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42. Streptococcal autolysin promotes dysfunction of swine tracheal epithelium by interacting with vimentin.

Author

Meng, Yu, Wang, Qing, Ma, Zhe, Li, Weiyi, Niu, Kai, Zhu, Ting, Lin, Huixing, Lu, Chengping, and Fan, Hongjie

Subjects
VIMENTIN, INTERMEDIATE filament proteins, MYOSIN light chain kinase, TRANSPOSONS, LUNGS, SPLIT genes, STREPTOCOCCUS suis
Abstract

Streptococcus suis serotype 2 (SS2) is a major zoonotic pathogen resulting in manifestations as pneumonia and septic shock. The upper respiratory tract is typically thought to be the main colonization and entry site of SS2 in pigs, but the mechanism through which it penetrates the respiratory barrier is still unclear. In this study, a mutant with low invasive potential to swine tracheal epithelial cells (STECs) was screened from the TnYLB-1 transposon insertion mutant library of SS2, and the interrupted gene was identified as autolysin (atl). Compared to wild-type (WT) SS2, Δatl mutant exhibited lower ability to penetrate the tracheal epithelial barrier in a mouse model. Purified Atl also enhanced SS2 translocation across STEC monolayers in Transwell inserts. Furthermore, Atl redistributed the tight junctions (TJs) in STECs through myosin light chain kinase (MLCK) signaling, which led to increased barrier permeability. Using mass spectrometry, co-immunoprecipitation (co-IP), pull-down, bacterial two-hybrid and saturation binding experiments, we showed that Atl binds directly to vimentin. CRISPR/Cas9-targeted deletion of vimentin in STECs (VIM KO STECs) abrogated the capacity of SS2 to translocate across the monolayers, SS2-induced phosphorylation of myosin II regulatory light chain (MLC) and MLCK transcription, indicating that vimentin is indispensable for MLCK activation. Consistently, vimentin null mice were protected from SS2 infection and exhibited reduced tracheal and lung injury. Thus, MLCK-mediated epithelial barrier opening caused by the Atl-vimentin interaction is found to be likely the key mechanism by which SS2 penetrates the tracheal epithelium. Author summary: Streptococcus suis serotype 2 (SS2), an emerging zoonotic agent, can breach the respiratory barrier and cause invasive disease in pigs. Here, we identified the novel role of autolysin Atl in penetration of the respiratory barrier by SS2 and its systemic dissemination and identified its binding partner, vimentin, a type III intermediate filament protein. Atl contributed to the MLCK-triggered redistribution of tight junctions to open the tracheal epithelial barrier. Knockout of vimentin abolished the ability of SS2 to penetrate the monolayer barrier and the activation of MLCK. Furthermore, vimentin null mice were protected from infection by intranasally administered SS2. This study is the first to demonstrate that the interaction between the GBS Bsp-like domain of Atl and vimentin promotes MLCK-mediated dysfunction of the epithelial barrier, which may provide theoretical information for prophylactic and/or therapeutic treatments against diseases caused by similar respiratory pathogens. [ABSTRACT FROM AUTHOR]

Published
2022
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