Deciphering tuberculosis: lysosome-centric insights into pathogenesis and therapies

Abstract

Tuberculosis is a widely spread disease caused by Mycobacterium tuberculosis (Mtb). The pathogenicity of the pathogen is closely associated with the immune defense mechanisms of the host cells. As key cellular degradation and metabolic centers, lysosomes critically regulate tuberculosis infection. When Mtb invades the host, it is taken up by macrophages and enters phagosomes. Subsequently, the phagosomes fuse with lysosomes and form phagolysosomes, which eliminate the pathogenic bacteria through the acidic environment and hydrolytic enzymes within lysosomes. However, Mtb can interfere with the normal functions of lysosomes through various strategies. It can secrete specific factors (such as ESAT-6, ppk-1, and AcpM) to inhibit the acidification of lysosomes, enzyme activity, and the fusion of phagosomes and lysosomes, thereby enabling Mtb proliferation within host cells. An in-depth exploration of the mechanism of the interaction between Mtb and lysosomes will both uncover bacterial immune evasion strategies and identify novel anti-tuberculosis therapeutic targets.

Keywords: Mycobacterium tuberculosis (Mtb); interaction; lysosomes; mechanism; treatment.

Figure 1

Mtb-induced lysosomal modulation and drug interventions following host invasion. This schematic delineates the autophagic and phagocytic pathways activated during Mtb infection: 1. Pathogen-Driven immune evasion: Mtb virulence factors, such as 1-TbAb, inhibit autophagosome maturation; 2. Therapeutic interventions: ① lysosomal potentiators like curcumin through upregulating lysosomal biogenesis; ② autophagy enhancers like Ison@Man-Se NPs through enhancing autophagosome–lysosome fusion.

Figure 2

(a) Membrane damage resolution. Mtb disrupts lysosomal integrity via ESX-1 secretion system. Host cells counteract this by mobilizing two repair pathways: 1. ESCRT machinery (ALIX/CHMP4): Mediates membrane scission and vesicle shedding to restore lysosomal continuity. 2. Galectin-3 (Gal3)–ubiquitin axis: Recognizes exposed glycans on damaged membranes, recruiting TRIM16 ubiquitin ligase to tag compromised lysosomes for selective autophagy (lysophagy). These coordinated responses inhibit Mtb proliferation by maintaining lysosomal bactericidal capacity. (b) Metabolic reprogramming in GBA1 deficiency. Loss of GBA1 elevates glucosylsphingosine (GlcSph) levels in lysosomes, which paradoxically 1. Enhances hydrolase activity: GlcSph stabilizes lysosomal enzymes (e.g., cathepsins), boosting proteolytic degradation of Mtb. 2. Disrupts lipid hijacking: Counters Mtb’s strategy to exploit MMGT1-GPR156 lipid droplet axis for survival.

Figure 3

Mtb-induced lysosomal damage and autophagic defense. (Mtb) disrupts lysosomal integrity to evade immune clearance. In response, host cells deploy a coordinated defense: 1. Damage sensing: Galectins (Gal3/8/9) detect lysosomal membrane damage and initiate repair. 2. Autophagy activation: The NUFIP2/G3BP1-Ragulator-RagA/B complex suppresses mTOR, enabling ULK1-mediated autophagosome formation, while AMPK amplifies this signal via energy stress sensing. 3. Lysosomal regeneration: Nuclear translocation of TFEB drives lysosomal biogenesis to replenish functional lysosomes. 4. Quality control: Irreparable lysosomes undergo TRIM-mediated ubiquitination for selective lysophagic degradation. 5. Pathogen clearance: Autophagosomes fuse with intact lysosomes, enabling enzymatic degradation of intracellular Mtb. This integrated response highlights the synergy between lysosomal repair and autophagy in combating TB infection.