMs to collaboratively induce phagosomal rupture and facilitate cytosolic access.M. tb exploits distinct mechanisms to regulate autophagy and evade immune responses.Phagosome damage activates cytoplasmic PRRs, inducing IL-1B and IL-18 production.Host cells employ stress granules, ESCRT complexes and GBPs to repair M. tb-induced phagosome damage.M. tb virulence factors EsxG and EsxH interfere with ESCRT-mediated membrane repair.Selective autophagy, including LAP and xenophagy, targets M. tb for lysosomal degradation.

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