Uropathogenic Escherichia coli escapes autolysosome exocytosis by inhibiting autophagosome-lysosome fusion.

Urinary tract infections (UTIs), predominantly caused by uropathogenic Escherichia coli (UPEC), represent a massive global health burden. UPEC infects bladder epithelial cells (BECs) via fusiform vesicles and then escapes into the cytosol, either establishing biofilm-like intracellular bacterial communities (IBCs), which protect UPEC from host immune clearance, or is captured by autophagy and expelled in a transient receptor potential cation channel 3-dependent manner from lysosomes. The mechanisms enabling UPEC to evade this exocytosis defense to establish IBCs remain poorly defined. Here, we reveal that UPEC nucleoside-diphosphate kinase (NDK) reduces the lysosomal exocytosis of BECs by inhibiting host cell autophagic flux in vitro and ex vivo. Mechanistically, NDK interacts with the small GTPase Rab7, thereby impairing autophagosome-lysosome fusion. Small interfering RNA interferes with Rab7 in 5637 cells and abrogates lysosomal exocytosis for UPEC. Thus, our results reveal a critical role for NDK in inhibiting autophagic flux, thereby favoring bacterial escape from host lysosomal exocytosis in UPEC.

Importance: Zhang et al. uncover a novel immune evasion strategy employed by uropathogenic Escherichia coli (UPEC), a leading cause of urinary tract infections. By demonstrating that the bacterial nucleoside-diphosphate kinase (NDK) directly targets the host small GTPase Rab7 to block autophagosome-lysosome fusion, this study reveals how UPEC resists lysosomal exocytosis-a key host defense mechanism that normally expels intracellular pathogens. Importantly, the authors validate that Rab7 interference via small interfering RNA reduces UPEC exocytosis, confirming the mechanistic necessity of this pathway. These insights fundamentally shift the understanding of UPEC pathogenesis from passive survival to active, molecular-level manipulation of host vesicular trafficking. Moreover, by identifying NDK-Rab7 interaction as a critical checkpoint in autophagic flux, this work opens new avenues for host-directed therapies that restore lysosomal exocytosis and enhance bacterial clearance, offering a promising alternative or adjunct to traditional antibiotics that face rising resistance.