Work

Distinct strategies of epithelial cell barrier disruption by Leptospira interrogans isolated from human patients in Okinawa, Japan

Year: 2025

Type: article

Abstract: BACKGROUND: Leptospirosis is a bacterial infection common in tropical and subtropical regions, which causes feverish conditions. Although approximately half of human leptospirosis cases in Japan are reported in Okinawa, a subtropical area, the pathogenic mechanisms of clinical isolates from this region remain unknown. This study aimed to identify the infection mechanisms of L. interrogans isolates from Okinawa (Oki-strains) in human renal proximal tubule epithelial cells (RPTECs). METHODOLOGY/PRINCIPAL FINDINGS: The transepithelial electrical resistance (TEER) measurements of 11 Oki-strains in infected renal proximal tubule epithelial cells (RPTECs) showed that all strains caused a decrease in TEER by 48 hours post-infection. Imaging analysis of RPTECs infected with two selected strains (Oki53 and Oki65) revealed that both strains induced the displacement of adherens junction (AJ) proteins E-cadherin, α-catenin, afadin, and nectin-2 and cytoskeletal F-actin disorganization. However, western blotting analysis revealed that AJ protein levels were not reduced, except for afadin-an important protein for linking F-actin to AJs. Chemical inhibition revealed that the proteosome inhibitors MG132 and bortezomib and pan-caspase inhibitor Z-VAD-FMK prevented the Oki53-induced TEER decrease, AJ protein mislocalization, afadin degradation, and F-actin disorganization. However, in Oki65-infected RPTECs, the inhibitors partially prevented these effects. Thus, the AJ-F-actin link and epithelial barrier were fully preserved in Oki53-infected RPTECs pretreated with these inhibitors at 24 h post-infection (~TEER 130% of initial TEER), whereas in Oki65-infected cells, the AJ-F-actin link was maintained only partially (~TEER 70%). CONCLUSIONS/SIGNIFICANCE: Our findings suggest that the maintenance of epithelial barrier integrity requires both the afadin-F-actin and α-catenin-F-actin links, and that Oki53 and Oki65 employ distinct strategies to disrupt the AJ-F-actin link and, thus, the epithelial barrier.

Source: PLoS neglected tropical diseases

DOI: 10.1371/journal.pntd.0013693

Authors: Tetsuya Kakita, Claudia Toma, Isabel Sebastián, Hunter Barbee, Tetsu Yamashiro

Institutions: University of the Ryukyus, Okinawa Prefectural Institute of Health and Environment

Language: English

Topic: Leptospirosis research and findings

Subfield: Parasitology

Field: Immunology and Microbiology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $2,670