Remote Host Manipulation by Pathogenic Bacterial Extracellular Vesicles

Bacterial extracellular vesicles (BEVs) are known to enhance infection susceptibility in vivo, yet the mechanistic basis for this remote preconditioning of host cells is unknown. Here, we discover an evolutionarily conserved, lipid-driven physical mechanism by which pathogenic bacterial EVs systemically arrest phagosome maturation in bystander host cells. Using live-cell fluorescence lifetime imaging, in vitro reconstitution and micromanipulation we show that EVs from diverse pathogens - Mycobacterium tuberculosis, Klebsiella pneumoniae, and Staphylococcus aureus - fuse with host plasma, phagosomal, and lysosomal membranes. This fusion increases membrane tension and perturbs early phagosomal maturation. Transcriptomic profiling confirms a broad downregulation of phagosome maturation genes while upregulation of lysosomal stress responsive genes. Crucially, in vitro reconstitution shows that EVs, and their purified lipids alone, are sufficient to induce phase separation and increase membrane tension, directly inhibiting phago-lysosomal fusion. Our findings establish a paradigm in which pathogens exploit EVs not merely as delivery vehicles, but as tools to remotely rewire host cell membrane mechanics to hijack phagosome maturation and host defense - a strategy that moves beyond canonical effector-based models of pathogenesis.