Shariq Mohd, Ahmed Farhan, Ansari Onaiza, Mursaleen Anam, Sheikh Javaid Ahmad
GITAM School of Life Sciences, Gandhi Institute of Technology and Management (GITAM) University, Hyderabad, India.
Department of Biotechnology, School of Chemical and Life Sciences, New Delhi, India.
Int Rev Immunol. 2025 Jul 18:1-27. doi: 10.1080/08830185.2025.2531828.
() 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, 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 is ubiquitinated by host E3 ligases, marking it for selective autophagy (xenophagy), yet evades degradation by manipulating autophagic flux. Simultaneously, -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 '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.
（某病原体）利用多种毒力因子来逃避免疫防御并在细胞内持续存在。ESAT-6分泌系统-1（ESX-1）VII型分泌系统（T7SS）释放EsxA、EspA和EspB，诱导吞噬体破裂并进入胞质，同时触发宿主防御，包括半乳糖凝集素募集和应激颗粒形成。为了对抗宿主反应，（该病原体）利用结核硬脂酸二霉菌酸酯（PDIMs）通过抑制NADPH氧化酶（NOX2）募集和活性氧（ROS）产生来抑制自噬和LC3相关吞噬作用（LAP）。此外，CspA阻断LC3脂化，损害LAP激活和吞噬体成熟。EsxG和EsxH干扰ESCRT介导的吞噬体修复，进一步提高细胞内存活率。胞质中的（该病原体）被宿主E3连接酶泛素化，标记其进行选择性自噬（异噬作用），然而（该病原体）通过操纵自噬通量来逃避降解。同时，（该病原体）衍生的DNA激活环鸟苷酸-腺苷酸合成酶-干扰素反应刺激因子cGAMP相互作用蛋白1（CGAS-STING1）轴，导致I型干扰素（IFN）信号传导和炎性小体激活，从而驱动IL-1B和IL-18分泌、坏死和焦亡，促进细菌传播。此外，感染期间释放的外泌体传播细菌成分，系统性地调节免疫反应。本综述独特地整合了关于ESX-1 T7SS和PDIMs在介导吞噬体破裂和免疫逃避中的协同作用的当前研究结果，为理解（该病原体）的细胞内存活策略提供了一个统一的框架。通过连接脂质和蛋白质介导的毒力机制及其对宿主自噬、炎性小体激活和吞噬体修复途径的影响，这项工作为旨在恢复宿主免疫功能的治疗靶点提供了新的见解。
