Disassembly of the apical junctional complex during the transmigration of Leptospira interrogans across polarized renal proximal tubule epithelial cells

Bacterial pathogens have evolved multiple strategies to disassemble epithelial cell apical junctional complexes (AJCs) and infect epithelial cells. Leptospirosis is a widespread zoonotic infection, mainly caused by Leptospira interrogans, and its dissemination across host cell barriers is essential for its pathogenesis. However, the mechanism of bacterial dissemination across epithelial cell barriers remains poorly characterised. In this study, we analysed the interaction of L. interrogans with renal proximal tubule epithelial cells (RPTECs) and found that at 24 hr post‐infection, L. interrogans remain in close contact with the plasma membrane of the RPTEC by extracellularly adhering or crawling. Leptospira interrogans cleaved E‐cadherin and induced its endocytosis with release of the soluble N‐terminal fragment into the extracellular medium. Concomitantly, a gradual decrease in transepithelial electrical resistance (TEER), mislocalisation of AJC proteins (occludin, claudin‐10, ZO‐1, and cingulin) and cytoskeletal rearrangement were observed. Inhibition of clathrin‐mediated E‐cadherin endocytosis prevented the decrease in TEER. We showed that disassembly of AJCs in epithelial cells and transmigration of bacteria through the paracellular route are important for the dissemination of L. interrogans in the host. The apical junctional complex (AJC) is composed of two types of intercellular junctions (adherens and tight junctions), which are linked to the actin cytoskeleton to create an adhesive network important for the epithelial cell barrier. Leptospira interrogans, a widespread zoonotic pathogen, induces E‐;cadherin cleavage, endocytosis, cytoskeletal rearrangement, and mislocalization of tight junction proteins, resulting in AJC disassembly. L. interrogans attaches to cell junctions and transmigrates through the epithelial monolayer via the paracellular route.