fig2
Figure 2. Key mechanisms by which Mtb EVs and HC EVs synergistically mediate Mtb immune evasion, metabolic reprogramming, and pathogen dissemination. Mtb EVs deliver immunomodulatory molecules such as lipoproteins (LprG, LpqH) and LAM to macrophages and T cells, impairing antigen presentation by suppressing MHC-II expression via the TLR2/MYD88/CIITA axis, inhibiting TCR signaling, and inducing T-cell anergy and apoptosis. Meanwhile, Mtb reprograms HC EVs, particularly exosomes, to carry altered profiles of miRNAs (e.g., miR-146a-5p, miR-18a, miR-766-3p) and bacterial proteins (e.g., Rv1818c). These EVs suppress host inflammatory responses, inhibit macrophage autophagy and apoptosis, downregulate the iron-restriction protein NRAMP1 in lung epithelial cells, and induce M2 macrophage polarization, thereby creating an intracellular environment favorable for Mtb survival. Under conditions of iron limitation or antibiotic stress, Mtb releases Mtb EVs enriched in mycobactin and protective lipids, which enhance iron acquisition and form a physical barrier against antibiotics. Collectively, these EVs-mediated processes exacerbate pulmonary inflammation, facilitate systemic bacterial dissemination, and contribute to the establishment of persistent and drug-resistant TB infections. Mtb: Mycobacterium tuberculosis; EVs: extracellular vesicles; Mtb EVs: Mycobacterium tuberculosis-derived extracellular vesicles; HC EVs: host cell-derived extracellular vesicles; TB: tuberculosis; LprG: lipoarabinomannan carrier protein LprG; LpqH: 19-kDa lipoprotein LpqH; LAM: lipoarabinomannan; MHC-II: major histocompatibility complex class II; TLR2: Toll-like receptor 2; MyD88: myeloid differentiation primary response protein 88; CIITA: class II transactivator; TCR: T-cell receptor; miR: microRNA; NF-κB: nuclear factor kappa B; NRAMP1: natural resistance-associated macrophage protein 1; M2: alternatively activated macrophage phenotype; ATM: ataxia-telangiectasia mutated; AMPK: AMP-activated protein kinase; Mcl-1: myeloid cell leukemia 1; IRAK1: interleukin-1 receptor-associated kinase 1; TRAF6: tumor necrosis factor receptor-associated factor 6; GRAIL: gene related to anergy in lymphocytes.
